Cambridge Stem Cell Institute Brochure 2012 by University of Cambridge

2012

Contents The Institute ……………………………………………2 2012 Annual Report …………….………………....4

Research Groups Roger Barker Parkinson’s and Huntingdon’s disease……….6 Kevin Chalut The Physical Biology of Pluripotency and Differentiation..…………………………………….……7 Robin Franklin Adult Neural Stem Cells and CNS Regeneration…………………………………...……....8 Michaela Frye Epithelial Stem Cell Homeostasis and Cancer……………………………………………………….9 Bertie Gottgens Transcriptional Regulation of Normal and Leukaemic Blood Stem Cells ……………….….10 Tony Green Haematopoiesis………………………………….…...11 Brian Hendrich Transcriptional Control of Stem Cell Fate………………………………..…...12 Brian Huntly Leukaemia Stem Cell Biology …………...….…13 Kim Jensen Epithelial Development, Maintenance and Regeneration……………………….………………….14 Thora Karadottir Neurotransmitter Signalling to CNS Progenitor Cells……………………………...……….15 Mark Kotter Neural stem cells, Cellular Reprogramming and Regenerative Medicine……….…….………16

Message from the Director Stem cells are remarkable cells that build, maintain and repair our bodies. In the laboratory they can be manipulated to reveal the mechanisms of human development and disease. Stem cells also hold the potential to be used in regenerative medicine and cell therapy to treat devastating conditions ranging from blindness, to multiple sclerosis, Parkinson’s disease and diabetes. The challenge in stem cell research is to elucidate the complex control processes that govern how stem cells function in order to take full command of their extraordinary capacities and harness them for medical benefit. Recognising

Rick Livesey Human stem cell models of neurological disease….…..17 Jennifer Nichols Embryonic Pluripotency…………………………………………….18 Katrin Ottersbach The Developmental Origins of Blood Stem Cells……….19 Roger Pedersen Mechanics of Mesoderm Differentiation in Mammalian Pluripotent Stem Cells…………………………………….………..20 Stefano Pluchino Central Nervous System Repair….……………………………..21 Emma Rawlins Stem Cell Fate in the Mammalian Lung …………………….22 Jose Silva Biology of Induced Pluripotency …………………….………...23 Ben Simons Tracing stem cell fate in development, maintenance, and disease ………………………………...……………………………24 Austin Smith Stem Cell Potency………………………..……..…………...……….25 Azim Surani Specification and programming of the germline for totipotency and development.………………………………....26 Ludovic Vallier Mechanisms Controlling Differentiation of Pluripotent Stem Cells into Definitive Endoderm………………………...27

Alan Warren Stem cell subversion and bone marrow failure syndromes……………………………………………………...…..29 Fiona Watt Epidermal Stem Cell Biology…...…………………………..30 Anton Wutz Epigenetic Regulation and Cell Identity Control......31

The Institute Facilities Advanced Vector Design & Recombineering………..32 Bioinformatics…………………………………………….……….33 Flow Cytometry…………………………………………………...34 Histology……………………………………………………………...35 Imaging………………………………………………………………..36 Next Generation Sequencing Libraries …………………37 Tissue Culture……………………………………………………...38 Other Resources…………………………………………………..39 Affiliate Members………………………………………………..40 Associate Members……………………………………………..41 Committees ………….…………………………………………..42 Funding ……………………...………………………...…………..43 Highlights of 2012.……………………………………………….44 2012 SCI Symposium…………………………………………...46 Conferences, Events and Seminars………………..…….48 PhD Programme in Stem Cell Biology & Medicine………………………………………...…………………..50 2012 Publications ………………………………………………..52

Juan-Jose Ventura Bronchioalveolar cellular and molecular hierarchy in homeostasis and disease ………...……………………….……..28

the excellence of the Cambridge stem cell community, in 2012 the Wellcome Trust (WT) and the Medical Research Council (MRC) partnered with the University to create the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute. “The Stem Cell Institute will play a vital part in accelerating our understanding of health and disease and in the development of new treatments, and will cement the UK’s position as a world leader in stem cell research.” Sir Mark Walport, Director of the Wellcome Trust I am immensely proud to be the first Director of the Cambridge Stem Cell Institute and am delighted to present here our inaugural public report. Austin Smith

The Institute Stem cell science is providing a stream of new knowledge about how our bodies are made and maintained. This research brings the promise that better understanding of stem cells will lead to future medical applications. Treatments may come through several routes:

Research Themes Pluripotency Pluripotent stem cells can be derived from early embryos, produced by epigenetic conversion of germ cells, or created by transcription factor mediated reprogramming of somatic cells. Our fundamental investigations are directed at the molecular foundations of pluripotency, mechanisms of lineage-specific differentiation and comparitive analyses between rodent and human.

 Human stem cells grown in

the laboratory can be used to produce experimental models of diseased tissues and to test therapeutic drugs.

 Some diseases, including

forms of cancer, involve abnormal behaviour of stem cells. As we learn how to control stem cells it may become possible to correct these faults.

 Stem cells could be used to

renew damaged tissues and replace missing cells in certain disorders.

 Learning how to prevent a

Theme Leader: Principal Investigators: Affiliate Investigators: Associate Investigators:

Haematopoiesis Haematopoiesis represents the best studied adult mammalian stem cell system and provides paradigms for the mechanisms whereby normal stem cells are subverted to form malignancies. The goal of this theme is to delineate the molecular and cellular mechanisms regulating normal and malignant haematopoiesis. A particular focus is our use of complimentary approaches in human and murine systems.

decline in numbers and activity of stem cells may help to maintain health during ageing.

Cambridge University has invested in recruiting high quality investigators in mammalian stem cell research at both senior and junior levels. There are now 25 mainstream stem cell laboratories comprising some 300 group memberes including postdoctoral researchers and PhD students. Leading research scientists, technology specialists and doctors work side by side to create a world-leading centre of excellence in stem cell biology and medicine. The Institute also provides high level training for young researchers from around the world and collaborates with bioindustry.

Surani Hendrich, Nichols, Silva, Smith, Vallier, Wutz, Chalut Martinez-Arias Bertone, Bradley, Hemberger, Liu, Reik, Rugg-Gunn, Skarnes

Theme Leader: Principal Investigators: Affiliate Investigators:

Green Gottgens, Huntly, Ottersbach, Warren Ghevaert

Neural Concepts regarding cell replacement and regeneration in the adult mammalian central nervous system (CNS) have undergone a radical shift in recent years. This is due in part to the discoveries of continuous neurogenic activity in distinct anatomical regions and of a robust propensity for replacement of oligodendrocytes that myelinate CNS axons. Nevertheless, the loss of neurons remains a major clinical challenge prompting a renewed effort in translational science aimed at prevention as well as replacement. Neuronal loss can occur as a result of (i) inherent defects, (ii) inflammation and (iii) loss of trophic support provided by myelinating cells. In this theme we bring stem cell biology to bear all three causes in an integrated programme of basic and translational research. Theme Leader: Principal Investigators: Affiliate Investigators: Associate Investigators:

Franklin Barker, Karadottir, Kotter, Livesey, Pluchino Ferguson-Smith, Martin Jones, Stingl, Winton 2

Epithelial Tissues Epithellia are the tissues that line body cavities and surfaces and are separated from the adjacent connective tissue by a basement membrane. The mediate diverse functions, including secretion, absorption, transcellular transport and protection from environmental assaults. Epithelial function is perturbed in a large number of conditions, such as psoriasis, emphysema and certain types of blindness. It is estimated that epithelial cancers account for 90% of human tumours. Theme Leader: Principal Investigators: Affiliate Investigators: Associate Investigators:

Frye Jensen, Rawlins, Simons, Ventura Philpott, Watson Jones, Stingl, Winton

Cardiovascular Stem cell research has great potential for improving understanding and treatment of cardiovascular disease. Cellbased therapies are currently limited by lack of knowledge about human stem cell differentiation and about the extent and kinetics of integration and survival of transplanted tissues. However, the progeny obtained by in vitro differentiation of pluripotent stem cells can provide unprecedented cellular systems for understanding fundamental cardiovascular disease mechanisms, for drug discovery and testing. The developing programme will explore the interface between stem cells and cardiovascular medicine with a focus on iPS cells as human cardiovascular disease models and the prospects for early mesodermal progenitors in regenerative approaches. Theme Leader: Affiliate Investigators:

Pedersen. Sinha

Institute Mission To explore and define the properties of stem cells in order to establish their true medical potential. Our overall aims are:

 To make fundamental discoveries that provide new insights into stem cell function and potency;

 To understand the role of stem and progenitor cells in disease and thereby to improve diagnosis and treatment

 To harness the capacity of endogenous stem and progenitor cells for repair and regeneration;

 To exploit stem cells as tools for studying the molecular

pathogenesis of human diseases and discovery of therapeutic agents;

 To nurture future generations of stem cell scientists and clinical investigators in an intellectually invigorating mix of basic and translational research.

The Centre for Stem Cell Research (CSCR) and the Laboratory for Regenerative Medicine (LRM) presently constitute twin bases for stem cell research in the School of Biological Sciences and the School of Clinical Medicine respectively. Stem cell groups are also housed in the Cambridge Institute for Medical Research (CIMR), Gurdon Institute, Centre for Brain Repair (CBR) and other Departments. This distribution reflects the intellectual diversity of the Cambridge stem cell community and the breadth of institutional support. The coalescence of basic stem cell research and translational medicine is key to development of clinical applications and therefore the University has invested in the establishment of the Stem Cell Institute. The following facilities support the research:

 Advanced Vector Design and       

Recombineering Bioinformatics Flow Cytometry Histology Imaging Next Generation Sequencing Libraries Tissue Culture Cambridge Biomedical Research Centre (BRC) hIPSCs Core Facility

2012 Annual Report This has been a significant year for the stem cell community in Cambridge. The Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute (SCI) was officially established on 1 July 2012, succeeding the former Wellcome Trust Centre for Stem Cell Biology and the MRC Centre for Regenerative Medicine. SCI draws together 25 stem cell research groups within the University into a coherent administrative and scientific organisation. These groups are currently spread across 7 different sites in Cambridge. Therefore a second very welcome development in the past 12 months has been the decision by the University to construct a new research building at the Cambridge Biomedical Research Campus to house the SCI laboratories. The new building will have the key advantage of proximity to clinical researchers and facilities. During the calendar year SCI groups published 168 papers in journals including Nature, Science, Cell, Nature Cell Biology, Cell Stem Cell, PNAS, EMBO Journal, Blood, Genes & Development, Development, J. Exp Med and Science Translational Medicine. A quarter of these papers are collaborations between two or more SCI groups and 34 include clinicians as authors. Among the most important achievements are:

 Demonstration of a functional link between two co-developing systems, the haematopoietic system and the sympathetic nervous system, and discovery that catecholamines regulate the production of the first haematopoietic stem cells.  Fitch SR, Kimber G, Wilson NK, Parker A, Mirshekar-Syahkal B, Göttgens B, Medvinsky A, Dzierzak E, Ottersbach K. (2012) Signaling from the sympathetic nervous system regulates hematopoietic stem cell emergence during embryogenesis. Cell Stem Cell 11:554-566 Collaboration between two SCI PIs, Katrin Ottersbach and Bertie Göttgens, and a PI from the Edinburgh MRC Centre (Alexander Medvinsky).

 Human cerebral cortex differentiation from pluripotent stem cells and application to model early Alzheimer's disease in Down syndrome.  Shi Y, Kirwan P, Smith J, Maclean G, Orkin SH, Livesey FJ (2012) A human stem cell model of early Alzheimer's disease pathology in down syndrome. Science Translational Medicine 4:124ra29  Shi Y, Kirwan P, Smith J, Robinson HP, Livesey FJ (2012) Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nature Neuroscience 15:477–486.

 Nuclear receptor Esrrb identified and validated as a central component of the pluripotency network, accounting for the self-renewal effect of glycogen synthase kinase-3 inhibition  Martello, G., Sugimoto, T., Diamanti, E., Joshi, A., Hannah, R., Ohtsuka, S., Göttgens, B., Niwa, H, Smith A (2012). Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal. Cell Stem Cell 11, 491-504. Collaboration between two SCI PIs, Bertie Gottgens and Austin Smith, with key support from core bioinformaticians to generate a reference compendium of mouse embryonic stem cell ChIP-seq data.

 Molecular control of transcriptional heterogeneity in stem cells through modulatory action of a “repressor”



 Reynolds N, Latos P, Hynes-Allen A, Loos R, Leaford D, O'Shaughnessy A, Mosaku O, Signolet J, Brennecke P, Kalkan T, Costello I, Humphreys P, Mansfield W, Nakagawa K, Strouboulis J, Behrens A, Bertone P, Hendrich B (2012). NuRD Suppresses Pluripotency Gene Expression to Promote Transcriptional Heterogeneity and Lineage Commitment. Cell Stem Cell 10: 583–594. Collaboration between SCI PI, Brian Hendrich, and Associate PI, Paul Bertone (EBI). Unique genome scale molecular features of naïve pluripotent stem cells  Marks H, Kalkan T, Menafra R, Denissov S, Jones K, Hofemeister H, Nichols J, Kranz A, Francis Stewart A, Smith A*, Stunnenberg HG (2102) The transcriptional and epigenomic foundations of ground state pluripotency. Cell 149: 590-604 *Co-corresponding author A novel human lung stem cell population  Oeztuerk-Winder F, Guinot A, Ochalek A, Ventura J-J (2012) Regulation of Human Lung Alveolar multipotent cells by a novel p38a MAPK/miR-17-92 axis. EMBO Journal 31:3431-41 4

 Link between an epigenetic mark and cell fate restriction during somatic cell differentiation that maintains cell identity and antagonises reprogramming a pluripotent stem cell state.  Radzisheuskaya A, Pasque V, Gillich A, Halley-Stott RP, Panamarova M, Zernicka-Goetz M, Surani MA, Silva JCR (2012) Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency. Journal of Cell Science 125: 6094-104. Collaboration between two SCI PIs, Jose Silva and Azim Surani. Selected by the Journal as paper of the year.

 Resolution of proliferative stem cell hierarchy in interfollicular epidermis and its dysregulation in the progression from papilloma to squamous cell carcinoma.  Mascre G, Dekoninck S, Drogat B, Youssef KK, Brohee S, Sotiropoulou PA, Simons BD, and Blanpain C (2012) Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489, 257-62  Driessens G, Beck B, Caauwe A, Simons BD, and Blanpain C (2012) Defining the mode of tumour growth by clonal analysis. Nature 488, 527-30 Collaboration between theoretical group of SCI PI Benjamin Simons and the experimental group of Cedric Blanpain (IRIBHM, Brussels), a member of the SCI ISAB.

 Mutated form of the USB1 protein causative for poikiloderma with neutropenia (an inherited leukaemia predisposition disorder affecting the haematopoietic stem cell compartment) disrupts the biogenesis and 3’ end processing of spliceosomal U6 small nuclear RNA.  Hilcenko C, Simpson PJ, Finch AJ, Bowler FR, Churcher MJ, Jin L, Packman LC, Shlien A, Campbell P, Kirwan M, Dokal I, Warren AJ (2013) Aberrant 3’ oligoadenylation of spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia. Blood. 121:1028-1038. Epub Nov 2012

 Remyelination in the aging mammalian central nervous system by endogenous progenitors, setting the stage for development of phase 1 clinical trial for multiple sclerosis  Ruckh JM, Zhao JW, Shadrach JL, van Wijngaarden P, Rao TN, Wagers AJ, Franklin RJ (2012) Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10:96-103 Selected for Best of Cell Stem Cell Collection 2012 In 2012, SCI had active research grants to a value of £12,932,422.76. During the year 17 new grants were awarded to SCI investigators. Of particular note, Benjamin Simons was awarded a Wellcome Trust Senior Investigator Award to start in 2013, Brian Hendrich renewed his Wellcome Trust Senior Research Fellowship and Michaela Frye has been awarded a CRUK Senior Fellowship to start in 2013. In response to our call for junior group leaders, Dr Bon-Kyoung Koo has been recruited from Hans Clevers’ laboratory in Utrecht where among other achievements he identified a new regulatory component of the Wnt pathway in intestinal stem cells (Koo BK et al. Tumour suppressor RNF43 is a stem cell E3 ligase that induces endocytosis of Wnt receptors. Nature 2012 488:665-9). Dr Koo will develop a molecular genetics programme centred on signalling in intestinal stem cells. He will move to Cambridge in April 2013. In addition, as part of our strategy for developing a programme in the physical biology of stem cells, Kevin Chalut, a Royal Society research fellow in the Department of Physics, has joined SCI and will relocate half of his laboratory. Dr Chalut is interested in the role of biomechanics in pluripotent stem cells (Chalut, K., Höpfler, M., Lautenschläger, F., Martinez-Arias, A., and Guck, J. (2012) Chromatin decondensation and nuclear softening accompany Nanog downregulation in embryonic stem cells. Biophysical Journal 103: 2060-2070.) The second Cambridge Stem Cell Institute International Symposium on the theme of “Cancer Stem Cells” was organised by Michaela Frye and Juan Ventura. The meeting was over-subscribed and very well received by those who did attend. The third Symposium on 9/10 July 2013 will be on “Physical Biology of Stem Cells” is being organised by Ben Simons, Alfonso Martinez-Arias and Austin Smith. The Cambridge Stem Cell Club resumed in 2012 providing a valuable networking forum. Meetings have been well attended with talks from a mixture of SCI Group Leaders and post-docs. As part of the Institute’s public engagement programme a set of activities were organised by PhD students for the Cambridge science festival and were well-received. Finally, a rebranded Stem Cell Institute WEB site (www.stemcells.cam.ac.uk) has been created. The site provides resources for both academic and lay audiences and also includes an intranet providing details on core facilities and facilitating exchange of resources between SCI research groups.

Parkinson’s and Huntingdon’s disease Our main interests are in the common, chronic neurodegenerative disorders of the nervous system in particular Parkinson's disease (PD) and Huntington's disease (HD).

Roger Barker Roger A. Barker is the Professor of Clinical Neuroscience and Honorary Consultant in Neurology at the University of Cambridge and at Addenbrooke's Hospital. He trained at Oxford and London and has been in his current position for over ten years having completed an MRC Clinician Scientist Fellowship just prior to this. He combines basic research looking at novel therapies to treat chronic neurodegenerative disorders of the brains with clinically based work on better defining them. He is the coordinator of the FP7 TRANSEURO project looking at fetal cell grafting in patients with early Parkinson's Disease.

Funding CHDI Foundation FP7-EU Parkinson's UK NIHR Evelyn Trust Butterfield Trust Cure-PD MRC

Group Members

We are interested in better understanding how these diseases develop and then how they change over time with the idea of better classifying patients into different subtypes of disease. These subtypes can then be used to test new therapies as some types of these diseases may be better suited for one type of experimental whilst others may not- e.g. dopamine cell therapies from stem cells may be better suited to younger PD patients. These new therapies involve not only cell based treatments as well as other novel approaches that try to stop or modify at the disease process itself. This we are now trying to "model in the dish" using the cells of patients which we collect from the skin and then turn into nerve cells in the lab with the hope that this will recapitulate the disease process that is ongoing in their brains.

New born nerve cells in the mouse Dr Claire Clelland

Key Publications Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA*, Gage FH*, Bussey TJ (2009). A functional role for adult hippocampal neurogenesis in spatial patter separation. Science 325;210-213. [*joint senior authors]. PMID: 19590004 Kuan W-L, Poole E, Fletcher M, Karniely S, Tyers P, Wills M, Barker RA*, Sinclair JH* (2011) A novel neuroprotective therapy for Parkinson’s disease using a viral non-coding RNA that protects mitochondrial Complex I activity. J Exp Med. 2011; 209: 1-10. (*equal last author).PMID:22184634 Williams-Gray CH, Evans JR, Goris A, Foltynie T, Ban M, Robbins TW, Brayne C, Kolachana BS, Weinberger DR, Sawcer SJ, Barker RA. The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort. Brain. 2009;132:2958-69. PMID: 19812213

Wei-Li Kuan Alexandra Fragniere Romina Vuono Fahad Ali Jing wei Zhao Simon Stott Janelle Ouellet-Drouin Alpar Lazar Francesca Panin Cristina Nombera Lucy Collins Sarah Mason Pam Tyers Xiaoling He Anna Gerritz Danielle Daft Natalie V. Guzman Su Metcalfe Gemma Cummins Stevan Wing Sarah Moore

The Physical Biology of Pluripotency and Differentiation The transformation of a stem cell system into mature tissue cells consists of a progression of highly regulated steps. Despite its importance both for bringing comprehension to the formation of the embryo and also for regenerative medicine purposes, the ways in which the process of differentiation are regulated – which have been primarily studied from a biochemical perspective – are not fully understood. We are particularly focused on illuminating differentiation and embryonic development by utilising optical, quantitative microscopy, and microfluidic techniques to probe biophysical aspects. These aspects include system level changes such as cell and nuclear mechanics, subcellular structure, and dynamic processes such as remodeling within cell nuclei. Using this foundation, we have observed broad biophysical changes in embryonic stem cells as they go through the process of differentiation; these changes include a modulation of nuclear substructure and mechanics, among others. Using the biotechnology we develop, we are investigating the meaning of these changes, both in stem cell cultures and in the embryo, and their universality in other developmental niches.

Kevin Chalut Kevin Chalut is a biophysicist with a PhD in Physics from Duke University, and is currently a Royal Society University Research Fellow (since 2011). His post-graduate background is in biotechnology and imaging, particularly with application to cancer detection and stem cell characterisation. He is currently a group leader both at the Cavendish Laboratory and the Wellcome Trust/Medical Research Council Stem Cell Institute. His work focuses on developing novel biotechnology to investigate physical states of cells such as mechanics and subcellular structure; in the last years he has focused almost exclusively on the biophysics of embryos and embryonic stem cells. The ultimate goal of his laboratory is to discover the physical mechanisms, and the importance of those mechanisms, to pluripotency, differentiation and reprogramming. Funding Wellcome Trust Royal Society

Key Publications Chalut, K., Höpfler, M., Lautenschläger, F., Martinez-Arias, A., and Guck, J. Chromatin decondensation and nuclear softening accompany Nanog downregulation in embryonic stem cells. Biophysical Journal, 2012, 103, 2060-2070. PMID: 23200040 Ekpenyong, A., Man, S., Achouri, S., Bryant, C., Guck, J., and Chalut, K. Bacterial infection of macrophages induces decrease in refractive index. Journal of Biophotonics, 2012, DOI: 10.1002/jbio.201200113. PMID:22887897 Ekpenyong, A., Whyte, G., Chalut, K., Pagliara, S., Lautenschläger, F., Fiddler, C., Paschke, S., Keyser, U., Beil, M., Chilvers, E., and Guck, J. Viscoelastic properties of differentiating cells are fate- and functiondependent. PLoS One, 2012, 7(9), e45237. PMID:23028868

Group Members Cynthia Fisher George Wylde Sarra Achouri Andrew Hodgson Chris Revell

Adult Neural Stem Cells and Central Nervous System Regeneration The Franklin lab studies the mechanisms of Central Nervous System (CNS) regeneration with a particular focus on remyelination, a regenerative process mediated by adult stem/precursor cell called OPCs, in which new myelin sheaths are restored to demyelinated axons.

Robin Franklin Robin Franklin is Professor of Neuroscience and Director of the Neural Stem Cell Programme the SCI. He obtained his undergraduate degrees in Physiology and Veterinary Medicine and his PhD in Neuroscience. He has worked predominantly on the biology of myelin repair (remyelination) and investigating strategies by which this important regenerative process may be enhanced therapeutically. His lab has focused on the possibility of enhancing remyelination through stimulating endogenous population of adult stem cells. He is at the forefront of studying the cellular and molecular mechanisms of remyelination and describing the mechanisms by which adult stem cells are recruited to areas of demyelination and the extrinsic and intrinsic factors that regulate their differentiation into remyelinating oligodendrocytes. He is currently Director of the UK MS Society Cambridge Centre for Myelin Repair, a consortium of Cambridge-based scientists and clinicians working towards stem cell -based therapies for myelin repair. Funding MS Society Wellcome Trust MRC BBSRC

Using a wide range of experimental approaches we are examining extrinsic (environmental) and intrinsic (transcriptional) factors that govern the responses of adult neural stem/precursor cells to injury and their differentiation into oligodendrocytes and other glia following CNS injury. The potential medical benefits of this research are to stop nerve cell degeneration and therefore provide a treatment for the currently untreatable secondary progressive phase of multiple sclerosis

The stages of remyelination

Key Publications Ruckh JM, Zhao JW, Shadrach JL, van Wijngaarden P, Rao TN, Wagers AJ, Franklin RJM (2012). Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10: 96-103. PMID: 22226359 Huang JK, Jarjour AA, Nait Oumesmar B, Kerninon C, Williams A, Krezel W, Kagechika H, Bauer J, Zhao C, Evercooren AB, Chambon P, Ffrench-Constant C, Franklin RJM. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nature Neuroscience. 2011 Jan;14 (1): 45-53. PMID: 21131950 Zawadzka, M., L. E. Rivers, S. P. Fancy, C. Zhao, R. Tripathi, F. Jamen, K. Young, A. Goncharevich, H. Pohl, M. Rizzi, D. H. Rowitch, N. Kessaris, U. Suter, W. D. Richardson and R. J. M. Franklin (2010). CNSresident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell 6 (6): 578-90. PMID: 20569695

Group Members Abbe Crawford Alerie Guzman Ilias Kazanis Dan Ma Daniel Morrison Muktha Natrajan Bjoern Neumann John Parker Francisco Rivera Sybil Stacpoole John Stockley Peter van Wijngaarden Bowei Wong Chao Zhao 8

Epithelial Stem Cell Homeostasis and Cancer Most adult tissues are maintained by stem cells and failure to control the generation or differentiation of stem cells contributes to cancer. We use the mammalian skin as a model system to identify novel key regulators and pathways that control tissue homeostasis by regulating stem cell growth and differentiation. The skin is an essential barrier that protects our body against the external environment. The maintenance of the skin epidermis is tightly balanced and controlled by stem cells that continuously maintain their population (self-renewal) while generating progeny (differentiation). Skin stem cells are established during development and are retained in adulthood allowing the body to replace, restore and regenerate dead, damaged or diseased epidermal cells. How the balance between stem cell self-renewal and differentiation is controlled is not fully understood, yet knowledge of regulatory pathways controlling these two states is fundamental to determine how stem cell misregulation causes human diseases.

Michaela Frye Michaela Frye completed her PhD in Frankfurt/Main in Germany in 2000 studying the role of epithelial defensins in Cystic Fibrosis. In 2001 she joined the lab of Fiona Watt as a Postdoctoral Fellow at the CR-UK London Research Institute where she developed her fascination for the question how stem cells in the skin are regulated. Michaela received a CR-UK Career Development Fellowship in 2007 when she started as a group leader at the WT-MRC Stem Cell Institute. She has renewed this fellowship in 2012 and is now a CR-UK Senior Fellow.

Labelling stem cells (green) in skin; Blue staining: nuclei; Red Staining keratin

Key Publications

Funding

Driskell I., Oda H., Blanco S., Nascimento E.M., Humphreys P., and Frye M* (2012). The histone methyltransferase Setd8 acts in concert with c-Myc and is required to maintain skin. EMBO J. 31:616-29. PMID: 22117221

Cancer Research UK ERC British Skin Foundation Wellcome Trust

Nascimento E.M., Cox C.L., MacArthur S., Hussain S., Trotter M., Blanco S., Menon S., Nichols J., K端bler B., Aznar Benitah S., Hendrich B., Odom D.T., and Frye M* (2011). The opposing transcriptional functions of Sin3A and c-Myc are required to maintain tissue homeostasis. Nature Cell Biology. 13:1395-405. PMID: 22101514 Blanco S., Kurowski A., Nichols J., Watt F.M., Aznar Benitah S., Frye M* (2011). The RNA methyltransferase Misu (NSun2) poises epidermal stem cells to differentiate. PLoS Genetics. 7:e1002403. PMID: 22144916 Group Members Sandra Blanco Shobbir Hussain Jelena Aleksic Roberto Bandiera Iwona Driskell Martyna Popis Joana Flores Mahalia Page Abdul Sajini Nikoletta Gkatza Carolin Witte

Transcriptional Regulation of Normal and Leukaemic Blood Stem Cells Blood stem cells provide the constant supply of new blood cells throughout a person’s lifetime. Their transcriptional regulation, i.e. the fine tuning of which genes should be active at any given time, is critical for their normal function. Moreover, a large number of leukaemias arise, when this fine balance of gene activities is disturbed. Transcription factors are genes responsible for controlling the activity of other genes, and they generally function as components of wider regulatory networks. Bertie Gottgens First Degree: Biochemistry, Tübingen University, 1992. Higher Degree: DPhil, Biological Sciences, University of Oxford, 1994. PostDoc; Haematology, University of Cambridge, 19942001. Leukaemia Research Fund Lecturer Haematology, University of Cambridge, 20022007. University Senior Lecturer, then Reader Haematology, University of Cambridge, 20072011. Professor of Molecular Haematology, University of Cambridge, since Oct 2011.

The Gottgens group uses a combination of experimental and computational approaches to study transcriptional regulatory networks in blood stem cells; to discover how transcription factor networks control the function of blood stem cells and identify how perturbations of such networks can cause leukaemia. Through collaboration with other groups within the SCI, the Gottgens group has also been able to apply their integrated experimental / computational approach to other areas of stem cell and regenerative medicine research, which has resulted in several high-profile collaborative publications since 2011.

Funding MRC Leukaemia & Lymphoma Research BBSRC MRC Cancer Research UK Leukemia & Lymphoma Foundation USA NIHR NC3Rs Microsoft Research Wellcome Trust

A Regulatory Network Model for the Development of Megakaryocytes from Blood Stem Cells

Key Publications Tijssen M.R., Cvejic A., Joshi A., Hannah R.L., Ferreira R., Forrai A., Bellissimo D.C., Oram S.H., Smethurst P.A., Wilson N.K., Wang X., Ottersbach K., Stemple D.L., Green A.R., Ouwehand W.H., Göttgens B. Genome-Wide Analysis of Simultaneous GATA1/2, RUNX1, FLI1, and SCL Binding in Megakaryocytes Identifies Hematopoietic Regulators. (2011). Dev Cell 20(5):597-609. PMID: 21571218 Griffiths D.S., Li J., Dawson M.A., Trotter M., Cheng Y.-H., Smith A.M., Mansfield W., Liu P., Kouzarides T., Nichols J., Bannister A.J., Green A.R., Göttgens B. LIF independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease. (2011) Nature Cell Biology 13: 13-21. PMID: 21151131

Group Members Fernando Calero Lila Diamanti Debbie Goode Rebecca Hannah Isabel Jimenez Viviane Kawata Sarah Kinston Winnie Lau Ana Leal Cervantes Vicki Moignard Felicia Ng David Ruau Judith Schütte Jonathan Sive Yosuke Tanaka Adam Wilkinson Nicola Wilson Steven Woodhouse

Wilson N.K., Foster S.D., Wang X., Knezevic K., Schütte J., Kaimakis P., Chilarska P., Kinston S., Ouwehand W.H., Dzierzak E., Pimanda J.E., de Bruijn M.F., Göttgens B. Combinatorial Transcriptional Control in Blood Stem/Progenitor Cells: Genome-wide Analysis of 10 major Transcriptional Regulators. (2010) Cell Stem Cell 7(4):532-544. PMID: 20887958

Haematopoiesis Tony Green’s research has focused on the mechanisms whereby blood stem cells are subverted during the genesis of haematological malignancies. Over the past decade his lab has increasingly concentrated on JAK/STAT signalling which is dysregulated in many cancers and plays a key role in multiple stem cell systems. His group have focused on the myeloproliferative neoplasms which harbour mutations that activate the JAK/STAT pathway, are experimentally tractable and provide a paradigm for the earliest stages of tumorigenesis, inaccessible in other cancers. His translational studies of MPN pathogenesis have already had direct clinical impact with improved classification, new diagnostic approaches embedded in international guidelines and multiple JAK inhibitors in clinical trials. His more basic research is illuminating the mechanisms whereby the JAK/STAT pathway regulates diverse aspects of cellular function including chromatin biology, DNA replication, genome-wide transcriptional programs and stem cell fate.

The panels show that a particular transcription factor (FOXO3A) is located in the nucleus in normal stem cells, but not in JAK2 V617F mutant stem cells. The blue colour represents the nucleus and the red colour is FOXO3A protein.

Tony Green Tony Green trained in medicine at the University of Cambridge (197477) and University College Hospital London (1977-80) subsequently completing his haematology training at the Royal Free Hospital and the University Hospital of Wales, Cardiff. His scientific training in molecular biology and haematopoiesis was gained at the Imperial Cancer Research Fund, London (1984-87) and the Walter and Eliza Hall Institute, Melbourne (1989-91), the latter as a HamiltonFairley Travelling Fellow. He moved to Cambridge in 1991 as a Wellcome Trust Senior Fellow and honorary Consultant and was elected Chair of HaematoOncology there in 1999. In 2001 he was elected Fellow of the Academy of Medical Sciences and in 2011 elected Newton Abraham Visiting Professor at the University of Oxford.

Key Publications

Funding

Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal PA, ErberWN, McMullin MF, Harrison CN, Warren AJ, Gilliland DG, Lodish HF, Green AR. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis, N Engl J Med 356: 459-468, 2007. PMID: 17267906

Leukaemia & Lymphoma Research Cancer Research UK The Leukemia & Lymphoma Society (Specialized Center of Research, USA) Kay Kendall Leukaemia Fund Wellcome Trust MRC

Dawson MA†, Bannister AJ†, Gottgens B, Foster SD, Bartke T, Green AR*, Kouzarides T* (*joint senior authors; †joint first author). JAK2 phosphorylates histone H3Y41 and excludes HP1a from chromatin. Nature, 461: 819-822, 2009. PMID: 19783980 Chen E, Beer PA, Godfrey AL, Ortmann CA, Li J, Costa-Pereira AP, Ingle CE, Dermitzakis ET, Campbell PJ, and Green AR. Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling. Cancer Cell, 18(5): 524-535, 2010. PMID: 21074499

Group Members Athar Aziz Danai Dimitropoulou Anna Godfrey Tina Hamilton David Kent Kristina Kirschner Karoline Kollman Juan Li Stephen Loughran Jyoti Nangalia Francesca Nice June Park Dean Pask Rachel Sneade Wolfgang Warsch

Transcriptional Control of Stem Cell Fate

Brian Hendrich Brian grew up near Seattle, Washington. He got his PhD from Stanford University in 1995 working on X chromosome inactivation with Huntington Willard. In 1995 he joined the lab of Adrian Bird at the University of Edinburgh and participated in the discovery and characterisation of a family of methyl-CpG binding proteins in mammals. In 2001 he started his own laboratory at the University of Edinburgh. In 2008 he moved to the Wellcome Trust Centre for Stem Cell Research in Cambridge. He is currently a Wellcome Trust Senior Research Fellow in the Basic Biomedical Sciences, and Director of the PhD Programme in Stem Cell Biology for the Cambridge Stem Cell Institute.

Funding Wellcome Trust MRC EU FP7

Embryonic stem (ES) cells hold enormous promise for personalised medicine and drug discovery since they can be maintained indefinitely and are pluripotent; that is they have the potential to form any adult cell type. While pluripotency makes ES cells potentially very useful, it also presents a problem: how do you get them to make the cell type you want, and not one you don't? Differentiation of pluripotent cells is exquisitely organised during normal embryogenesis, but controlling differentiation of stem cells in culture presents a major challenge. Since all cells in an organism are genetically identical, the observable differences in their functions and behaviours come down to which genes they express and which genes they don’t express. Therefore in order to understand how to direct cellular identity, we seek to understand how cells regulate gene expression during differentiation. We also seek to understand how subtle differences in gene expression patterns in seemingly identical cells influence any subsequent differentiation decisions. To do this we focus on how the DNA is packaged in the cell and study the proteins involved in regulating this chromatin packaging. We use biochemistry, genetics, in vitro stem cell culture and manipulation, single cell analyses, genome-wide analyses and collaborate with bioinformaticians and computer programmers to better understand how control of transcription facilitates decision making in stem cells. By understanding how ES cells make different developmental decisions this work will bring the medical promise of stem cells closer to realisation.

A colony of mouse embryonic stem cells stained in blue. While the cells look identical, staining for expression of one protein linked to pluripotency (green) shows that the cells are actually different.

Key Publications Reynolds, N., O’Shaughnessy, A. and Hendrich, B. (2013) "Transcriptional repressors: multifaceted regulators of gene expression" Development, 140(3), 505–512. doi:10.1242/dev.083105 PMID: 23293282 Reynolds, N., Latos, P., Hynes-Allen, A., Loos, R., Leaford, D., O’Shaughnessy, A., Mosaku, O., Signolet, J., Brennecke, P., Kalkan, T., Costello, I., Humphreys, P., Mansfield, W., Nakagawa, K., Strouboulis, J., Behrens, A. Bertone, P., and Hendrich, B. (2012) “NuRD suppresses pluripotency gene expression to promote transcriptional heterogeneity and lineage commitment” Cell Stem Cell 10(5): 583-594. 10.1016/ j.stem.2012.02.020 PMID: 22560079 Reynolds, N., Salmon-Divon, M., Dvinge, H., Hynes-Allen, A., Balasooriya, G., Leaford, D., Behrens, A., Bertone, P. and Hendrich, B. (2012) “NuRD-mediated deacetylation of H3K27 facilitates recruitment of Polycomb Repressive Complex 2 to direct gene repression” The EMBO Journal. 31(3), 593–605. doi:10.1038/emboj.2011.431 PMID: 22139358

Group Members Thomas Burgold Sarah Gharbi Antony Hynes-Allen Anzy Miller Aoife O'Shaughnessy-Kirwan Meryam Rasler Nicola Reynolds Jason Signolet

Leukaemia Stem Cell Biology Leukaemias and many other cancers have recently been demonstrated to be wholly dependent upon a small population of so -called cancer stem cells for their continued growth and propagation. These cells represent the most critical targets for treatment of leukaemia and a greater understanding of their biology and its interface with normal stem cell function is fundamental to improving treatment outcomes in leukaemia. The focus of the Huntly laboratory is on this interface between normal and malignant haematopoietic stem cell biology. We use a combination of techniques in cell line and animal models as well as confirmatory studies in primary human tissue to dissect stem cell function. Our group is complemented by a number of other local researchers within the Stem Cell Insitute with similar interests (Professors Green Gottgens and Warren and Dr Ottersbach). Our aim is to understand how normal stem cell stem cell function is subverted in cancer and how these processes might be therapeutically targeted to improve the outcome in haematological cancers, many of which have a dismal survival rate. A recent example of our work is the identification of the Bromodomain and extra terminal (BET) proteins as critical mediators of leukaemia stem cells in acute myeloid leukaemia (AML) and the development of an inhibitor of these proteins that is about to enter early phase clinical trials in relapsed blood cancers.

Brian Huntly Dr Brian Huntly is a clinical academic who combines running a laboratory group with his practice as a Consultant Haematologist in Addenbrookes Hopsital. He studied Medicine at Edinburgh, trained in Haematology in Dundee and Cambridge and is a member of the Royal College of Physicians and a Fellow of the Royal College of Pathologists. He studied for his PhD in Cambridge and performed post-doctoral work at Harvard, prior to returning to Cambridge to set up his own research group. .

Funding Inhibition of BET proteins switches off critical pathways in leukaemia stem cells. In the left panel, the MLL-AF4/AF9 leukaemia mutation is localized to DNA by the BET proteins Brd3 and 4, where it causes expression of drivers of leukaemia such as BCL2, C-MYC and CDK6. Inhibition of this localization with BET inhibitors (I-BET), switches off this the expression of these genes and causes the leukaemia to regress.

Leukaemia Lymphoma Research Wellcome Trust Kay Kendal Leukaemia Fund Leukemia Lymphoma society of America

Key Publications

Group Members

Dawson MA, Prinjha RK, Dittman A, Giotopoulos G, Bantscheff M, Chan WI, Robson SC, Chung C, Hopf C, Savitski MM, Huthmacher C, Gudgin E, Lugo D, Beinke S, Soden PE, Dรถhner K, Delwel R, Burnett AK, Auger KR, Mirguet O, Jeffrey P, Drewes G, Lee K, Huntly BJP *, Kouzarides T *. Displacement of BRD3/4 from chromatin as an effective treatment for MLL-fusion leukaemia Nature. 2011 Oct 2 *joint senior authors. PMID:21964340

George Giotopoulos Mark Dawson Sarah Putwain Sarah Horton Eshwar Meduri Paulo Gallipoli Faisal Basheer Chun Fong Jessica Morrison

Anand S, Stedham FE, Gudgin E, Beer PA, Bench AJ, Erber W, Green AR, Huntly BJP. The JAK2 V617F mutation alters myeloid ontogeny predominantly through effects outside of the hematopoietic stem and progenitor compartment. Blood. 2011 May 11. [Epub ahead of print] PMID:21562050 Kvinlaug BT, Chan WI, Bullinger L, Sears C, Paul D, Okabe R, Lee BH, Benner A, De Silva I, Valk P, Delwel R, Armstrong SA, Dรถhner H, Gilliland DG, Huntly BJP. Common and overlapping pathways contribute to the evolution of acute myeloid leukaemias. Cancer Res. 2011 Apr 19. [Epub ahead of print] PMID:21505102

Epithelial Development, Maintenance and Regeneration Adult stem cells can be found in most adult tissues. Here they play an important role in tissue maintenance and repair following damage. Stem cells in different organs will behave according to the tissue specific requirements for tissue turnover. Certain tissues like the epithelial lining of the intestine have a high cell turnover, whereas the turnover in the skin is lower. This is however carefully regulated in order to ensure life-long equilibrium of the tissue in question.

Kim Jensen Kim Jensen received his PhD in molecular biology from the University of Aarhus in 2003. He subsequently joined Professor Fiona Wattâ&#x20AC;&#x2122;s group at the London Research Institute, Cancer Research UK, as a post-doctoral fellow. Based on cutting edge technologies and analysis of mouse models he went on to identified Lrig1, a negative regulator of receptor tyrosine kinases, as a novel marker of both human and mouse epidermal stem cells. In 2010 Kim received a Wellcome Trust Career Development Fellowship to establish his own group at the University of Cambridge. Here Kimâ&#x20AC;&#x2122;s group has focused on the role of adult stem cells in tissue homeostasis.

Funding Wellcome Trust MRC

Our work focuses on the epithelium of the skin and the intestine. Stem cells have in both of these tissues been carefully characterised, however, it is still not clear how their behaviour is regulated. We know that their immediate surroundings and neighbours via intrinsic and extrinsic factors play an important role in this regulation. In certain tissue such as the skin, local differences provide the bases for the establishment of multiple distinct populations of stem cells with specific functions. Our goal is to define the functional significance of multiple stem cells compartment and establish how adult epithelial stem cells are regulated during steady state homeostasis. Such regulatory mechanisms are likely to be affected during epithelial disease such as cancer and will constitute prime targets for therapeutic intervention.

The stem cell marker Lrig1 controls stem cell proliferation in both the skin and the epidermis demonstrating the existence of common regulatory mechanisms.

Key Publications Jensen, K.B., Driskell, R.R. and Watt, F.M. (2010) Assaying proliferation and differentiation capacity of stem cells using disaggregated adult mouse epidermis. Nature Protocols, 5, 898-911 . PMID: 20431535 Wong, V.W.Y, Stange, D.E., Page, M.E., Buczacki, S., Wabik, A., Itami, S., van de Wetering, M., Poulsom, R., Wright, N.A., Trotter, M.W.T., Watt, F.M., Winton, D.J., Clevers, H. and Jensen, K.B. Lrig1 controls intestinal stem cell homeostasis by negative regulation of ErbB signalling. (2012) Nature Cell Biology 14, 401-408. PMID:22388892

Group Members

Jensen, K.B., Collins, C.A., Nascimento, E., Tan, D.W., Frye, M., Itami, S. and Watt, F.M Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. (2009) Cell Stem Cell, 4, 427439. PMID:19427292

Mahalia Page Robert Fordham

Neurotransmitter Signalling to Central Nervous System Progenitor Cells The lab’s esearch interests are neurotransmitter signalling to oligodendrocyte progenitor cells (OPC; a type of CNS stem cell), in both health and disease. For our brain to work properly, enabling us to feel, move, talk, see , think and learn, fast electrical communication between nerve cells is essential. This is achieved by insulating the nerves with a fatty substance called myelin. In diseases like multiple sclerosis, spinal cord injury and stroke, myelin is lost, while in cerebral palsy myelin fails to develop. Lack of myelin causes physical and mental disability. Myelin is provided by cells called oligodendrocytes, which develop from oligodendrocyte precursor cells (OPCs). OPCs are 5% of all cells in the adult brain and can to turn into most cell types in the brain. Most importantly, OPCs can repair myelin, but this repair often fails. We have discovered that OPCs express a protein previously only thought to be expressed in neurons, as it is known for being essential for learning. But in OPCs it enables them to sense activity in the neurons. Furthermore, we found that OPCs enter into a dialogue with neurons and this dialogue and neuronal activity, acting on the protein we found, directs OPCs to become myelin-making oligodendrocytes in both health and disease. We are now investigating how signals in the cells’ environment interact with OPCs to instruct them to move to regions where myelin is needed, and to generate myelin-making oligodendrocytes, with special focus on the neuron to OPCs dialogue. The long-term aim of this work is to understand how OPCs become myelinating cells, and how we can influence them to repair myelin in disease.

Ragnhildur Thóra Káradóttir Ragnhildur Thora Karadottir graduated with a degree in Biochemistry from the University of Iceland in 2000. Then she did a 4 year Wellcome Trust PhD in Neuroscience at UCL under the supervision of Prof. David Attwell. She continued working with Prof. Attwell as a postdoctoral researcher, before being awarded a Royal Society Dorothy Hodgkin Research Fellowship which she used to work with Prof. Charles ffrench-Constant at University of Cambridge. In 2008 she established her own independent research group in Cambridge and in 2011 she was awarded the Wellcome Trust Research Career Development fellowship. She is currently editor of Brain Plasticity and for a special issue for Neuroscience on White matter.

Funding Myelinated fibres in the brain, these fibres provide superfast communication between neurons.

Wellcome Trust MRC

Key Publications Bakiri Y, Káradóttir R, Cossell L, Attwell D (2011) Morphological and electrical properties of oligodendrocytes in the white matter of the corpus callosum and cerebellum. J Physiol 589:559. PMID: 21098009 Káradóttir R, Hamilton N, Bakiri Y & Attwell D (2008).Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter. Nature Neuroscience 11(4): 450-456. PMID: 18311136 Bakiri Y, Hamilton N, Káradóttir R & Attwell D (2008). NMDA receptor block as a therapeutic strategy for reducing ischaemic damage to oligodendrocytes. Glia, 15;56(2): 233-240. PMID: 18046734 Group Members Kimberly Evans Katrin Volbracht Sylvia Agathou Sergey Sitnikov Sonia Spitzer Moritz Matthey John Stockley

Neural Stem Cells, Cellular Reprogramming and Regenerative Medicine My group is interested in the biology of adult CNS stem and precursor cells. With respect to regeneration in the CNS we are particularly interested in mechanisms of CNS remyelination, a stem/ precursor cell-mediated process in which new myelin sheaths are restored to demyelinated nerve fibres (axons). To understand how the differentiation of multipotent oligodendrocyte precursor cells (OPCs) is regulated we use a combination of in vitro and in vivo models.

Mark Kotter I am an academic neurosurgeon who undertook postgraduate medical training in Austria (Vienna), Germany (Göttingen), and the UK (Cambridge). During my PhD at the University of Cambridge I have established the importance of macrophages for the regeneration of CNS white matter. I continue to work on extrinsic and extrinsic regulators of CNS remyelination and have developed an interest in mechanisms of direct cellular reprogramming. I am particularly interested in clinical translation with a view to promoting regeneration in a clinical setting.

Funding NIHR UKMS Society Wings for Life Qatar Science Foundation

A second focus of o the lab are cellular re-programming techniques. A limited set of transcription factors enables trans-lineage reprogramming of somatic cells into distinct neural cell types. We use cellular re-programming techniques to 1. study transcriptional and epigenetic events that determine the cellular identity of OPCs, NSCs, and differentiated neural cell types, 2. generate patient specific disease models, and 3. develop cellular platforms that can be used for drug discovery and toxicological investigation. We aim at bedside to bench translation as well as translating our findings into clinical studies.

Human induced Oligodendrocyte precursor cell

Key Publications Kotter MR, Stadelmann C, Hartung HP Enhancing CNS remyelination in disease – can we wrap it up. Brain. 2011 Jul;134(Pt 7) PMID:21507994 Syed YA, Hand E, Möbius M, Zhao C, Hofer M, Nave KA, Kotter MR Inhibition of CNS remyelination by the presence of Semaphorin. J Neurosci. 2011 Mar 9;31(10) . PMID:21389227

Group Members

Baer AS, Syed YA, Vig R, Hoeger H, ffrench-Constant C, Franklin RJM, Altmann F,Lubec G, Kotter MR. Myelin-mediated inhibition of oligodendrocyte precursor cell differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling Brain, 132:465-81, 2009 PMID:19208690

Yasir Ahmed Syed Ana Amaral Matthias Pawlowski Ginez Gonzalez Sarah Ali Abdulla Kelly Inthanthon Saifur Rahman

Human stem cell models of neurological disease Making a brain depends on producing all of the different types of nerve cells in the correct places and at the appropriate times before wiring those nerve cells together to make functional circuits. Growing human brain cells in a dish enables us to study them using techniques which are not possible to perform in vivo. Differentiating cortical nerve cells from induced pluripotent stem cells enables us to study patient-specific neurons for a range of conditions. We study how neural stem and progenitor cells build the executive centre of the brain, the cortex. The cortex is the part of the front of the brain that mammals, including humans, use to perceive physical sensations, sound and vision and where thoughts are generated and movement initiated. The consequences of changes to important genes or of mis-wiring in the cortex are neurological diseases, disability, and neuro-degeneration; including epilepsy and autism, major learning disabilities and dementia. An understanding of how the cortex is built normally is essential for understanding these disorders, as is our research into what causes the system to break down.

Human stem cell-derived neuropithelial rosettes expressing cerebral cortex transcription factors

Key Publications

Rick Livesey Rick did his undergraduate and preclinical medical studies in Cork, Ireland before joining the MB/PhD programme at the University of Cambridge Clinical School. He did his PhD at the MRC LMB in Steve Hunt's group and post-doctoral work with Connie Cepko at the Department of Genetics, Harvard Medical School. Rick started his group at the Gurdon Institute in September 2001.

Funding Wellcome Trust MRC

Pereira JD, Sansom SN, Smith J, Dobenecker MW, Tarakhovsky A and Livesey FJ (2010) Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex Proc Natl Acad Sci USA 107, 15957-15962. PMID: 20798045 Andersson T, Rahman S, Sansom SN, Alsio JM, Kaneda M, Smith J, Oâ&#x20AC;&#x2122;Carroll D,Tarakhovsky A and Livesey FJ (2010) Reversible block of mouse neural stem cell differentiation in the absence of dicer and microRNAs PLoS ONE 5, e13453 PMID: 20976144 Subkhankulova T,Yano K, Robinson HP and Livesey FJ (2010) Grouping and classifying electrophysiologically- defined classes of neocortical neurons by single cell, whole-genome expression profiling Front Mol Neurosci 3, 10. PMID: 20428506 Group Members Tatyana Dias Steven Moore Peter Kirwan Natalie Saurat Tomoki Otani Teresa Krieger Mac Hughes James Smith Amelia McGlade

Embryonic Pluripotency

Jennifer Nichols Jenny Nichols began her research career with Professor Richard Gardner at the University of Oxford, where she developed a fascination for early mammalian development. She subsequently moved to Edinburgh to join Austin Smith in his newly formed group at the Centre for Genome Research to focus on investigating how the epiblast lineage is established in the embryo and how pluripotent cells can be captured and propagated efficiently in culture as embryonic stem cell lines. She obtained her PhD in Edinburgh in 1995 and continued as a post doctoral research fellow in Austin Smith's lab until 2006, when she moved to Cambridge to become a group leader under the direction of Professor Smith at the CSCR.

Unlike most other model organisms, the early mammalian embryo possesses an amazing capacity to regulate its own development. Murine embryos develop a pluripotent epiblast at the late blastocyst stage, which can be propagated in vitro in the form of embryonic stem (ES) cells. The first ES cells were derived directly from mouse blastocysts using culture medium supplemented with serum and a 'feeder layer' of mitotically inactivated fibroblasts. The process by which ES cells emerge was not understood, but their potential applications were immediately realised to be enormous. The purpose of our research is to try to understand how the pluripotent cells are assigned and maintained in the embryo; how they can be harnessed and propagated in culture as ES cell lines and how the process of ES cell derivation can be controlled and improved. Addition of selected inhibitors to the culture medium has obviated the requirement for exogenous cytokines for the maintenance and derivation of murine ES cells, apparently by simply removing the option to differentiate. ES cells can be very efficiently derived from mouse and rat embryos cultured in these conditions. This efficiency is apparently attributable to the ability of the inhibitors both to prevent differentiation and to promote expansion of the epiblast. We have applied this technology to derive ES cells efficiently from hitherto recalcitrant strains of mice, including non-obese diabetic (NOD) mice. Although pluripotent cell lines have been derived from other mammals, these lines differ from murine ES cells, and are more similar to so called â&#x20AC;&#x2DC;epiblast stem

Confocal image of a late blastocyst showing epiblast (pink) and hypoblast (green).

Funding Wellcome Trust MRC

Key Publications Nichols, J.,* Silva, J.,* Roode, M. and Smith, A. (2009). Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development 136, 3215-3222. PMID: 19710168 Nichols, J., Jones, K., Phillips, J. M., Newland, S. A., Roode, M., Mansfield, W., Smith, A. and Cooke, A. (2009). Validated germlinecompetent embryonic stem cells from nonobese diabetic mice. Nat Med 15, 814-8. PMID:19491843

Group Members Stoyana Alexandrova Thorsten Boroviak Kenneth Jones Agata Kurowski

Roode, M., Blair, K., Snell, P., Elder, K., Marchant, S., Smith, A. and Nichols, J. (2012). Human hypoblast formation is not dependent on FGF signalling. Dev. Biol. 361, 358-63. PMID:22079695

The Developmental Origins of Blood Stem Cells Blood stem cells (BSCs) have been intensely studied for many decades as a model system for stem cell biology. Our work focuses on the emergence and regulation of the first BSCs in the mouse embryo in order to identify the basic mechanisms that control their generation from precursor cells and their initial expansion and dissemination to the different blood-generating organs. Knowledge of these early regulatory pathways has proven to be invaluable for understanding how adult BSCs can be manipulated for clinical purposes and how interference with these processes may result in blood-related disorders. Our research therefore complements that of several groups on the Addenbrookes site which also work on various aspects of normal and leukaemic stem cell biology. Adult-type BSCs are first detected at day 10.5 during mouse development in a region of the embryo around the main aorta that is known as the AGM region. A day later these cells can also be detected in the yolk sac and the foetal liver. Our previous work has identified the placenta as another organ that harbours BSCs during development. We have recently further defined the region of the AGM where BSCs are first detected and have used thsi information to carry out screening experiments which resulted in the identification of novel regulators of BSC generation in the AGM. Furthermore, we have unveiled a functional interplay between the embryonic blood and nervous systems which develop in close proximity. More recently, we have also started focussing on how these pathways are corrupted in infant leukaemia.

Emergence of blood stem cells (green) from the wall of the aorta (red).

Key Publications Fitch S.R., Kimber G., Wilson N.K., Parker A., Mirshekar-Syahkal B., GĂśttgens B., Medvinsky A., Dzierzak E. & Ottersbach K. (2012). Signaling from the sympathetic nervous system regulates hematopoietic stem cell emergence during embryogenesis. Cell Stem Cell 11:554-566 PMID: 23040481

Katrin Ottersbach Katrin Ottersbach obtained her undergraduate degree in Biochemistry at the University of Edinburgh in 1997. She carried out her PhD research at the Beatson Institute for Cancer Research in Glasgow under the supervision of Prof. Gerard Graham. After completion of her PhD in 2001, she moved to Rotterdam, Netherlands, to take up a postdoctoral position in the group of Prof. Elaine Dzierzak. In 2006, she moved to the University of Cambridge, UK, to set up her own lab at the Cambridge Institute for Medical Research She became a Principal Investigator in the Wellcome Trust â&#x20AC;&#x201C; Medical Research Council Cambridge Stem Cell Institute when it was formed in 2012.

Funding Wellcome Trust MRC British Society for Haematology Kay Kendall Leukaemia Fund Leukaemia & Lymphoma Research

Mascarenhas M.I., Parker A., Dzierzak E. & Ottersbach K. (2009). Identification of novel regulators of hematopoietic stem cell development through refinement of stem cell localization and expression profiling. Blood 114:4645-53 PMID: 19794138 Ottersbach K. & Dzierzak E. (2005). The Murine Placenta Contains Hematopoietic Stem Cells within the Vascular Labyrinth Region. Developmental Cell 8:377-87 PMID: 15737933

Group Members Chrysa Kapeni Maria Mascarenhas Neil Barrett Wendi Bacon Simon Fitch Camille Malouf Kankan Xia

Mechanics of Mesoderm Differentiation in Mammalian Pluripotent Stem cells

Roger Pedersen Roger Pedersen is Professor of Regenerative Medicine in the Department of Surgery at the University of Cambridge. After receiving a PhD in biology from Yale University in 1970, he specialised in mammalian embryology. From 1971, he headed a research programme at the University of California, San Francisco, exploring developmental potency and cell fate in early mouse development. That work, together with clinical service in assisted reproductive therapies, led him to studies on human embryos and stem cells. In 2001, confronting federal funding restrictions for this work, he relocated to the University of Cambridge, where he heads a team of researchers devoted to delivering human embryonic stem cells to clinical use.

Our principal objective is to define the molecular and genetic basis for the maintenance of the pluripotent status of human embryonic stem cells, and similarly, the basis for their differentiation into the primary body lineages: mesoderm, endoderm and neuroectoderm. Previous studies had revealed that pluripotency of human embryonic stem cells was not maintained by similar mechanisms as for mouse embryonic stem cells, whose self-renewal depends on Leukemia Inhibitor Factor and Bone Morphogenetic Protein. We have examined the effects of other growth factors known to be important in cell fate decisions of mammalian and other vertebrate embryos. We found that signaling through the Activin/Nodal pathway is critical for maintenance of pluripotency and that basic Fibroblast Growth Factor augments this pathway. We hypothesise that their effects in human embryonic stem cells involve alternative intermediate transcription factor(s) and target genes, which is the subject of our current studies.

Migratory behaviour in human embryonic stemcells

Funding Wellcome Trust MRC

Group Members Paula McPhee Morgan Alexander Rachel Pain Maria Ortiz Kathy Niakan Sissy Wamaitha Andreia Bernardo Sasha Mendjan Thomas Moreau Liz Callery Lily Cho Tiago Faial Smruthi Jayasundar Yifan Ng Daniel Ortmann Rob Fordham Filipa Soares Victoria Mascetti Stan Wang

Key Publications Bernardo AS, Faial T, Niakan KK, Ortmann D, Gardner L, Senner CE, Callery EM, Trotter MW, Hemberger M, Smith JC, Moffett A, Bardwell L and Pedersen RA. (2011). BRACHYURY and CDX2 mediate BMPinduced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages. Cell Stem Cell 9: 144155. PMID:21816365 Chng Z, Teo A, Pedersen RA, Vallier L. (2010). SIP1 mediates cell-fate decisions between neuroectoderm and mesendoderm in human pluripotent stem cells. Cell Stem Cell, 6: 59-70. PMID:20074535 Vallier L, Mendjan S, Brown S, Chng Z, Teo A, Smithers LE, Trotter MW, Cho CH, Martinez A, Rugg-Gunn P, Brons G, Pedersen RA. (2009) Activin/Nodal signalling maintains pluripotency by controlling Nanog expression. Development 136: 1339-1349. PMID:19279133

Central Nervous System Repair The development of cell-based therapies aimed to promote tissue repair in central nervous system (CNS) diseases, represents one of the most challenging areas of investigation in the field of regenerative medicine. Several cell-replacement strategies have been developed in the last few years. Recent evidence from our own and other laboratories indicates that undifferentiated neural stem/ precursor cells (NPCs) might very efficiently protect the CNS from chronic degeneration induced by inflammation both in small rodents as well as in primates. However, before envisaging any potential human applications of such innovative therapies we need to confront with some preliminary and still unsolved questions: 1. The ideal stem cell source for transplantation, whether it has to be from pluripotent or multipotent sources; 2. The ideal route of cell administration, whether it has to be focal or systemic; 3. The ideal balance between differentiation and persistence of stem cells into the targeted tissue and – last but not least – 4. The ideal mechanism of tissue repair to foster, whether it has to be cell replacement or tissue protection (rescue). Current projects in the laboratory are further exploring the cellular and molecular mechanisms regulating the therapeutic plasticity of NPCs in complex CNS diseases such as multiple sclerosis, and spinal cord injury. Besides some classical experimental cell therapy approaches with pluripotent stem cell-derived precursors/ progenitors, we are devoting special attention to the different modalities by which NPCs engage programs of horizontal cell-to-cell communication with cells in the microenvironment.

Volocity®-based 3D reconstruction of a mouse neurosphere in vitro.

Key Publications Kalra H, et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 2012 Dec;10 (12):e1001450. doi: 10.1371/journal.pbio.1001450; PMID: 23271954 Martino G, Pluchino S, Bonfanti L, Schwartz M. Brain regeneration in physiology and pathology: the immune signature driving therapeutic plasticity of neural stem cells. Physiol Rev. 2011 Oct;91(4):1281-304 PMID: 22013212 Cusimano M, Biziato D, et al. Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. Brain. 2012 Feb;135(Pt 2):447-60 PMID:22271661

Stefano Pluchino After receiving his MD (1995) and PhD in Neuroscience (2004) from the University of Siena (Italy), Stefano Pluchino completed a residency program in Neurology at the same University (1999) and received additional training at the MRC Brain Repair Centre, Cambridge University, UK (19961998). He then completed two subsequent post-doctoral fellowships (2004-2005) at the San Raffaele Scientific Institute, Milan (Italy), where he progressed to the position of Project and then Group leader (2005-2010). He is currently a University Lecturer in Brain Repair and Honorary Consultant in Neurology within the John van Geest Centre for Brain Repair (2010 -). He is also a European Research Council (ERC) Starting Independent Researcher and editorial board member for Brain. Dr Pluchino has made significant contributions to the understanding of the mechanisms of therapeutic plasticity of neural stem/precursor cells (NPCs) after systemic transplantation in laboratory animals with experimental inflammatory neurological diseases. Funding Italian MS Society The Evelyn Trust IRP/IFP European Neurological Society The John & Lucille van Geest Trust FEBS European Research Council EU FP7 Group Members Elena Giusto Nunzio Iraci Jayden A. Smith Matteo Donega' Bing Huang Tommaso Leonardi Julia Schaeffer Silvia Basilico Diana Breitmeier Cecilia Icoresi-Mazzeo Luca Peruzzotti-Jametti Giulia Mallucci Joan Pidgeon

Stem Cell Fate in the Mammalian Lung From first breath to last gasp, our lungs are an essential organ. Lung architecture is complex and must be maintained throughout life. If things go wrong with lung maintenance, the resulting changes can contribute to multiple different lung diseases. Many of these are degenerative diseases â&#x20AC;&#x201C; such as Chronic Obstructive Pulmonary Disease â&#x20AC;&#x201C; and are associated with ageing. Consequently, they are increasing in prevalence worldwide. In common with other organs, the lung is maintained by the function of tissue-specific stem cells which must act on demand to replace old or dying cells. Specifically, the stem cells must do two things: Emma Rawlins Emma Rawlins is an MRC Career Development Fellow. She obtained her PhD in developmental biology from the University of Edinburgh where she worked with Prof. Andrew Jarman. Her postdoctoral training was at Duke University Medical School, North Carolina, USA in the lab of Prof. Brigid Hogan. This was where she first worked on mouse lung stem cells. She was one of the first people to use modern genetic techniques to study mouse lung stem cells and has been instrumental in identifying several stem cell populations.

1. produce new daughter cells when required to do so: either too few or too many cells can be disastrous for lung function. 2. produce the correct types of daughter cells: changes to cell identity can also disrupt lung function. The Rawlins lab investigates the mechanisms which control stem cell behaviour in the lungs. We are most interested in how the stem cells in the normal adult lung know which type of daughter cell they need to make and when. Our approach is to use the power of mouse genetics to understand the control of lung stem cell behaviour at the single cell level. This allows individual cells to be analyzed quantitatively in vivo, or by live-imaging in organ culture systems. In collaboration with Ben Simons, we are currently characterizing a new stem cell population in the airways of the adult mouse lung which is already committed to produce a specific type of daughter cell.

Lineage-labelled bronchiolar cells (green) in the growing mouse lung. These cells are descended from an specific lung stem cell population.

Funding Key Publications MRC Wellcome Trust March of Dimes

Rawlins EL, Clark CP, Xue Y and Hogan BLM (2009). The Id2 distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development 136, 3741-3745 PMID: 19855016 Rawlins EL, Okubo T, Xue Y, Brass DM, Auten RL, Hasegawa H, Wang F and Hogan BLM (2009). The role of Scgb1a1+ Clara cells in the longterm maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 4, 525-534 PMID: 19497281

Group Members

Rawlins EL and Hogan BLM (2008). Ciliated epithelial cell lifespan in the mouse trachea and lung. American Journal of Physiology: Lung Cell Molecular Physiology 295, L231-234 PMID: 18487354

Gayan Balasooriya Christoph Budjan Jo-Anne Johnson Usua L. Garay Marko Nikolic Chandika Rao

Biology of Induced Pluripotency The aim of our lab is to understand the underlying biology of the conversion of a somatic epigenome back into a pluripotent epigenome, a process known as induced pluripotency. We are particularly interested in determining the molecular mechanisms by which the key players in this process work. Fully understanding induced pluripotency and better characterising iPS and ES cells is indispensible before these can be used in biomedical applications.

José Silva

A colony of stem cells reprogrammed to a pluripotent state from adult brain cells.

Key Publications Radzisheuskaya A, Chia GLB, Santos R, Theunissen TW, Castro LFC, Nichols J, Silva JCR. A defined Oct4 level governs cell state transitions of pluripotency entry and differentiation into all embryonic lineages. Nature Cell Biology. 30 April (2013) doi:10.1038/ncb2742.PMID: 23629142 Costa Y, Ding J, Theunissen TW, Faiola F, Hore TA, Shliaha PV, Fidalgo M, Saunders A, Lawrence M, Dietmann S, Das S ,Levasseur DN, Li Z, Xu M, Reik W, Wang J#, Silva JCR#. Nanog-dependent function of Tet1 and Tet2 in establishment of pluripotency. Nature. (2013) doi:10.1038/nature11925. PMID: 23395962 Radzisheuskaya A, Pasque V, Gillich A, Halley-Stott RP, Panamarova M, Zernicka-Goetz M, Surani MA, Silva JCR. Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency. Journal of Cell Science. Oct 17, (2012) doi: 10.1242/jcs.113019. PMID: 23077180

José received his first degree in Biology from the University of Porto, in Portugal. He joined the GABBA graduate program from University of Porto and then went on to do his PhD studies at Imperial College under the supervision of Professor Neil Brockdorff on heritable silencing mechanisms during mouse development. Professional History In 2003 and following his PhD, José moved to Professor Austin Smith's laboratory at the University of Edinburgh as an EMBO postdoctoral fellow to investigate factors involved in nuclear reprogramming. This work has led to the identification of Nanog as the first defined gene with nuclear reprogramming capacity in the conversion of a somatic cell into pluripotency. In 2008 José started as a group leader at the CSCR investigating the underlying biology of the process of induced pluripotency. His work was initially supported by a Next Generation Award (2008) and subsequently by a Wellcome Trust Career Development Fellowship Award (2009). Funding Wellcome Trust MRC Next Generation Award Isaac Newton Trust

Group Members Yael Costa Moyra Lawrence Aliaksandra Radzisheuskaya Rodrigo Santos Hannah Stuart

Tracing stem cell fate in development, maintenance, and disease

Ben Simons Ben has a background in theoretical condensed matter physics. Having obtained his PhD at the Cavendish Laboratory in Cambridge researching high temperature superconductivity, he undertook post-doctoral research in mesoscopic physics at MIT and NEC Research Inc. in Princeton. In 1994 he transferred to a Royal Society Research Fellowship and was appointed to a Lectureship at Imperial College before moving to the Cavendish Laboratory in 1995. In 2002, he was promoted to a Chair in Theoretical Condensed Matter Physics. In 2011, Ben was appointed to the Herchel Smith Chair in the Physics of Medicine.

Theories of tissue maintenance place stem cells at the apex of proliferative hierarchies, possessing the lifetime property of selfrenewal. In homeostasis the number of stem cells remains fixed imposing an absolute requirement for fate asymmetry in the daughters of dividing stem cells, such that only half are retained as stem cells. In recent years, much emphasis has been placed on resolving the extrinsic factors controlling stem cell fate and the spatial organization associated with the stem cell niche. Guided by the paradigm of invariant asymmetry, many studies have sought to identify factors that provide proliferative control, and ensure stem cell longevity. However, by addressing long-term lineage tracing studies involving several adult tissue types, from interfollicular epidermis and intestine to germ line, we have found that stem cell loss, leading to population asymmetric renewal, is central to homeostasis. By drawing upon concepts from statistical physics and mathematics, we have shown that tissue homeostasis permits just three classes of stem cell behaviour, discriminated by universal patterns of long-term clonal evolution. As well as achieving a functional classification of tissue stem cell types, this identification provides a general framework that we are using to interpret lineage tracing and mosaicchimera studies, and to explore mechanisms of dysregulation. In a separate but closely related programme of research we are also using these general concepts and lineage tracing methodologies to elucidate patterns of progenitor cell fate in the late stage development of tissues, from retina and cortex to pancreas and heart.

His research is supported by grant income from EPSRC, MRC, and the Wellcome Trust with whom he holds a Senior Investigator Award.

Funding Wellcome Trust EPSRC

In intestinal crypt, stem cells (marked by Lgr5 expression) lie intercalated between Paneth cells at the base of the crypt. In homeostasis, the frequent and stochastic loss of stem cells is compensated by the self-renewal of neighbours. As a result, the clonal progeny of stem cells undergo a pattern of neutral drift dynamics in which clonal loss is compensated by the expansion of others until the crypt becomes fully clonal.

Key Publications

Group Members Juergen Fink Philip Greulich Teresa Krieger Cheryl Lee Crystal McClain Steffen Rulands Hinal Tanna Gen Zhang

G. Driessens, B. Beck, A. Caauwe, B. D. Simons and C. Blanpain. Defining the mode of tumour growth by clonal analysis. (2012) Nature 488, 527-530. PMID: 22854777 B. D. Simons and H. Clevers. Strategies for Homeostatic Stem Cell Self -Renewal in Adult Tissues. (2011) Cell 145, 851-862. PMID: 21663791 Snippert H J, van der Flier L G, Sato T, van Es J H, van den Born M, Kroon-Veenboer C, Barker N, Klein A M, van Rheenen J, Simons B D and Clevers H. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. (2010) Cell 143, 134-144. PMID: 20887898

Stem Cell Potency We study embryonic stem (ES) cells. These are pluripotent cells, meaning they can generate all other types of cell. Our goal is to understand how they maintain this remarkable ability and how they decide which cell types to make when they do differentiate. We are analysing the degree of conservation between pluripotent cells from different mammalian species in order to find common principles underlying embryonic stem cell properties. We are also investigating the relationship between stem cells grown in the laboratory and progenitor cells in the embryo. We aim to use the knowledge gained to control the growth and differentiation of human stem cells for better understanding of human embryo development and for applications in drug discovery and regenerative medicine.

Austin Smith Austin Smith was captivated by pluripotency as a student in Oxford. He pursued this through PhD studies in Edinburgh and postdoctoral research back in Oxford. He returned to Edinburgh as a Group Leader in 1990 and from 1996 was Director of the Centre for Genome Research, later the Institute for Stem Cell Research. In 2006 he moved to Cambridge where he is Director of the Stem Cell Institute. Professor Smith is a Medical Research Council Professor, an EMBO Member, and a Fellow of the Royal Societies of Edinburgh and of London. In 2010 he was awarded the Louis Jeantet Prize.

Scheme of progression from pluripotency to differentiation

Key Publications

Funding

Martello G, Sugimoto T, Diamanti E, Joshi A, Hannah R, Ohtsuka S, Gottgens B, Niwa H, Smith A. (2012) Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal. Cell Stem Cell, Volume 11, Issue 4, 491-504, 5 October 2012 PMID: 23040478

Wellcome Trust MRC BBSRC EC HFSP EMBO SNF

Marks H, Kalkan T, Menafra R, Denissov S, Jones K, Hofemeister H, Nichols J, Kranz A, Francis Stewart A, Smith A* and Stunnenberg HG*. (2012) The transcriptional and epigenomic foundations of ground state pluripotency. Cell Apr; 149(3):590-604 PMID: 22541430 Nichols J, Smith A (2012) Pluripotency in the embryo and in culture. Cold Spring Harb Perspect Biol. 2012 Aug 1;4(8):a008128 PMID: 22855723

Group Members Joerg Betschinger Yaoyao Chen James Clarke Rosalind Drumond Ge Guo Tuzer Kalkan Masaki Kinoshita Raja Kittappa Martin Leeb Meng Amy Li Graziano Martello Gillian Morrison Carla Mulas Melanie Rittirsch Rika Takashima Yasuhiro Takashima Elena Tzouanacou

Specification and programming of the germline for totipotency and development

Azim Surani Born in Kenya and received PhD in 1975 at Cambridge University under Professor Sir Robert Edwards FRS (Nobel Laureate, 2010). Joined the Babraham Institute in 1979 and discovered Genomic Imprinting in 1984 and subsequently, novel imprinted genes and their functions, with mechanisms through establishment and erasure of DNA methylation. He was elected the Marshall-Walton Professor (1992), and Director of Germline and Epigenomics Research (2013) at Cambridge University. He has recently established the genetic basis for germ cell specification and epigenetic programming. He was elected a Fellow of the Royal Society (1990) and Fellow of the Academy of Medical Sciences (2001) He was awarded a Royal Medal in 2010.

Specification of primordial germ cell (PGC) occurs after development of equipotent epiblast cells following their exit from na誰ve pluripotent state. These epiblast cells can give rise to both somatic and germ cells in vivo and in vitro. Recent studies show that BLIMP1, PRDM14 and AP2g are necessary and sufficient for PGC specification. This mutually interdependent tripartite genetic network is involved in the repression of the somatic program, the initiation of the germ cell program and reexpression of pluripotency genes in early germ cells. The network also initiates sequential, orderly and dynamic epigenetic changes in histone modifications, reactivation of the X chromosome and comprehensive global DNA demethylation and imprints erasure. These epigenetic changes are essential towards imprinting of functional differences between parental genomes and the establishment of the totipotent state, which follows after fertilisation and establishment of the zygote. Whereas a repressive complex maintains unipotency of germ cells, dedifferentiation of unipotent PGCs to pluripotent stem cells in vitro is accompanied by the reversal of the PGC specification process. Early germ cells also exhibit unprecedented genome-wide DNA demethylation and chromatin remodelling, which are essential towards the establishment of totipotency. We are gathering insight into the mechanisms involved in epigenetic programming in germ cells, and continuing to identify the key factors that are crucial at these times. We are interested in exploiting the knowledge gained from studies on germ cells by creating in vitro models for induced epigenetic reprogramming, and using these models towards attempts at rejuvenation of somatic cells. Mouse germline cycle and the origin of primordial germ cells. The figure depicts key stages of early development and the origin of pluripotent stem cells.

Funding Wellcome Trust Human Frontier Science Programme BIRAX Regenerative Medicine Initiative

Key Publications Hackett JA, Sengupta RA, Zylicz JJ, Murakami K, Lee C, Down TA, Surani MA (2012) Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 339, 448-452. PMID:23223451 Gillich A, Bao S, Grabole N, Hayashi K, Trotter MWB, Pasque V, Magnusdottir E, Surani MA (2012) Epiblast stem cell-based system reveals reprogramming synergy of germ line factors. Cell Stem Cell 6 425-43922482507. PMID: 22482507

Group Members Delphine Cougot Vinh Dang Do Lynn Froggett Wolfram Gruhn Ufuk G端nesdogan Jamie Hackett Yun Huang Naoko Irie Elena Itskovich Shinseog Kim Toshihiro Kobayashi Caroline Lee Roopsha Sengupta Walfred Tang Julia Tischler Jan Zylicz

Tang, F., Barbacioru, C., Bao, S., Lee, C., Nordman, E., Wang, X., Lao, K. & Surani, M. A. Tracing the derivation of embryonic stem cells from the inner cell mass by single-cell RNA-Seq analysis. Cell Stem Cell 6, 468-478, (2010). PMID:20452321

Mechanisms Controlling Differentiation of Pluripotent Stem Cells into Definitive Endoderm We are primarily interested in two chronic neurodegenerative disorders of the brain- Parkinson’s disease (PD) which affects 120,000 people in the UK and has an unknown cause in the majority of cases, and Huntington’s disease (HD) which a genetic disorder affecting between 5-6000 people in the UK. We seek to better define the true extent of clinical deficits in these disorders and their temporal expression and variability, such that we can build a more complete model of disease heterogeneity and its basis which will then serve to inform us as to how we can best translate stem cell therapies to clinic by targeting the right sub-group of patients at the optimal stage of disease. This is currently being undertaken not with stem cells, but primary fetal human allografts in patients with mildmoderate HD (e.g. Rosser et al 2002) and will soon be undertaken with fetal ventral mesencephalic tissue in a TransEuropean trial in PD. In addition we seek to better understand adult neurogenesis in the brain in these disorders, and how this can be exploited to effect repair, whilst also giving us insights into how stem cells grafted in the chronic neurodegenerative and/or aged brain (as opposed to the normal young brain) will behave. So far this work has shown that adult neurogenesis is abnormal in the HD and PD brain and that in part this relates to changes in diffusely projecting neurotransmitter systems and as such may be amenable to drug therapy and environmental manipulation.

Key Publications Brons IGM, Smithers LE., Trotter M., Rugg-Gunn P., Chuva de Sousa Lopes SM., Howlett SK., Clarkson A., Ahrlund-Richter L., Pedersen RA., Vallier L. (2007). Derivation of pluripotent Epiblast Stem Cells from pluripotent embryos Nature. 12;448(7150):191-5. PMID:17597762 Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang – Doran I, Ahrlund- Richter L, Skepper J, Griffin J, Semple R, Weber A, Lomas DA, Vallier L. (2010) Modelling inherited metabolic disorders of the liver with human induced pluripotent stem cells. Journal of Clinical Investigations. J Clin Invest. 2010 Sep 1;120(9):3127 -36. PMID:20739751 Chng ZZ, Teo A, Pedersen R*, Vallier L*(2010) SIP1 mediates cell fate decisions between neuroectoderm and mesendoderm in human embryonic pluripotent stem cells. Cell Stem Cell. 6(1). 59-70 * joint authorship. PMID:20074535

Ludovic Vallier Ludovic graduated in Molecular biology and Immunology from the University Claude Bernard Lyon I in 1997. In 2001, he earned his PhD at Ecole Normale Superieur of Lyon in the group of Jacques Samarut, under the supervision of Pierre Savatier, studying mechanisms that control the cell cycle in mouse embryonic stem (ES) cells. Following a year in the biotechnology industry, Ludovic joined Professor Pedersen's group at the University of Cambridge Department of Surgery . In 2008 he joined the newly opened Anne McLaren Laboratory for Regenerative Medicine (LRM) as a Principal Investigator. Ludovic is now Reader in Stem Cells and Regenerative Medicine and member of the Cambridge Stem Cell Institute. He is also the director of the Cambridge National Institute for Health Research (NIHR)/Biomedical Research Centre HiPSC (human induced pluripotent stem cell) core facility.

Funding Wellcome Trust MRC BHF

Group Members Stephanie Brown Nicholas Hannan Siim Pauklin Mina Brimpari Sheik Tamir Rashid Candy Cho Imbisaat Geti Fiona Doherty Foad Rouhani Charis-Patricia Segeritz Neil Singh 27

Bronchioalveolar cellular and molecular hierarchy in homeostasis and disease

Juan-Jose Ventura Juan started his PhD studies in Molecular Biology at the University Complutense of Madrid focusinghis work on the role of inflammatory signals in liver development. Following his interest in MAPKs, he moves to Roger Davis group at the HHMI/UmassMed school in Worcester, MA. After that period, Juan moved back to Madrid with a Ramon y Cajal contract to work at the CNIO with Angel Nebreda. In this group, they uncover a novel role for the p38a/MAPK in lung homeostasis and cancer. Juanâ&#x20AC;&#x2122;s growing interest in this topic led him to become a PI and start his own group at the newly established CSCR in the University of Cambridge. He has been trying to study the insights of lung bronchioalveolar regulation since then.

The Ventura lab is interested in deciphering the ways used by the lung to replenish its damaged tissue in normal conditions and how that can go wrong in disease, and especially in lung cancer. Using animal models and human samples we are trying to determine the existence of specific groups of cells with a potential to differentiate and regenerate any other cell types that can have died, allowing the maintenance of lung functionality. Defining molecules that specifically can be targeted for distinct populations will allow the tracking, isolation, study and potential use as cellular therapy to regenerate damaged areas. Knowing the intracellular mechanisms involved in regulating when those progenitors should differentiate and into what cell type will be essential to understand the process of regeneration and any possible used in the clinic. We have uncovered some molecular targets that target progenitor populations with diverse differentiation potential and mechanisms involved in maintaining the proper process of regeneration. Failure of the mechanisms regulating these cell populations results in lung diseases as lung fibrosis or cancer. Combining in vivo experiments with the optimization of lab methods we are increasing our knowledge on lung physiology and the possibility to manipulate it to combat disease.

Lineage tracing of Lrig1 cells after bronchiolar injury

Funding MRC CRUK EMBO Herchel-Smith

Key Publications F. Oeztuerk-Winder, A. Guinot, A. Ochalek and J-J. Ventura. Corresponding author..Regulation of Human Lung Alveolar multipotent cells by a novel p38a MAPK/miR-17-92 axis. EMBO J. 2012 Jul 24;31(16):3431-41. doi: 10.1038/emboj.2012.192. Epub 2012 Jul 24. PMID::22828869 F. Oeztuerk-Winder and J-J. Ventura. Corresponding author. The many faces of p38 mitogen-activated protein kinase in progenitor/ stem cell differentiation. REVIEW. Biochem J. 445(2012), 1-10. PMID: 22702973

Group Members

J-J. Ventura, S. Tenbaum, E. Perdiguero, C. Guerra, M. Barbacid, M. Pasparakis, and AR. Nebreda. Corresponding author Essential role of p38Îą MAP kinase in lung stem/progenitor cell proliferation and differentiation: implications for tumorigenesis Nat Genetics. 39 (2007). 750-58. Epub 2007 Apr 29. DOI.10.1038/ng2037. PMID: 17468755

Feride Oeztuerk-Winder Anna Guinot Josue Ruiz Medina

Stem cell subversion and bone marrow failure syndromes Our long-term goal is to elucidate the molecular mechanisms of ribosome assembly and to understand how defects in this process subvert haematopoietic stem cell function to cause bone marrow failure and leukaemia predisposition. Assembly of the two subunits of the ribosome is an essential, conserved process involving around 200 assembly factors. A major bottleneck in understanding the mechanism of ribosome synthesis is to elucidate the precise function of each of the assembly factors. This represents not only a fundamental biological problem, but it is also important in oncology as a novel class of human cancer predisposition disorder has recently emerged that is caused by mutations in components of the ribosome assembly pathway. In particular, we discovered that the SBDS gene that is mutated in the leukaemia predisposition disorder ShwachmanDiamond syndrome (SDS) has a key conserved role in maturation of the large ribosomal subunit. This is the first convincing demonstration of a human cancer predisposition disorder that is caused by deficiency of a ribosome assembly factor. More recently, mutations in ribosomal proteins have also been identified in sporadic acute lymphoblastic leukaemia. Novel insights into the mechanisms of ribosome assembly are potentially exploitable for cancer drug discovery. Thus, small molecules that activate p53 by perturbing ribosome synthesis are currently in clinical trials for the treatment of a number of haematological malignancies.

Solution NMR structure of the human SBDS protein with disease-associated mutations indicated in red (modify stability) and blue (modify surface epitopes).

Key Publications Wong CC, Traynor D, Basse N, Kay RR, Warren AJ. (2011), Blood Defective ribosome assembly in Shwachman-Diamond syndrome. Plenary Paper. Published online before print July 29, 2011, doi: 10.1182/blood-2011-06-353938. PMID: 21803848 Finch AJ, Hilcenko C, Basse N, Drynan LF, Goyenechea B, Menne TF, González Fernández Á, Simpson P, D’Santos CS, Arends MJ, Donadieu J, Bellanné-Chantelot C, Costanzo M, Boone C, McKenzie AN, Freund SM, Warren AJ. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes and Development (2011) 25: 917-929. PMID: 21536732 Menne TM, Goyenechea B, Sánchez-Puig N, Wong CC, Tonkin LM, Ancliff P, Brost RL, Costanzo M, Boone C and Warren AJ. The Shwachman-Bodian-Diamond syndrome protein mediates translational activation of ribosomes in yeast. Nature Genetics (2007) 39: 486-95 PMID: 17353896

Alan Warren Alan Warren obtained his undergraduate degrees in Biochemistry (1983) and Medicine (1986) at the University of Glasgow. He completed his PhD in Molecular Biology in 1995 in the laboratory of Dr. Terry Rabbitts at the MRC Laboratory of Molecular Biology where he discovered that the LIM-only protein Lmo2 is required for haematopoiesis. He subsequently elucidated the DNA binding mechanism of the AML1CBFβ transcription factor using Xray crystallography. More recently, his lab has made the surprising discovery that the inherited leukaemia predisposition disorder Shwachman-Diamond syndrome is a “ribosomopathy” that is caused by impaired maturation of the large ribosomal subunit. This work has provided fundamental new insight into the process of ribosome assembly and has stimulated a new field addressing how defective ribosome biogenesis subverts haematopoietic stem cell function to cause bone marrow failure and cancer predisposition. He is currently Professor of Haematology at the University of Cambridge, UK. Funding Wellcome Trust MRC Leukaemia and Lymphoma Research NIHR Ted’s Gang

Group Members Mark Churcher Tobias Fleischmann Christine Hilcenko Shengjiang Tan Félix Weis

Epidermal Stem Cell Biology The lab studies the stem cells of adult mammalian epidermis, the outer covering of the skin. The epidermis is a highly tractable system in which to study the properties of adult stem cells in normal tissue homeostasis and in disease.

Fiona Watt Fiona Watt obtained her DPhil from Oxford University and was a postdoc at M.I.T. She initially established a laboratory at the Kennedy Institute in London and then moved to the Cancer Research UK (CR-UK) London Research Institute (formerly known as the Imperial Cancer Research Fund). She is now the Herchel Smith Professor of Molecular Genetics at the University of Cambridge. She is Deputy Director of the Wellcome Trust Centre for Stem Cell Research and Deputy Director of the CR-UK Cambridge Research Institute. She is a member of EMBO, a fellow of the Academy of Medical Sciences and a fellow of the Royal Society. She will be moving to Kings College London in 2012.

The epidermis is maintained throughout adult life by stem cells, which self-renew and produce progeny that undergo terminal differentiation along the lineages of the hair follicles (HF), sebaceous glands (SG) and interfollicular epidermis (IFE). Several different stem cell populations have now been identified in the IFE, sebaceous gland and hair follicle. Stem cells in each location are functionally interconvertible, but normally give rise to a more restricted repertoire of differentiated cells because of local microenvironmental cues. We are investigating the following questions: 1. What is the relationship between different epidermal stem cell populations? 2. What are the microenvironmental cues that regulate whether a stem cell will self-renew or initiate terminal differentiation? 3. What are the signalling pathways that regulate differentiation along the different epidermal lineages?

Micro-epidermis: controlling epidermal stem cells differentiation and segregation using ECM microarrays

Funding Wellcome Trust MRC EC

Key Publications Jensen, K.B., Collins, C.A., Nascimento, E., Tan, D.W., Frye, M., Itami, S. and Watt, F.M. (2009) Lrig1 expression defines a distinct multipotent stem cell population in mammalian epidermis. Cell Stem Cell 4: 427439 PMID: 19427292 Fujiwara H, Ferreira M, Donati G, Marciano DK, Linton JM, Sato Y, Hartner A, Sekiguchi K, Reichardt LF, Watt FM. The basement membrane of hair follicle stem cells is a muscle cell niche. Cell. 2011. 144: 577-589. PMID: 21335239

Group Members Mariya Chhatriwala Denny Cottle Ryan Driskell Celine Gomez Emma Heath Victoria Highland Kai Kretzschmar Marta Lesko Kif Liakthali Beate Lichtenberger Elizabeth MacRae Maria Mastrogiannaki Fabian Oceguera-Yanez Wesley Chua Grace Kaushal Pawel Schweiger Betina Wingreen Jensen - PA

Connelly, J.T., Gautrot, J.E., Trappmann, B., Tan, D.W.-M., Donati, G., Huck, W.T.S. and Watt, F.M. (2010) Actin and serum response factor transduce physical cues from the microenvironment to regulate epidermal stem cell fate decisions. Nat. Cell Biol. 12:711-718 PMID: 20581838

Epigenetic Regulation and Cell Identity Control For successful development, the information stored in the genome needs to be precisely regulated. During differentiation, each individual cell uses an ever-changing repertoire of epigenetic mechanisms to achieve proper control of gene expression. Our research focuses on understanding how the cell nucleus specifies the identities of the different cell types in the body, and how changes of cell identity are regulated in development. Our groupâ&#x20AC;&#x2122;s interest is in nuclear mechanisms that regulate changes of cellular identity during stem cell differentiation and specify the diverse cell types of the body. Previously, we have used the mammalian dosage compensation process, X inactivation, as an experimentally tractable system for studying the developmentally regulated establishment of silent chromatin. This has put us in a position to apply previously generated tools for studying aspects in stem cell biology.

Separation of epigenetic modifications and gene silencing

Anton Wutz Anton Wutz received his PhD from the Technical University of Graz in 1997 based on his work performed at the Research Institute of Molecular Pathology in Vienna, Austria. After postdoctoral work with Rudolf Jaenisch at the Whitehead Institute for Biomedical Research in Cambridge (USA) he joined the Research Institute of Molecular Pathology as a group leader in 2001. In 2009 he moved to the Wellcome Trust Centre for Stem Cell Research at the University of Cambridge. His research activities focus on nuclear mechanisms that regulate changes of cellular identity during stem cell differentiation and specify the diverse cell types of the body. His laboratory has also contributed to the development of genetic strategies for studying mammalian pathways. Anton is leaving for Institute of Molecular Health Sciences in Zurich in 2012.

Key Publications

Funding

Leeb, M., Walker, R., Mansfield, B., Nichols, J., Smith, A., Wutz, A. (2012) Germline potential of parthenogenetic haploid mouse embryonic stem cells. Development 139(18):3301-5. PMID: 22912412

Wellcome Trust

Leeb, M., Wutz, A. (2011) Derivation of haploid embryonic stem cells from mouse embryos. Nature 479(7371):131-134. PMID: 21900896 Ohhata, T., Senner, C., Hemberger, M., Wutz, A. (2011) Lineagespecific function of the noncoding Tsix RNA for Xist repression and Xi reactivation in mice. Genes Dev 25(16):1702-1715. PMID: 21852535

Group Members Asun Monfort Masaaki Oda Agata Kurowski Andreas Lackner Deborah McGee

Advanced Vector Design and Recombineering

Katharina Boroviak

Recombineering (recombination-mediated genetic engineering) enables fast and efficient construction of vectors for subsequent manipulation of mouse genomes. It is based on homologous recombination which is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks. As this technology is based on homologous recombination it is incredibly versatile and can be used to create vectors for protein tagging (N or C terminal), reporters, knock-in and (conditional) knockout. Our BAC recombineering system is based on Gateway (Invitrogen) and thus provides great flexibility due to its modularity. It also avoids the amplification of the reporter construct by PCR and is therefore less prone to the introduction of mutations. Services The Advanced Vector Design and Recombineering Facility provides Institute scientists with the following services:     

BAC recombineering TALENs CRISPRs Vector design for recombinant protein production Help and advice for PhD students and PostDocs when designing and cloning the vectors for their projects

The following services are currently being established:  Transposon mediated BAC-transgenesis

Staff Katharina Boroviak 32

Bioinformatics

Sabine Dietmann & Patrick Lombard

Hierarchical clustering of genomic regions bound by pluripotency regulators

Bioinformatics is an interdisciplinary field which addresses biological questions with computational and statistical methods. A major activity in bioinformatics is to develop and adapt software tools to generate useful biological knowledge in close collaboration with experimentalists. Bioinformatics has become an integral part of many research projects in stem cell biology. It plays a role in the analysis and interpretation of gene and protein expression and regulation. It aids in sequencing and annotating transcription and chromatin factor binding sites and epigenetic profiles. It plays a role in the textual mining of biological literature and the development of biological and gene ontologies to organize and query biological data. Bioinformatics tools aid in the comparison of genetic and genomic data and more generally in the understanding of evolutionary aspects of molecular biology. At a more integrative level, it helps analyze and catalogue the biological pathways and networks that are an important part of systems biology. In structural biology, it aids in the simulation and modeling of DNA, RNA, and protein structures as well as molecular interactions. Services and Equipment Computational resources comprise an integrated storage and computing infrastructure, with additional access to wider University computing facilities. The facility provides terabyte-level distributed data storage with reciprocal back-up of information stored at different sites, a secure data-exchange and online results display facility, and server-based multi-core computing facilities for use by core bioinformaticians. Data-handling and downstream analyses are implemented via the combination of custom and thirdparty, open-source and commercial software. The provision of licenses for popular commercial bioinformatics software to SCI members is in development. Training Training for experimentalists is provided in PERL scripting, R/Bioconductor statistical computing and applications of open-source software platforms, such as Galaxy. Staff

Transcription factor network for PGC specification

Sabine Dietmann Lila Diamante Patrick Lombard

Flow Cytometry

Andy Riddell

Flow cytometry is a laser-based, biophysical technology employed in cell counting, cell sorting, biomarker detection and protein engineering, by suspending cells in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and chemical characteristics of thousands of particles every second. Flow cytometry is routinely used in the diagnosis of health disorders but has many other applications in basic research, clinical practice and clinical trials. A common variation is to physically sort particles based on their properties, so as to purify populations of interest. Services We have a multi-site facility comprising of expert-led highspeed cell sorters and self-use sorter/analyser equipment. Our services include sorting, assay design and training. Equipment Sorters: Beckman Coulter MoFlo 3 laser system with up to 12 parameters. BioRad S3 Bench to sorter with 2 lasers and 7 parameters. A BD Aria IIu sorter with 3 lasers and up to 12 parameters. Analysers: A BD Fortessa with 4 lasers and 20 parameters. A Beckman Coulter CyAn with 3 lasers and 10 parameters Training Training is given on the systems by request.

Staff Andy Riddell 34

Histology

Peter Humphreys and Helen Skelton

Histology is the study of the microscopic anatomy of cells and tissue. It is commonly performed by examining cells and tissues by sectioning and staining, followed by examination under a light microscope or electron microscope. Histological studies may be conducted via tissue culture, where live cells can be isolated and maintained in a proper environment outside the body. The ability to visualize or differentially identify microscopic structures is frequently enhanced through the use of histological stains. Services Our histology facility provides a service for paraffin processing and embedding of fixed samples, paraffin section cutting and cryostat sectioning of samples frozen in OCT blocks. Routine haematoxylin and eosin staining of slides is also available, together with staining slides by H&E. Equipment The facility is well equipped with a Leica tissue processor and embedding centre and two rotary microtomes for paraffin work, cryostat is available for frozen section work. There is a Leica Autostainer for H&E staining or dewaxing paraffin sections prior to other methods, and a microwave for antigen retrieval techniques. A Ventana Benchmark IHC stainer is also available. Training Training is available for all SCI members in cryosectioning and microtomy.

Preparation of Tissue micro arrays using Beecher MTA-1

Staff Peter Humphreys Helen Skelton 35

Imaging

Peter Humphreys

Our advanced multi-user imaging facility provides SCI members with resources including confocal microscopy, live cell imaging, high content screening and colony analysis, image analysis and reconstruction. Equipment Leica SP5 Confocal Microscopes  Andor Revolution XD Spinning Disk Confocal microscope  Leica Matrix High Content screening/live cell imaging microscope  Nikon Biostation IM  Essen Incucyte HD  Zeiss Imager structured illumination & transmitted light (H&E)  Tissue Culture Microscopes & research grade fluorescence microscopes.  Fluorescence Correlation Spectroscopy/ lifetime imaging Training Expert advice, assistance and training are able for the following:  All aspects of imaging for researchers  Image analysis and custom analysis tools  Processing of image volumes (deconvolution, 3D reconstruction)  Creation of figures for publication

Cell Tracking

Live cell timelapse

Data Analysis  Workstations for 3d Reconstruction, volumetric measurement and analysis.  High content analysis and cell tracking. Image analysis

Colony analysis Staff Peter Humphreys 3D reconstruction 36

Next Generation Sequencing Libraries

Maike Paramor

This facility provides the preparation of DNA/RNA libraries for Next Generation Sequencing (NGS) projects to support SCI scientists. In recent years, the demand for high throughput sequencing methods has increased rapidly in the field of stem cell research. However, the technical challenge of library production is often daunting and time-consuming, and forms the major bottleneck for many projects. To accommodate this, the Institute has created a state-of-theart facility which produces NGS libraries on demand. This facility provides a fast turnaround for standard library preparation. Moreover, individual and non-standard methods are being developed as well. We strive to provide a local and flexible service to anybody within the Institute. Services  Help and advice with project planning  Transcriptome/RNA-seq libraries  Small RNA libraries  ChIP-seq libraries  DNA/amplicon libraries  individual projects and non-established methods will be considered Moreover, we offer the use of our Covaris for shearing of DNA/ RNA samples or chromatin samples. Training can be provided on request. Sequencing The sequencing itself is not done in-house. However, we are soon providing direct access to use the Illumina HiSeq sequencer in the CRI here in Cambridge. Access to a MiSeq and a Roche 454 is provided by the Biochemistry DNA sequencing facility. Currently available preparations/kits:  Illumina small RNA library kit  Nextflex directional RNA seq kit (Illumina)  Nextflex adapters for multiplexing up to 24 samples (Illumina)  NEBNext reagents for standard Illumina  DNA libraries and ChIP libraries  Covaris S2 instrument for DNA/RNA shearing and chromatin shearing Staff Maike Paramor 37

Tissue Culture

Sally Lees and Emma Harkness

Tissue culture is the growth in an artificial medium of cells derived from living tissue. This is typically facilitated via the use of a liquid, semi-solid, or solid growth medium, such as broth or agar allowing cells to be grown on petri dishes. Tissue culture is an important tool for the study of the biology of cells enabling stem cells to be cultured, manipulated and assessed in an in-vitro state. Our facility includes fully managed designated primary, derivation and cell culture rooms. Services Cell banks: Cell banks of WT Mefs, DS red Mefs and DR4 Mefs are produced for use as feeder cells. Banks of other popular cell lines such as HEK293, 293FT, Cos-7 and E14 cells are also available Growth factors/proteins: Quality assured proteins that are produced within the University are available at a fraction of commercial products are provided. These include growth factors such as mLIF, huLIF, FGF2, actavin, and BMP4

Stem cell colonies on a six well plate

Serum: Variation in the quality of serum and itâ&#x20AC;&#x2122;s suitability for particular applications in cell culture can have a dramatic effect on experiments. To ensure this variability is kept to a minimum all serum is batch tested and large stocks held to provide consistency in the cell culture, so making the results obtained more consistent. Mycoplasma Screening: Mycoplasma infections may induce cellular changes, including chromosome aberrations, changes in metabolism and cell growth, having a huge detrimental effect on research. All laboratories and cell lines are routinely screened to ensure the Institute remains mycoplasma free. Quality assurance: Variation in batches of reagents, specifically those used in serum free media can have major impact on the down stream processing of differentiation assays and cell culture, assays that can take several months to perform. To reduce this impact reagents are subjected to a barrage of assays to determine there suitability for the culture of cells and application in specific assays.

MEFs

Training As cell culture is a fundamental skill used by all scientists working with stem cells, training is available to all staff to ensure they have a solid foundation in cell and ES culture. Staff Sally Lees Emma Harkness Kathryn Cook

Chromosome spread 38

Other Resources Research Resources, Facilities and Equipment The Stem Cell Institute has invested in a platform of core facilities providing its members with access to the requisite equipment including the latest technologies and specialist expertise. These cutting-edge facilities enhance research and training and enable investigators to perform pilot studies at the forefront of current research. Cambridge Biomedical Centre (BRC) hIPSCs core facility The Cambridge Biomedical Centre (BRC) hIPSCs core facility was created in 2009 to promote the clinical applications of human Induced Pluripotent Stem Cells (hIPSCs) and to answer the increasing need for deriving new lines for disease modelling in vitro. During the past two years, this platform, unique in Europe, has derived and characterised more the 400 hIPSC lines from 70 patients suffering from neurodegenerative diseases, cardiovascular syndromes, metabolic and blood disorders. These projects have been directed by clinicians associated with diverse departments of University of Cambridge, including Neurosciences, Metabolic Science, Cardiovascular Medicine, Haematology, Surgery and Hepatology/Thoracic Medicine. The main objective of this platform is the production of hIPSC lines on demand for the development of in vitro models of disease, compatible with drug development and basic mechanistic studies. In addition, a growing activity of the BRC hIPSCs core facility will be in training clinicians and basic scientists to derive, grow and differentiate hIPSC lines. Located in the Anne McLaren Laboratory for Regenerative Medicine (LRM), the BRC hIPSC core facility benefits from state of the art environment for stem cell research and also from the broad expertise of research groups on the Addenbrookes Biomedical Campus.

Administration and Support Services The SCI administrative and support staff run the day to day operations of the Institute. They support the scientists in activities including IT, HR, finance/ grants, building and equipment maintenance, PhD programme, cleaning, glass washing and organizing conferences and public engagement. The team is led by the Institute Administrator, Lynn Kennedy. General Administration Institute Administrator: Lynn Kennedy Principal Assistant: Mark Hammond SCI Coordinator: Jenny Nelder Senior Clerical Assistant: Jo Jack Principal Sec./Austin Smithâ&#x20AC;&#x2122;s PA: Genevieve Blais Administrative Assistant (HR): Edita Paralova Receptionist: Klara Cichovska Finance Team Senior Grants/Accounts Clerk: Louise Carter Accounts Clerk: Thomas Jeffrey Accounts Clerk: Laura Spong IT Facility Computer Officer: Paul Sumption Computing Technician: Paul Barrow Building Maintenance Team Snr. Chief Building Services Tech.: Alistair Finlayson Chief Building Services Technician: Paul Vaes Custodian: Jim Bagstaff Assistant: Andrew Ayling Cleaner: Roy Pelegrin Cleaner: Amjadali Khan Glasswash and media Technicians 39

Affiliate Members University-based Principal Investigators whose research is partly concerned with stem cell biology and who have collaborations with SCI members or associate members. In addition to established researchers, affiliate status is open to junior investigators with independent funding who have emerging programmes in stem cell biology or translation. Affiliate Members have access for collaborative studies to SCI core platforms that are not available in their host department/ institute. Affiliate Members are eligible to be a partner in seed-funding projects and to be supervisors or co-supervisors on the 4-year PhD programme. Affiliate Members may also apply to enroll students in the PhD Programme discussion series which provides critical exposure to a broad range of mammalian stem cell biology. Affiliate Members and their lab members are encouraged to participate in most seminars and networking activities of SCI.

Professor Anne Ferguson -Smith Stem cells and the epigenetic programme

Dr Cedric Ghevaert In vitro production of platelets for transfusion in humans from pluripotent stem cells

Dr Anna Philpott Co-ordination of proliferation and differentiation in stem and progenitor cells

Professor Keith Martin Neuroprotection and repair of the visual system

Dr Sanjay Sinha Regulation of vascular smooth muscle cell development and disease

Professor Alfonso Martinez-Arias The structure and function of living matter

Professor Christine Watson Stem cell and lineage determining factors in mammary glands

Associate Members Principal Investigators with a major interest in stem cell research who are based outside the University in research institutes such as the Wellcome Trust Sanger Institute, the Babraham Institute, the CRUK Cambridge Research Institute or the European Bioinformatics Institute Associate status recognises ongoing contributions to the stem cell community and interactions with Universitybased stem cell investigators. Associate Members have access to any SCI core platforms that are not available in their own institute. Associate Members are eligible to be partners in seed-funding projects and can be cosupervisors of students on the Stem Cell PhD programme. They may also apply to enroll students in the PhD Programme discussion series which provides critical exposure to a broad range of mammalian stem cell biology. Associate Members and their lab members are encouraged to participate in all seminars and networking activities of SCI including the annual retreat.

Dr Paul Bertone Stem Cell Transcriptomics

Dr Pentao Liu Human iPS Cells

Professor Allan Bradley Genome Engineering

Dr Myriam Hemberger Trophoblast Stem Cells

Dr Peter Rugg-Gunn Stem Cell Research

Professor Wolf Reik Epigenetics

Dr John Stingl Mammary Stem Cells

Dr Doug Winton Intestinal Stem Cels

Dr Phil Jones Epidermal Stem Cells

Dr Bill Skarnes ES Cells

Committees Steering Committee

Austin Smith Institute Director Chair

Robin Franklin Theme Leader: Neural

Michaela Frye Theme Leader: Epithelial

Tony Green Theme Leader: Haematopoiesis

Brian Hendrich Postgraduate Training Director

Katrin Ottersbach Junior Group Leader

Ben Simons Physical Sciences

Azim Surani Theme Leader: Pluripotency

Lynn Kennedy Institute Administrator

Jenny Nelder SCI Coordinator

International Scientific Advisory Board

Professor Janet Rossant Chair The Hospital for Sick Children, University of Toronto

Prof Cédric Blanpain Université Libre de Bruxelles

Prof Maarten van Lohuizen The Netherlands Cancer Institute

Dr Meinrad Busslinger Vienna Biocenter

Dr Ruth McKernan King’s College, London and Pfizer

Dr Shin-Ichi Nishikawa

Prof David Rowitch UCSF Children’s Hospital 42

Funding 2012 SCI Budget The Institute is funded by the University of Cambridge and also a core grant from the Wellcome Trust and Medical Research Council. In addition to this funding researchers secure individual research grants from a variety of funding sources. Research Grant Funding

Student Funding

Excludes University and Wellcome Trust/MRC Core Funding

Funding Bodies and Sponsors The Stem Cell Institute would like to thank the following organisations for their continuing support.

Highlights of 2012 New Stem Cell Institute

Two of the UK’s largest funders of medical research invested £8 million in establishing the Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute (SCI). The aim is to create a worldleading centre for stem cell biology and medicine. The SCI was officially established on 1 July 2012, succeeding the former Wellcome Trust Centre for Stem Cell Biology and the MRC Centre for Regenerative Medicine. It unites 25 leading research teams with expertise across the three main types of stem cell: embryonic, adult and induced pluripotent cells with the aim of advancing our understanding of stem cells and their potential to treat a range of life-threatening conditions that currently have no effective cures.

New Group Leader

Dr Bon-Kyoung Koo will develop a molecular genetics programme centred on signalling in intestinal stem cells. Dr Koo will join the SCI in April 2013.

Wellcome Trust Senior Investigators Award

Public Engagement

Members of the Stem Cell Institute took part in 4 separate Cambridge Science Festival events including “Stem Cells 2012: Racing into the future”.

Lundbeck Fellowship

Kim Jensen Ben Simons

How does a stem cell stand out from the crowd? 2nd Annual Cambridge Stem Cell Symposium “Stem Cells in Cancer”

New Group Leader

Dr Kevin Chalut will be working on the role of biomechanics in pluripotent stem cells.

CRUK Senior Fellowship

Michaela Frye

Organised by Michaela Frye and Juan Ventura. The meeting was over-subscribed and very well received by those who did attend.

Bronze Clinical Excellence Award

Keith Martin

How do seemingly identical early embryonic cells eventually give rise to all cell types present in an adult organism? We show how cells maintain subtle differences in gene expression amongst seemingly identical cells, and that this precise control of gene expression underpins the amazing differentiation capacity of stem cells. Reynolds N, Latos P, HynesAllen A, Loos R, Leaford D, O'Shaughnessy A, Mosaku O, Signolet J, Brennecke P, Kalkan T, Costello I, Humphreys P, Mansfield W, Nakagawa K, Strouboulis J, Behrens A, Bertone P, Hendrich B (2012). NuRD Suppresses Pluripotency Gene Expression to Promote Transcriptional Heterogeneity and Lineage Commitment. Cell Stem Cell 10: 583–594. 44

Tracing the fate of skin stem cells in maintenance and disease

To maintain epidermis, new cells must be generated to replace those shed daily from the surface of skin. This life-long turnover is supported by epidermal stem cells and their progeny. Despite intense interest, the identity of epidermal stem cells and their strategy for self-renewal has remained in question. By using genetic labelling techniques, researchers in Cambridge and Belgium have used statistical approaches to elucidate the identity and fate behaviour of stem cells. Following a parallel approach, the same group has traced the evolution of cells and their progeny in squamous skin tumours, providing a concrete experimental basis for the cancer stem cell paradigm. Mascre G, Dekoninck S, Drogat B, Youssef KK, Brohee S, Sotiropoulou PA, Simons BD, and Blanpain C (2012) Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489, 25762 Driessens G, Beck B, Caauwe A, Simons BD, and Blanpain C (2012) Defining the mode of tumour growth by clonal analysis. Nature 488, 527-30

Wellcome Trust Senior Research Fellowship in Basic Biomedical Science

The negative effects of ageing on brain regeneration are reversible

Brian Hendrich

Alzheimer’s disease in a dish

A problem for understanding Alzheimer’s disease is that we can't study the disease inside people's brains while they are alive. We have used human stem cells to make a test tube model of the early stages of Alzheimer’s disease in the type of nerve cells affected by the disease. We are using this system to work out how the disease starts and then spreads through the brain, and for testing possible drug treatments.

MRC Centenary Early Career Awards

Shi Y, Kirwan P, Smith J, Maclean G, Orkin SH, Livesey FJ (2012) A human stem cell model of early Alzheimer's disease pathology in down syndrome. Science Translational Medicine 4:124ra29

Emma Rawlins

Shi Y, Kirwan P, Smith J, Robinson HP, Livesey FJ (2012) Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nature Neuroscience 15:477–486.

One of the main inhibitor of tissue regeneration is the inescapable process of ageing. Nowhere is this truer than in the regeneration of the myelin sheaths that surround and insulate nerve fibres in the brain, which are lost during multiple sclerosis (MS). The early adulthood the brains own stem cells give rise to myelin forming cells with great efficiency. However, this ability is lost with ageing. The Franklin laboratory, in collaboration with the laboratory of Amy Wagers at the Harvard Stem Cell Institute, has demonstrated, however, that the brain stem cells are ageing mice can be made to regenerate myelin just as efficiently as in young mice. This means that medicines that promote myelin regeneration, which are being developed by the Franklin laboratory and others in SCI, will be effective throughout the duration of the disease, and thus pave the way for early clinical trails of regenerative medicines in MS. Ruckh JM, Zhao JW, Shadrach JL, van Wijngaarden P, Rao TN, Wagers AJ, Franklin RJ (2012) Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10:96-103

The Waddington Medal

Alfonso Martinez-Arias

2012 SCI International Symposium Stem Cells in Cancer Session 1 Sean Morrison Howard Hughes Medical Institute, US “Stem cell self-renewal mechanisms are hijacked by cancer cells” Maria Pia Cosma CRG, Spain “Wnt signaling and the reprogramming of cell fate to pluripotency” Ruggero de Maria Regina Elena National Cancer Institute, Italy “New preclinical models based on Cancer Stem Cells from solid tumors” Eduard Batlle IRB, Spain “From Colon Stem Cells to Colorectal Cancer” Anna Guinot University of Cambridge, UK “Role of lung specific microRNAs in p38a-dependent regulation of lung homeostasis and lung cancer”

Our second annual International Symposium attracted 115 participants from 14 countries. X posters were presented It was organised by Michaela Frye and Juan Ventura Opening Session The Merck KGaA Keynote Lecture by: Irving Weissman Stanford School of Medicine, USA “Normal and Neoplastic Stem Cells” Catherin Niemann University of Cologne – CMMC, Germany “Control of tumor plasticity and malignant progression but not tumor incidence in stem cell driven epidermal cancer” Edwin Hawkins Imperial College, UK “The role of asymmetric cell division in haematopoiesis, malignant stem cells and the function of haematopoietic lineage cells”

Michele Cioffi CNIO, Spain “Chemoresistance of pancreatic cancer stem cells is mediated by miR-17-92 family” Session 2 Anton Berns The Netherlands Cancer Institute, The Netherlands “Cells of origin of (non) small cell lung cancer” John Stingl Cancer Research UK – CRI, UK “Mammary stem and progenitor cells: Understanding the cellular context of breast cancer” Walid Khaled The Sanger Institute, UK “BCL11A: A Novel Breast Cancer Gene which Plays a Critical Role in Mammary Stem Cells and Suppresses p53” Patrizia Cammareri The Beatson Institute, UK “KRAS mutation expands the cell of origin of intestinal cancer to non stem cells

Our Stem Cell Symposium Series Session 3

Andreas Trumpp DKFZ & HI-STEM, Germany “Circulating Metastasis-Initiating Cells in Breast Cancer” Fiona Watt University of Cambridge & CRUK - CRI, UK “Contribution of stem cells and differentiated cells to development of tumours of multilayered epithelia” Pier G Pelicci European Institute of Oncology, Italy “Regulation of self renewal in Cancer Stem Cells” Ashley Hamilton London Research Institute, UK “Investigation into the cross-talk between AML cells and the bone marrow microenvironment” Jane Holland Max Delbrueck Center for Molecular Medicine, Germany “Wnt and Met Signaling Controls Self-renewal and Differentiation in Mammary Gland Cancer Stem Cells” Session 4 The EMBO Young Investigator Lecture by: Cedric Blanpain Université Libre de Bruxelles, Belgium “Cutaneous cancer stem cells” Thomas Brabletz University of Freiburg, Germany “microRNAs, EMT and Cancer Stem Cells” Matt Smalley Cardiff University, UK “Stem and progenitor cells as the origins of breast cancer subtypes” Tony Green University of Cambridge, UK “JAK/STAT signalling, stem cell subversion and myeloproliferative neoplasms” Alejandra Bruna Cancer Research UK – CRI, UK “TGFβ induces breast tumour initiating cells in claudinlow breast cancer using a NEDD9-Smad-SRF pathway” Steven Pollard University College London, UK “Epigenetic resetting of human glioblastoma cells leads to lineage specific reactivation of tumour suppressors”

Future

Conferences, Events and Seminars Stem Cell Club Seminar Series Date

Title

16/02/12

Fate switching enables progenitors to maintain and regenerate oesophageal Phil Jones epithelium Bioinformatic analysis of transcriptional control mechanisms in blood cells

21/03/13

12/04/12

17/05/12

19/06/12

12/07/12

11/10/12

Speaker(

The logistics of neurogenesis in the adult brain

Dr Anagha Joshi, CIMR, UK lias Kazanis

Role of Oct4 in the induction of pluripotency

Jose Silva

A functional Genomics Approach for identification of Tcf3 target genes in mouse embryonic stem cells

Graziano Martello

RNA methylation pathways and stem cell differentiation in adult tissues Cell-Surface Proteomics Identifies Lineage-Specific Markers of EmbryoDerived Stem Cells

Michaela Frye Peter Rugg-Gunn,

Defining a lineage hierarchy for fibroblasts in the mammalian skin

Ryan Driskell

Epigenetic regulation of adult muscle stem cell fate

Jenny Pell

Mammary stem and progenitor cells: Understanding the cellular context of breast cancer

John Stingl

Modelling vascular smooth muscle cell development and disease using human pluripotent stem cells Derivation and Characterization of haploid embryonic stem cells from mouse embryos

Sanjay Sinha

Modelling vascular biology and disease using patient specificstem and progenitor cells

Amer Rana

Role of DNA hydroxymethylation in reprogramming and stem cells Producing platelets for transfusion in humans from human iPSCs by a forward programming method

Gabriella Ficz CĂŠdric Ghevaert

Fine-tuning proliferation signals â&#x20AC;&#x201C; a requirement for tissue homeostasis Generation of functional organs from pluripotent stem cells Rebuilding pluripotency from primordial germ cells

Kim Jensen Hiromitsu Nakauchi, IMSUT, Japan Harry Leitch

The nature and liaisons of human lung bronchioalveolar stem cells

Juan-Jose Ventura,

Anton Wutz

Understanding the logic of signalling and transcriptional control in stem cell Kathy Niakan, differentiation

22/11/12

Exit from pluripotency is gated by intracellular redistribution of the bHLH Joerg Betschinger transcription factor Tfe3 Vertebrate appendage regeneration requires a return to an embryonic, oxi- Yaoyao Chen dative cellular state Cell Cycle Directs Differentiation of Human Pluripotent Cells Characterising the niche of emerging haematopoietic stem cells

Siim Pauklin Katrin Ottersbach

The Stem Cell Club Seminar series catering is kindly sponsored by:

Seminars by external speakers Date

Title

Speaker(s)

23/02/12

Axonal transport in motor neurons: from in vitro screens to real time in vivo assays Isolation, Clonal characterization and Hibernation of Hematopoietic Stem Cells

Giampietro Schiavo, London Research Institute Hiro Nakauchi

Identification of a novel stem / progenitor population within the adrenal gland The Insulin/IGF/Foxo signalling axis in epidermal morphogenesis and homeostasis

Roberto Bandiera, INSERM, France Carien Niessen, CMM, Germany

Functional integration of large ncRNAs in the circuitry controlling pluripotency and differentiation Molecular and Functional Characterisation of the human gastrula organiser

Mitchell Guttman, MIT/Harvard, USA Nadav Sharon, Silberman Institute

22/11/12

X chromosome inactivation and mammalian infertility

James Turner NIMR, UK

06/12/12

Relevant stem cell models for chemical screening in cancer and regenerative medicine Myelin development and disease

Davide Danovi, UCL, UK

24/05/12 24/07/12 04/10/12 18/10/12 22/10/12

11/12/12

David Rowitch-HHMI, USA

Internal Seminar Series The Stem Cell Institute also has a vibrant programme of internal seminars on a fortnightly basis where SCI members present seminars on their work.

Stem Cell Institute Conferences & Meetings Date

Title

9/07/12 26/09/12 10/12/12

2nd Annual Cambridge Stem Cell International Symposium: “Stem Cells in Cancer” Centre for Stem Cell Research Retreat SCI Retreat and International Scientific Advisory Board Meeting

Public Engagement Date

Title

12/03/12

Cambridge Science Festival: “Stem Cells: Racing into the Future”

The Stem Cell Institute also contributes to a large number of other public engagement events throughout the year which range from public talks to teaching in schools as well as radio broadcasts and tours of the Institute.

PhD Programme in Stem Cell Biology and Medicine The Institute offers a unique environment for high-level research training in stem cell biology. The University of Cambridge is exceptional in the depth and diversity of its research in this area, and has a dynamic and interactive research community that is ranked amongst the foremost in the world. Our PhD programme enables students to take full advantage of the strength and breadth of stem cell research available in Cambridge. Our studentships are funded from a variety of sources including the Wellcome Trust, MRC and CRUK. Additional studentships funded by other sponsors are regularly available within the Institute. We also welcome applications from selffunded students. Brian Hendrich, Postgraduate Training Director

The Wellcome Trust 4-Year PhD Programme The Wellcome Trust generously funds our highly competitive 4-Year PhD Programme in Stem Cell Biology and Medicine. The programme has been run annually since 2007 and provides students with an opportunity to spend time in three different labs during their first 'rotation' year before making a decision about where they would like to undertake their thesis work for years 2-4. In year one students receive practical research training through rotation projects; overviews of current basic and translational stem cell research through interactive critical discussion sessions and specialist workshops; and learn scientific writing via assessed rotation reports and a written PhD proposal. Students on this programme are awarded an MRes qualification at the end of this year. At the end of year one the students choose a supervisor and topic for their full PhD and spend the next three years embedded in that laboratory. Current 4-Year â&#x20AC;&#x2DC;Stem Cell Biologyâ&#x20AC;&#x2122; Programme Students 2009 Starters The programme is perfect for shaping future scientists and helping them find the exact research field they want to work in. Paulina Chilarska

Robert Fordham *

Hayley Frend

Nicola Love

Jason Signolet *

2010 Starters

Joana Flores

Moyra Lawrence

Ana Leal Cervantes

Victoria Moignard *

Hinal Tanna *

2011 Starters

Anne-Louise Miller

Martyna Popis

Jan Zylicz 2012 Starters

Agnieskza Wabik

Philipp Berg

Juergen Fink

Elena Itzsovich *

Moritz Matthey

Students funded by the MRC

Other Current SCI Students All PhD students in the Institute have the opportunity to participate in the critical discussion sessions with the Wellcome Trust students. The following students are funded from a variety of sources and are supervised by SCI members.

Sarah Ali Abdulla

Anna Guinot

Stoyana Alexendrova

Matthias Hofer

Carla Mulas

Yifan Ng

Shyamanga Borooah

Morteza Jalali

Daniel Ortmann

Lily Cho

Smruthi Jayasundar

Mahalia Page

Wesley Chua

Fatima Junaid

Matthias Pawlowski

Fiona Docherty

Kai Kretzschmar

Aliaksandra Radzisheuskaya

Tiago Faial

Ginez Gonzalez

Agata Kurowski

Victoria Mascetti

Abdulrahim Sajini

Rodrigo Santos

There are many highly motivated and inspiring scientists around and that makes the SCI an amazing place to be a student! Charis-Patricia Segeritz

Filipa Soares

Hannah Stuart

Stan Wang

SCI Student Events Annual PhD Day - SCI students present posters and give talks to all SCI members. PhD Seminar Series - A fortnightly seminar series where up to 3 students present their work to their peers 4-Year PhD Presentation Day - 4-year Wellcome Trust / MRC funded students present their work to fellow programme members and the PhD programme committee. Students also give regular presentations and receive feedback at other SCI group meetings. 51

2012 Publications Touboul, T., Hannan, NRF, Vallier L, Directed Differentiation of Pluripotent Stem Cells into Hepatic-Like Cells, Book Chapter: Human Stem Cell Manual, 2nd Edition: A Laboratory Guide, PMID:None Wray J, Kalkan T, Gomez-Lopez S, Eckardt D, Cook A, Kemler R, Smith A, Inhibition of glycogen synthase kinase-3 alleviates Tcf3 repression of the pluripotency network and increases embryonic stem cell resistance to differentiation., Nat Cell Biol. 2011 Jun 19;13(7):838-45. doi: 10.1038/ncb2267., PMID:21685889 Arwert EN, Mentink RA, Driskell RR, Hoste E, Goldie SJ, Quist S, Watt FM, Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation, Oncogene. 2012 Feb 23;31(8):9921000. doi: 10.1038/onc.2011.298, PMID:21765471 Juliandi B, Abematsu M, Sanosaka T, Tsujimura K, Smith A, Nakashima K, Induction of superficial cortical layer neurons from mouse embryonic stem cells by valproic acid, Neurosci Res. 2012 Jan;72(1):23-31. doi: 10.1016/ j.neures.2011.09.012, PMID:22001759 Grabarek JB, Zyzyńska K, Saiz N, Piliszek A, Frankenberg S, Nichols J, Hadjantonakis A-K, Plusa B, Differential plasticity of epiblast and primitive endoderm precursors within the ICM of the early mouse embryo, Development. 2012 Jan;139(1):129-39. doi: 10.1242, PMID:22096072 Driskell RR, Juneja VR, Connelly JT, Kretzschmar K, Tan DW-M, Watt FM, Clonal growth of dermal papilla cells in hydrogels reveals intrinsic differences between Sox2-positive and -Negative cells in vitro and in vivo, J Invest Dermatol. 2012 Apr;132(4):1084-93. doi: 10.1038/jid.2011.428, PMID:22189784 Trappmann B, Gautrot JE, Connelly JT, Strange DGT, Li Y, Oyen ML, Cohen Stuart MA, Boehm H, Li B, Vogel V, Spatz JP, Watt FM, Huck WTS, Extracellular-matrix tethering regulates stem-cell fate, Nat Mater. 2012 May 27;11(7):6429. doi: 10.1038/nmat3339., PMID:22635042 Ventura JJ, Oeztuerk-Winder F, isolation, culture and potentiality assessment of lung alveolar stem cells , Methods Mol Biol. 2012;916:23-30. doi: 10.1007/978-1-61779-980-8_3, PMID:22914930 Huang JK, Franklin RJ, Current status of myelin replacement therapies in multiple sclerosis., Prog Brain Res. 2012;201:219-31. doi: 10.1016/B978-0-444-59544-7.00011-1, PMID:23186717 Evans JR, Mason SL, Barker RA, Current status of clinical trials of neural transplantation in Parkinson's disease., Prog Brain Res. 2012;200:169-98. doi: 10.1016/B978-0-444-59575-1.00008-9., PMID:23195419 Bolton S, Hassall D, Hildebrand D, Brück W, Huang JK, Pluchino S, McKevitt T, Parry J, McFarlane M, Fagg R, Roulois A, Anti-inflammatory Disease Therapies: Challenges and Strategies in Drug Development., Toxicol Pathol January 2012 vol. 40 no. 1 122-125, PMID: None Dawson MA and Huntly BJP, The Pathogenesis, Diagnosis and Treatment of Polycythemia Vera., Neoplastic Diseases of the Blood, PMID: None Hannan NRF*, Rashid T. Vallier L., Regenerative Medicine, Stem Cells and the Liver, Book Chapter: Applying pluripotent stem cell technology to modelling human liver disease., PMID: None Muñoz Descalzo S, de Navascues J, Martinez-Arias A, Wnt/Notch signaling: an integrated mechanism regulating transitions between cell states, Bioessays. 2012 Feb;34(2):110-8. doi: 10.1002/bies.201100102, PMID:22215536 Trott J, Hayashi K, Surani A, Babu MM, Martinez-Arias A, Dissecting ensemble networks in ES cell populations reveals micro-heterogeneity underlying pluripotency., Mol Biosyst. 2012 Mar;8(3):744-52. doi: 10.1039/ c1mb05398a, PMID:22222461 Morey L, Pascual G, Cozzuto L, Roma G, Wutz A, Benitah SA, Di Croce L, Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells., Cell Stem Cell. 2012 Jan 6;10(1):47-62. doi: 10.1016/ j.stem.2011.12.006, PMID:22226355 Ruckh JM, Zhao J-W, Shadrach JL, Van Wijngaarden P, Rao TN, Wagers AJ, Franklin RJM, Rejuvenation of regeneration in the aging central nervous system, Cell Stem Cell. 2012 Jan 6;10(1):96-103. doi: 10.1016/ j.stem.2011.11.019., PMID:22226359 Cheung C, Bernardo AS, Trotter MW, Pedersen RA, Sinha S, Generation of human vascular smooth muscle subtypes provides insight into embryological origin-dependent disease susceptibility., Nat Biotechnol. 2012 Jan 15;30(2):165-73. doi: 10.1038/nbt.2107., PMID:22252507 Giangreco A, Lu L, Vickers C, Teixeira VH, Groot KR, Butler CR, Ilieva EV, George PJ, Nicholson AG, Sage EK, Watt FM, Janes SM, β-Catenin determines upper airway progenitor cell fate and preinvasive squamous lung cancer progression by modulating epithelial-mesenchymal transition, J Pathol. 2012 Mar;226(4):575-87. doi: 10.1002/ path.3962, PMID:22081448 Falk A, Koch P, Kesavan J, Takashima Y, Ladewig J, Alexander M, Wiskow O, Tailor J, Trotter M, Pollard S, Smith A, Brüstle O, Capture of neuroepithelial-like stem cells from pluripotent stem cells provides a versatile system for in vitro production of human neurons., PLoS One. 2012;7(1):e29597. doi: 10.1371/journal.pone.0029597, PMID:22272239 52

Chalut KJ, Ekpenyong AE, Clegg WL, Melhuish IC, Guck J, Quantifying cellular differentiation by physical phenotype using digital holographic microscopy., Integr Biol (Camb). 2012 Mar;4(3):280-4. doi: 10.1039/c2ib00129b, PMID:22262315 Kretzschmar K, Watt FM, Lineage Tracing, Cell, Volume 148, Issue 1, 33-45, PMID:22265400 Ber S, Lee C, Voiculescu O, Surani MA, Dedifferentiation of foetal CNS stem cells to mesendoderm-like cells through an EMT process., PLoS One. 2012;7(1):e30759. doi: 10.1371/journal.pone.0030759, PMID:22276221 Cusimano M, Biziato D, Brambilla E, Donega M, Alfaro-Cervello C, Snider S, Salani G, Pucci F, Comi G, GarciaVerdugo JM, De Palma M, Martino G, Pluchino S, Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord, Brain. 2012 Feb;135(Pt 2):447-60. doi: 10.1093/brain/ awr339, PMID:22271661 Chong SYC, Rosenberg SS, Fancy SPJ, Zhao C, Shen Y-AA, Hahn AT, McGee AW, Xu X, Zheng B, Zhang LI, Rowitch DH, Franklin RJM, Lu QR, Chan JR, Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination, Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1299-304. doi: 10.1073/ pnas.1113540109, PMID:22160722 Smith AM, Calero-Nieto FJ, Schütte J, Kinston S, Timms RT, Wilson NK, Hannah RL, Landry JR, Göttgens B, Integration of Elf-4 into stem/progenitor and erythroid regulatory networks through locus-wide chromatin studies coupled with in vivo functional validation, Mol Cell Biol. 2012 Feb;32(4):763-73. doi: 10.1128/MCB.05745-11, PMID:22158964 Giangreco A, Hoste E, Takai Y, Rosewell I, Watt FM, Epidermal Cadm1 expression promotes autoimmune alopecia via enhanced T cell adhesion and cytotoxicity., J Immunol. 2012 Feb 1;188(3):1514-22. doi: 10.4049/ jimmunol.1003342., PMID:22210910 Lindvall O, Barker RA, Brüstle O, Isacson O, Svendsen CN, Clinical translation of stem cells in neurodegenerative disorders, Cell Stem Cell, Volume 10, Issue 2, 151-155, 3 February 2012, PMID:22305565 Muñoz Descalzo S, Martinez Arias A, The structure of Wntch signalling and the resolution of transition states in development, Semin Cell Dev Biol. 2012 Jun;23(4):443-9. doi: 10.1016/j.semcdb.2012.01.012, PMID:22326376 Shi Y, Kirwan P, Smith J, Robinson HP, Livesey FJ, Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses., Nat Neurosci. 2012 Feb 5;15(3):477-86, S1. doi: 10.1038/nn.3041, PMID:22306606 Tavares L, Dimitrova E, Oxley D, Webster J, Poot R, Demmers J, Bezstarosti K, Taylor S, Ura H, Koide H, Wutz A, Vidal M, Elderkin S, Brockdorff N, RYBP-PRC1 complexes mediate H2A ubiquitylation at polycomb target sites independently of PRC2 and H3K27me3., Cell. 2012 Feb 17;148(4):664-78. doi: 10.1016/j.cell.2011.12.029, PMID:22325148 Rashid ST, Lomas DA, Stem cell-based therapy for α₁-antitrypsin deficiency., Stem Cell Res Ther. 2012 Feb 9;3(1):4. doi: 10.1186/scrt95., PMID:22340671 Cossetti C, Alfaro-Cervello C, Donegà M, Tyzack G, Pluchino S, New perspectives of tissue remodelling with neural stem and progenitor cell-based therapies., Cell Tissue Res. 2012 Jul;349(1):321-9. doi: 10.1007/s00441-012-1341-8, PMID:22322425 Schütte J, Moignard V, Göttgens B, Establishing the stem cell state: Insights from regulatory network analysis of blood stem cell development, Wiley Interdiscip Rev Syst Biol Med. 2012 May-Jun;4(3):285-95. doi: 10.1002/ wsbm.1163, PMID:22334489 Dryden NH, Sperone A, Martin-Almedina S, Hannah RL, Birdsey GM, Khan ST, Layhadi JA, Mason JC, Haskard DO, Göttgens B, Randi AM, The transcription factor Erg controls endothelial cell quiescence by repressing activity of nuclear factor (NF)-κB p65, J Biol Chem. 2012 Apr 6;287(15):12331-42. doi: 10.1074/jbc.M112.346791, PMID:22337883 Shi Y, Kirwan P, Smith J, MacLean G, Orkin SH, Livesey FJ, A human stem cell model of early Alzheimer's disease pathology in Down syndrome., Sci Transl Med. 2012 Mar 7;4(124):124ra29. doi: 10.1126/scitranslmed.3003771, PMID:22344463 Hammachi F, Morrison G, Sharov A, Livigni A, Narayan S, Papapetrou E, O'Malley J, Kaji K, Ko M, Ptashne M, Brickman J, Transcriptional Activation by Oct4 Is Sufficient for the Maintenance and Induction of Pluripotency., Cell Rep. 2012 Feb 23;1(2):99-109. doi: 10.1016/j.celrep.2011.12.002, PMID:22832160 Arwert EN, Hoste E, Watt FM, Epithelial stem cells, wound healing and cancer., Nat Rev Cancer. 2012 Feb 24;12 (3):170-80. doi: 10.1038/nrc3217, PMID:22362215 Chalancon G, Ravarani CNJ, Balaji S, Martinez-Arias A, Aravind L, Jothi R, Babu MM, Interplay between gene expression noise and regulatory network architecture, Trends Genet. 2012 May;28(5):221-32. doi: 10.1016/ j.tig.2012.01.006, PMID:22365642

2012 Publications continued Halley JD, Smith-Miles K, Winkler DA, Kalkan T, Huang S, Smith A, Self-organizing circuitry and emergent computation in mouse embryonic stem cells., Stem Cell Res. 2012 Mar;8(2):324-33. doi: 10.1016/j.scr.2011.11.001, PMID:22169460 Niakan KK, Han J, Pedersen RA, Simon C, Pera RA, Human pre-implantation embryo development., Development. 2012 Mar;139(5):829-41. doi: 10.1242/dev.060426., PMID:22318624 Yang VS, Carter SA, Ng Y, Hyland SJ, Tachibana-Konwalski K, Fisher RA, Sebire NJ, Seckl MJ, Pedersen RA, Laskey RA, Gonzalez MA, Distinct activities of the anaphase-promoting complex/cyclosome (APC/C) in mouse embryonic cells., Cell Cycle. 2012 Mar 1;11(5):846-55. doi: 10.4161/cc.11.5.19251, PMID:22333576 Follows GA, Ferreira R, Janes ME, Spensberger D, Cambuli F, Chaney AF, Kinston SJ, Landry JR, Green AR, Göttgens B, Mapping and functional characterisation of a CTCF-dependent insulator element at the 3' border of the murine Scl transcriptional domain., PLoS One. 2012;7(3):e31484. doi: 10.1371/journal.pone.0031484, PMID:22396734 Benz C, Copley MR, Kent DG, Wohrer S, Cortes A, Aghaeepour N, Ma E, Mader H, Rowe K, Day C, Treloar D, Brinkman RR, Eaves CJ, Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs, Cell Stem Cell. 2012 Mar 2;10(3):273-83. doi: 10.1016/j.stem.2012.02.007., PMID:22385655 Wong VW, Stange DE, Page ME, Buczacki S, Wabik A, Itami S, van de Wetering M, Poulsom R, Wright NA, Trotter MW, Watt FM, Winton DJ, Clevers H, Jensen KB, Lrig1 controls intestinal stem-cell homeostasis by negative regulation of ErbB signalling., Nat Cell Biol. 2012 Mar 4;14(4):401-8. doi: 10.1038/ncb2464, PMID:22388892 Adams D, Altucci L, Antonarakis SE, Ballesteros J, Beck S, Bird A, Bock C, Boehm B, Campo E, Caricasole A, Dahl F, Dermitzakis ET, Enver T, Esteller M, Estivill X, Ferguson-Smith A, Fitzgibbon J, Flicek P, Giehl C, Graf T, Grosveld F, Guigo R, Gut I, Helin K, Jarvius J, Küppers R, Lehrach H, Lengauer T, Lernmark Å, Leslie D, Loeffler M, Macintyre E, Mai A, Martens JH, Minucci S, Ouwehand WH, Pelicci PG, Pendeville H, Porse B, Rakyan V, Reik W, Schrappe M, Schübeler D, Seifert M, Siebert R, Simmons D, Soranzo N, Spicuglia S, Stratton M, Stunnenberg HG, Tanay A, Torrents D, Valencia A, Vellenga E, Vingron M, Walter J, Willcocks S, BLUEPRINT to decode the epigenetic signature written in blood., Nat Biotechnol. 2012 Mar 7;30(3):224-6, PMID:22398613 Hampton DW, Innes N, Merkler D, Zhao C, Franklin RJM, Chandran S, Focal immune-mediated white matter demyelination reveals an age-associated increase in axonal vulnerability and decreased remyelination efficiency, Am J Pathol. 2012 May;180(5):1897-905. doi: 10.1016/j.ajpath.2012.01.018, PMID:22426338 Messerschmidt DM, de Vries W, Ito M, Solter D, Ferguson-Smith A, Knowles BB, Trim28 is required for epigenetic stability during mouse oocyte to embryo transition., Science 23 March 2012: Vol. 335 no. 6075 pp. 1499-1502. PMID:22442485 Evans AL, Faial T, Gilchrist MJ, Down T, Vallier L, Pedersen RA, Wardle FC, Smith JC, Genomic targets of Brachyury (T) in differentiating mouse embryonic stem cells., PLoS One. 2012;7(3):e33346. doi: 10.1371/ journal.pone.0033346, PMID:22479388 Camnasio S, Carri AD, Lombardo A, Grad I, Mariotti C, Castucci A, Rozell B, Lo Riso P, Castiglioni V, Zuccato C, Rochon C, Takashima Y, Diaferia G, Biunno I, Gellera C, Jaconi M, Smith A, Hovatta O, Naldini L, Di Donato S, Feki A, Cattaneo E, The first reported generation of several induced pluripotent stem cell lines from homozygous and heterozygous Huntington's disease patients demonstrates mutation related enhanced lysosomal activity, Neurobiol Dis. 2012 Apr;46(1):41-51. doi: 10.1016/j.nbd.2011.12.042., PMID:22405424 Hindley C, Ali F, McDowell G, Cheng K, Jones A, Guillemot F, Philpott A., Post-translational modification of Ngn2 differentially affects transcription of distinct targets to regulate the balance between progenitor maintenance and differentiation, Development. 2012 May;139(10):1718-23. doi: 10.1242/dev.077552, PMID:22491944 Bull ND, Guidi A, Goedert M, Martin KR, Spillantini MG, Reduced axonal transport and increased excitotoxic retinal ganglion cell degeneration in mice transgenic for human mutant P301S tau., PLoS One. 2012;7(4):e34724. doi: 10.1371/journal.pone.0034724., PMID:22496848 Bull ND, Chidlow G, Wood JPM, Martin KR, Casson RJ, The mechanism of axonal degeneration after perikaryal excitotoxic injury to the retina, Exp Neurol. 2012 Jul;236(1):34-45. doi: 10.1016/j.expneurol.2012.03.021, PMID:22504112 Gillich A, Bao S, Grabole N, Hayashi K, Trotter MW, Pasque V, Magnúsdóttir E, Surani MA, Epiblast stem cell-based system reveals reprogramming synergy of germline factors., Cell Stem Cell. 2012 Apr 6;10(4):425-39. doi: 10.1016/ j.stem.2012.01.020., PMID:22482507 Latos PA, Helliwell C, Mosaku O, Dudzinska DA, Stubbs B, Berdasco M, Esteller M, Hendrich B, NuRD-dependent DNA methylation prevents ES cells from accessing a trophectoderm fate., Biol Open. 2012 Apr 15;1(4):341-52. doi: 10.1242/bio.2012513, PMID:23213424 Horton SJ, Huntly BJ, Recent advances in acute myeloid leukemia stem cell biology., Haematologica. 2012 Jul;97 (7):966-74. doi: 10.3324/haematol.2011.054734, PMID:22511496

Chhatriwala MK, Cipolat S, Sevilla LM, Nachat R, Watt FM, Exons 5-15 of kazrin are dispensable for murine epidermal morphogenesis and homeostasis., J Invest Dermatol. 2012 Aug;132(8):1977-87. doi: 10.1038/ jid.2012.110, PMID:22513779 Chen E, Staudt LM, Green AR, Janus kinase deregulation in leukemia and lymphoma., Immunity. 2012 Apr 20;36 (4):529-41. doi: 10.1016/j.immuni.2012.03.017, PMID:22520846 De Navascués J, Perdigoto CN, Bian Y, Schneider MH, Bardin AJ, Martínez-Arias A, Simons BD, Drosophila midgut homeostasis involves neutral competition between symmetrically dividing intestinal stem cells, EMBO J. 2012 May 30;31(11):2473-85. doi: 10.1038/emboj.2012.106., PMID:22522699 Tanaka Y, Joshi A, Wilson NK, Kinston S, Nishikawa S, Göttgens B, The transcriptional programme controlled by Runx1 during early embryonic blood development., Dev Biol. 2012 Jun 15;366(2):404-19. doi: 10.1016/ j.ydbio.2012.03.024, PMID:22554697 Höglinger GU, Barker RA, Hagg T, Arias-Carrión O, Caldwell MA, Hirsch EC, Quantitative evaluation of the human subventricular zone, Brain. 2012 Aug;135(Pt 8):e221, 1-4; author reply e222, 1-6. doi: 10.1093/brain/aws087, PMID:22539257 Gautrot JE, Wang C, Liu X, Goldie SJ, Trappmann B, Huck WTS, Watt FM, Mimicking normal tissue architecture and perturbation in cancer with engineered micro-epidermis, Biomaterials. 2012 Jul;33(21):5221-9. doi: 10.1016/ j.biomaterials.2012.04.009, PMID:22541538 Khan MA, Rafiq MA, Noor A, Hussain S, Flores JV, Rupp V, Vincent AK, Malli R, Ali G, Khan FS, Ishak GE, Doherty D, Weksberg R, Ayub M, Windpassinger C, Ibrahim S, Frye M, Ansar M, Vincent JB, Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal-Recessive Intellectual Disability, Am J Hum Genet. 2012 May 4;90 (5):856-63. doi: 10.1016/j.ajhg.2012.03.023, PMID:22541562 Marks H, Kalkan T, Menafra R, Denissov S, Jones K, Hofemeister H, Nichols J, Kranz A, Stewart AF, Smith A, Stunnenberg HG, The transcriptional and epigenomic foundations of ground state pluripotency., Cell. 2012 Apr 27;149(3):590-604. doi: 10.1016/j.cell.2012.03.026, PMID:22541430 Marsh JC, Bacigalupo A, Schrezenmeier H, Tichelli A, Risitano AM, Passweg JR, Killick SB, Warren AJ, Foukaneli T, Aljurf M, Al-Zahrani HA, Schafhausen P, Roth A, Franzke A, Brummendorf TH, Dufour C, Oneto R, Sedgwick P, Barrois A, Kordasti S, Elebute MO,, Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party, Blood. 2012 Jun 7;119(23):5391-6. doi: 10.1182/ blood-2012-02-407684, PMID:22544699 Torres J, Prieto J, Durupt FC, Broad S, Watt FM, Efficient differentiation of embryonic stem cells into mesodermal precursors by BMP, retinoic acid and Notch signalling., PLoS One. 2012;7(4):e36405. doi: 10.1371/ journal.pone.0036405, PMID:22558462 Cossetti C, Smith JA, Iraci N, Leonardi T, Alfaro-Cervello C, Pluchino S, Extracellular membrane vesicles and immune regulation in the brain., Front Physiol. 2012;3:117. doi: 10.3389/fphys.2012.00117, PMID:22557978 Lima MJ, Docherty HM, Chen Y, Vallier L, Docherty K, Pancreatic Transcription Factors Containing Protein Transduction Domains Drive Mouse Embryonic Stem Cells towards Endocrine Pancreas, PLoS One. 2012;7 (5):e36481. doi: 10.1371/journal.pone.0036481, PMID:22563503 Strogantsev R, Ferguson-Smith AC, Proteins involved in establishment and maintenance of imprinted methylation marks., Brief Funct Genomics. 2012 May;11(3):227-39. doi: 10.1093/bfgp/els018., PMID:22760206 Reynolds N, Latos P, Hynes-Allen A, Loos R, Leaford D, O'Shaughnessy A, Mosaku O, Signolet J, Brennecke P, Kalkan T, Costello I, Humphreys P, Mansfield W, Nakagawa K, Strouboulis J, Behrens A, Bertone P, Hendrich B, NuRD suppresses pluripotency gene expression to promote transcriptional heterogeneity and lineage commitment., Cell Stem Cell. 2012 May 4;10(5):583-94. doi: 10.1016/j.stem.2012.02.020., PMID:22560079 Goldie SJ, Mulder KW, Tan DW, Lyons SK, Sims AH, Watt FM, FRMD4A upregulation in human squamous cell carcinoma promotes tumor growth and metastasis and is associated with poor prognosis., Cancer Res. 2012 Jul 1;72(13):3424-36. doi: 10.1158/0008-5472.CAN-12-0423, PMID:22564525 van Oosten AL, Costa Y, Smith A, Silva JC, JAK/STAT3 signalling is sufficient and dominant over antagonistic cues for the establishment of naive pluripotency., Nat Commun. 2012 May 8;3:817. doi: 10.1038/ncomms1822., PMID:22569365 Martinez FJ, Lee JH, Lee JE, Blanco S, Nickerson E, Gabriel S, Frye M, Al-Gazali L, Gleeson JG, Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome, J Med Genet. 2012 Jun;49(6):380-5. doi: 10.1136/jmedgenet-2011-100686, PMID:22577224 Oliver CH, Khaled WT, Frend H, Nichols J, Watson CJ, The Stat6-regulated KRAB domain zinc finger protein Zfp157 regulates the balance of lineages in mammary glands and compensates for loss of Gata-3., Genes Dev. 2012 May 15;26(10):1086-97. doi: 10.1101/gad.184051.111., PMID:22588720 Barker RA, Cicchetti F, Current understanding of the glial response to disorders of the aging CNS., Front Pharmacol. 2012;3:95. doi: 10.3389/fphar.2012.00095, PMID:22654755 55

2012 Publications continued Fujimoto Y, Abematsu M, Falk A, Tsujimura K, Sanosaka T, Juliandi B, Semi K, Namihira M, Komiya S, Smith A, Nakashima K., Treatment of a Mouse Model of Spinal Cord Injury by Transplantation of Human iPS Cell-derived Long-term Self-renewing Neuroepithelial-like Stem Cells, Stem Cells. 2012 Jun;30(6):1163-73. doi: 10.1002/ stem.1083, PMID:22419556 Leeb M, Wutz A, Establishment of epigenetic patterns in development., Chromosoma. 2012 Jun;121(3):251-62. doi: 10.1007/s00412-012-0365-x, PMID:22427185 Reilly JT, Mcmullin MF, Beer PA, Butt N, Conneally E, Duncombe A, Green AR, Michaeel NG, Gilleece MH, Hall GW, Knapper S, Mead A, Mesa RA, Sekhar M, Wilkins B, Harrison CN, Guideline for the diagnosis and management of myelofibrosis, Br J Haematol. 2012 Aug;158(4):453-71. doi: 10.1111/j.1365-2141.2012.09179.x, PMID:22651893 Lancrin C, Mazan M, Stefanska M, Patel R, Lichtinger M, Costa G, Vargel O, Wilson NK, Möröy T, Bonifer C, Göttgens B, Kouskoff V, Lacaud G, GFI1 and GFI1B control the loss of endothelial identity of hemogenic endothelium during hematopoietic commitment., Blood. 2012 Jul 12;120(2):314-22. doi: 10.1182/blood-2011-10-386094, PMID:22668850 Lorber B, Tassoni A, Bull ND, Moschos MM, Martin KR, Retinal ganglion cell survival and axon regeneration in WldS transgenic rats after optic nerve crush and lens injury., BMC Neurosci. 2012 Jun 6;13:56. doi: 10.1186/1471-220213-56., PMID:22672534 Pedersen RA, Mascetti V, Mendjan S, Synthetic organs for regenerative medicine., Cell Stem Cell. 2012 Jun 14;10 (6):646-7. doi: 10.1016/j.stem.2012.04.003., PMID:22704499 Collins CA, Jensen KB, MacRae EJ, Mansfield W, Watt FM, Polyclonal origin and hair induction ability of dermal papillae in neonatal and adult mouse back skin, Dev Biol. 2012 Jun 15;366(2):290-7. doi: 10.1016/ j.ydbio.2012.03.016, PMID:22537489 Campbell PJ, MacLean C, Beer PA, Buck G, Wheatley K, Kiladjian J-J, Forsyth C, Harrison CN, Green AR, Correlation of blood counts with vascular complications in essential thrombocythemia: Analysis of the prospective PT1 cohort, Blood. 2012 Aug 16;120(7):1409-11. doi: 10.1182/blood-2012-04-424911, PMID:22709688 Mulder KW, Wang X, Escriu C, Ito Y, Schwarz RF, Gillis J, Sirokmány G, Donati G, Uribe-Lewis S, Pavlidis P, Murrell A, Markowetz F, Watt FM, Diverse epigenetic strategies interact to control epidermal differentiation., Nat Cell Biol. 2012 Jun 24;14(7):753-63. doi: 10.1038/ncb2520., PMID:22729083 Galpern WR, Corrigan-Curay J, Lang AE, Kahn J, Tagle D, Barker RA, Freeman TB, Goetz CG, Kieburtz K, Kim SYH, Piantadosi S, Rick AC, Federoff HJ, Sham neurosurgical procedures in clinical trials for neurodegenerative diseases: scientific and ethical considerations, Lancet Neurol. 2012 Jul;11(7):643-50, PMID:22710757 Wareing S, Mazan A, Pearson S, Goettgens B, Lacaud G, Kouskoff V, The Flk1-Cre-Mediated Deletion of ETV2 Defines Its Narrow Temporal Requirement During Embryonic Hematopoietic Development, Stem Cells. 2012 Jul;30 (7):1521-31., PMID:22570122 Spensberger D, Kotsopoulou E, Ferreira R, Broccardo C, Scott LM, Fourouclas N, Ottersbach K, Green AR, Göttgens B, Deletion of the Scl +19 enhancer increases the blood stem cell compartment without affecting the formation of mature blood lineages, Exp Hematol. 2012 Jul;40(7):588-598.e1. doi: 10.1016/j.exphem.2012.02.006, PMID:22401818 Aznar Benitah S, Frye M, Stem cells in ectodermal development, J Mol Med (Berl). 2012 Jul;90(7):783-90. doi: 10.1007/s00109-012-0908-x, PMID:22570240 Oeztuerk-Winder F, Ventura JJ, The many faces of p38 mitogen-activated protein kinase in progenitor/stem cell differentiation., Biochem J. 2012 Jul 1;445(1):1-10. doi: 10.1042/BJ20120401., PMID:22702973 Jagielska A, Norman AL, Whyte G, Van Vliet KJ, Guck J, Franklin RJM, Mechanical Environment Modulates Biological Properties of Oligodendrocyte Progenitor Cells, Stem Cells Dev. 2012 Nov 1;21(16):2905-14., PMID:22646081 Surani A, Tischler J, STEM CELLS:A sporadic super state, Nature. 2012 Jul 4;487(7405):43-5, PMID:22763548 Bao S, Leitch HG, Gillich A, Nichols J, Tang F, Kim S, Lee C, Zwaka T, Li X, Surani MA, The Germ Cell Determinant Blimp1 Is Not Required for Derivation of Pluripotent Stem Cells, Cell Stem Cell. 2012 Jul 6;11(1):110-7, PMID:22770244 Wutz A, Epigenetic Alterations in Human Pluripotent Stem Cells: A Tale of Two Cultures, Cell Stem Cell. 2012 Jul 6;11(1):9-15, PMID:22770238 Zohren F, Souroullas GP, Luo M, Gerdemann U, Imperato MR, Wilson NK, Göttgens B, Lukov GL, Goodell MA, The transcription factor Lyl-1 regulates lymphoid specification and the maintenance of early T lineage progenitors, Nat Immunol. 2012 Jul 8;13(8):761-9, PMID:22772404 Magnúsdóttir E, Gillich A, Grabole N, Surani MA, Combinatorial control of cell fate and reprogramming in the mammalian germline, Curr Opin Genet Dev. 2012 Oct;22(5):466-74, PMID:22795169 56

Mirshekar-Syahkal B, Haak E, Kimber GM, van Leusden K, Harvey K, O'Rourke J, Laborda J, Bauer SR, de Bruijn MF, Ferguson-Smith AC, Dzierzak E, Ottersbach K., Dlk1 is a negative regulator of emerging hematopoietic stem and progenitor cells, Haematologica. 2012 Jul 16, PMID:22801971 Doupé DP, Alcolea MP, Roshan A, Zhang G, Klein AM, Simons BD, Jones PH, A single progenitor population switches behavior to maintain and repair esophageal epithelium, Science. 2012 Aug 31;337(6098):1091-3, PMID:22821983 Oeztuerk-Winder F, Guinot A, Ochalek A, Ventura JJ, Regulation of human lung alveolar multipotent cells by a novel p38α MAPK/miR-17-92 axis., The EMBO Journal (2012) 31, 3431 - 3441, PMID:22828869 Cho LT, Wamaitha SE, Tsai IJ, Artus J, Sherwood RI, Pedersen RA, Hadjantonakis AK, Niakan KK, Conversion from mouse embryonic to extra-embryonic endoderm stem cells reveals distinct differentiation capacities of pluripotent stem cell states., Development. 2012 Aug;139(16):2866-77, PMID:22791892 Nichols J, Smith A, Pluripotency in the embryo and in culture., Cold Spring Harb Perspect Biol. 2012 Aug 1;4 (8):a008128, PMID:22855723 Kipp M, Victor M, Martino G, Franklin RJM, Endogeneous Remyelination: Findings in Human Studies, CNS Neurol Disord Drug Targets. 2012 Aug;11(5):598-609, PMID:22583436 Wu K, O'Keeffe D, Politis M, O'Keeffe GC, Robbins TW, Bose SK, Brooks DJ, Piccini P, Barker RA, The catechol-Omethyltransferase Val(158)Met polymorphism modulates fronto-cortical dopamine turnover in early Parkinson's disease: a PET study, Brain. 2012 Aug;135(Pt 8):2449-57., PMID:22843413 Wong VW, Jensen KB, Environmental stimuli and intestinal stem cell behavior., Cell Cycle. 2012 August 1; 11(15): 2767–2768. PMID:22801538 Sugimoto Y, König J, Hussain S, Zupan B, Curk T, Frye M, Ule J, Analysis of CLIP and iCLIP methods for nucleotideresolution studies of protein-RNA interactions., Genome Biol. 2012 Aug 3;13(8):R67, PMID:22863408 Fordham RP, Jensen KB, Reporting live from the epidermal stem cell compartment!, Cell Stem Cell. 2012 Aug 3;11 (2):141-2. doi: 10.1016/j.stem.2012.07.008., PMID:22862938 Lorber B, Guidi A, Fawcett JW, Martin KR, Activated retinal glia mediated axon regeneration in experimental glaucoma, Neurobiol Dis. 2012 Jan;45(1):243-52. doi: 10.1016/j.nbd.2011.08.008, PMID:21867754 Godfrey AL, Chen E, Pagano F, Ortmann CA, Silber Y, Bellosillo B, Guglielmelli P, Harrison CN, Reilly JT, Stegelmann F, Bijou F, Lippert E, McMullin MF, Boiron J-M, Dohner K, Vannucchi AM, Besses C, Campbell PJ, Green AR, JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone, Blood. 2012 Sep 27;120(13):2704-7, PMID:22898600 Dawson MA, Kouzarides T, Huntly BJP, Targeting Epigenetic Readers in Cancer, N Engl J Med. 2012 Aug 16;367 (7):647-57, PMID:22894577 Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C, Defining the mode of tumour growth by clonal analysis, Nature. 2012 Aug 23;488(7412):527-30, PMID:22854777 Ribeiro D, Goya RL, Ravindran G, Vuono R, Parish CL, Foldi C, Piroth T, Yang S, Parmar M, Nikkhah G, Hjerling-Leffler J, Lindvall O, Barker RA, Arenas E, Efficient expansion and dopaminergic differentiation of human fetal ventral midbrain neural stem cells by midbrain morphogens, Neurobiol Dis. 2012 Aug 24;49C:118-127, PMID:22940632 Khandanpour C, Krongold J, Schütte J, Bouwman F, Vassen L, Gaudreau MC, Chen R, Calero-Nieto FJ, Diamanti E, Hannah R, Meyer SE, Grimes HL, van der Reijden BA, Jansen JH, Patel CV, Peeters JK, Löwenberg B, Dührsen U, Göttgens B, Möröy T, The human GFI136N variant induces epigenetic changes at the Hoxa9 locus and accelerates KRAS driven myeloproliferative disorder in mice., Blood. 2012 Nov 8;120(19):4006-17. PMID:22932805 Dumon S, Walton DS, Volpe G, Wilson N, Dasse E, Del Pozzo W, Landry J-R, Turner B, O'Neill LP, Gottgens B, Frampton J, Itga2b Regulation at the Onset of Definitive Hematopoiesis and Commitment to Differentiation, PLoS One. 2012;7(8):e43300, PMID:22952660 Raphel L, Talasila A, Cheung C, Sinha S, Myocardin overexpression is sufficient for promoting the development of a mature smooth muscle cell-like phenotype from human embryonic stem cells., PLoS One. 2012; 7(8): e44052. PMID:22937150 Johnson TV, Martin KR, Cell transplantation approaches to retinal ganglion cell neuroprotection in glaucoma., Curr Opin Pharmacol. 2013 Feb;13(1):78-82. doi: 10.1016/j.coph.2012.08.003, PMID:22939899 Káradóttir RT, Stockley JH, Deconstructing myelination: it all comes down to size., Nat Methods. 2012 Sep;9(9):8834. doi: 10.1038/nmeth.2145., PMID:22936168 Huang JK, Ferrari CC, Monteiro de Castro G, Lafont D, Zhao C, Zaratin P, Pouly S, Greco B, Franklin RJ, Accelerated axonal loss following acute CNS demyelination in mice lacking protein tyrosine phosphatase receptor type Z., Am J Pathol. 2012 Nov;181(5):1518-23, PMID:22940073 57

2012 Publications continued Frye M, Benitah SA, Chromatin regulators in mammalian epidermis., Semin Cell Dev Biol. 2012 Oct;23(8):897-905, PMID:22944592 Tuorto F, Liebers R, Musch T, Schaefer M, Hofmann S, Kellner S, Frye M, Helm M, Stoecklin G, Lyko F, RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis, Nat Struct Mol Biol. 2012 Sep;19 (9):900-5, PMID:22885326 Cummins G, Barker RA, What is the most promising treatment for Parkinson's disease: genes, cells, growth factors or none of the above?, Regen Med. 2012 Sep;7(5):617-21, PMID:22954429 He J, Zhang G, Almeida AD, Cayouette M, Simons BD, Harris WA, How variable clones build an invariant retina., Neuron. 2012 Sep 6;75(5):786-98, PMID:22958820 Mascré G, Dekoninck S, Drogat B, Youssef KK, Brohée S, Sotiropoulou PA, Simons BD, Blanpain C, Distinct contribution of stem and progenitor cells to epidermal maintenance, Nature. 2012 Sep 13;489(7415):257-62, PMID:22940863 Shi Y, Kirwan P, Livesey FJ, Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks, Nat Protoc. 2012 Oct;7(10):1836-46, PMID:22976355 Marina N, Sajic M, Bull ND, Hyatt AJ, Berry D, Smith KJ, Martin KR, Lamotrigine monotherapy does not provide protection against the loss of optic nerve axons in a rat model of ocular hypertension., Exp Eye Res. 2012 Nov;104:1 -6. doi: 10.1016/j.exer.2012.09.002, PMID:22982756 Kazanis I, Neurogenesis in the adult Mammalian brain: how much do we need, how much do we have?, Curr Top Behav Neurosci. 2013;15:3-29. doi: 10.1007/7854_2012_227., PMID:22976273 Leeb M, Walker R, Mansfield B, Nichols J, Smith A, Wutz A, Germline potential of parthenogenetic haploid mouse embryonic stem cells., Development. 2012 Sep;139(18):3301-5, PMID:22912412 Scherf N, Herberg M, Thierbach K, Zerjatke T, Kalkan T, Humphreys P, Smith A, Glauche I, Roeder I, Imaging, quantification and visualization of spatio-temporal patterning in mESC colonies under different culture conditions, Bioinformatics. 2012 Sep 15;28(18):i556-i561, PMID:22962481 Fidalgo M, Faiola F, Pereira C-F, Ding J, Saunders A, Gingold J, Schaniel C, Lemischka IR, Silva JCR, Wang J, Zfp281 mediates Nanog autorepression through recruitment of the NuRD complex and inhibits somatic cell reprogramming, Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16202-7, PMID:22988117 Dawson MA, Foster SD, Bannister AJ, Robson SC, Hannah R, Wang X, Xhemalce B, Wood AD, Green AR, Goettgens B, Kouzarides T, Three Distinct Patterns of Histone H3Y41 Phosphorylation Mark Active Genes, Cell Rep. 2012 Sep 27;2 (3):470-7, PMID:22999934 Chalut KJ, Ekpenyong AE, Whyte G, Pagliara S, Lautenschläger F, Fiddler C, Paschke S, Keyser UF, Chilvers ER, Guck J, Viscoelastic properties of differentiating blood cells are fate- and function-dependent., PLoS One. 2012;7 (9):e45237, PMID:23028868 Ohhata T, Wutz A, Reactivation of the inactive X chromosome in development and reprogramming., Cell Mol Life Sci. 2012 Sep 30, PMID:23052214 Forment JV, Walker RV, Jackson SP, A high-throughput, flow cytometry-based method to quantify DNA-End resection in mammalian cells, Cytometry A. 2012 Oct;81(10):922-8, PMID:22893507 Godfrey AL, Green AR, Genotype-phenotype interactions in the myeloproliferative neoplasms., Hematol Oncol Clin North Am. 2012 Oct;26(5):993-1015, PMID:23009934 Hackett JA, Reddington JP, Nestor CE, Dunican DS, Branco MR, Reichmann J, Reik W, Surani MA, Adams IR, Meehan RR, Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline., Development. 2012 Oct;139(19):3623-32, PMID:22949617 Andre V, Longoni D, Bresolin S, Cappuzzello C, Dander E, Galbiati M, Bugarin C, Di Meglio A, Nicolis E, Maserati E, Serafini M, Warren AJ, te Kronnie G, Cazzaniga G, Sainati L, Cipolli M, Biondi A, D'Amico G, Mesenchymal stem cells from Shwachman-Diamond syndrome patients display normal functions and do not contribute to hematological defects, Blood Cancer J. 2012 Oct 12;2:e94, PMID:23064742 Franklin RJM, Ffrench-Constant C, Edgar JM, Smith KJ, Neuroprotection and repair in multiple sclerosis, Nat Rev Neurol. 2012 Nov 5;8(11):624-34, PMID:23026979 Sinha S, Vascular disease in a dish: all the right ingredients?, Circulation. 2012 Oct 2;126(14):1676-7. doi: 10.1161/ CIRCULATIONAHA.112.134387., PMID:23027809 Livesey FJ, A potential link between obesity and neural stem cell dysfunction, Nat Cell Biol. 2012 Oct 3;14(10):987-9, PMID:23033050

Martello G, Sugimoto T, Diamanti E, Joshi A, Hannah R, Ohtsuka S, Goettgens B, Niwa H, Smith A, Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal, Cell Stem Cell. 2012 Oct 5;11(4):491-504, PMID:23040478 Fitch SR, Kimber GM, Wilson NK, Parker A, Mirshekar-Syahkal B, Goettgens B, Medvinsky A, Dzierzak E, Ottersbach K, Signaling from the Sympathetic Nervous System Regulates Hematopoietic Stem Cell Emergence during Embryogenesis, Cell Stem Cell. 2012 Oct 5;11(4):554-66, PMID:23040481 Luo Y, Lim CL, Nichols J, Martinez-Arias A, Wernisch L, Cell signalling regulates dynamics of Nanog distribution in embryonic stem cell populations, J R Soc Interface. 2012 Oct 10, PMID:23054952 Bench AJ, White HE, Foroni L, Godfrey AL, Gerrard G, Akiki S, Awan A, Carter I, Goday-Fernandez A, Langabeer SE, Clench T, Clark J, Evans PA, Grimwade D, Schuh A, McMullin MF, Green AR, Harrison CN, Cross NCP, Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations, Br J Haematol. 2012 Oct 11, PMID:23057517 Valent P, Bonnet D, De Maria R, Lapidot T, Copland M, Melo JV, Chomienne C, Ishikawa F, Schuringa JJ, Stassi G, Huntly B, Herrmann H, Soulier J, Roesch A, Schuurhuis GJ, Wรถhrer S, Arock M, Zuber J, Cerny-Reiterer S, Johnsen HE, Andreeff M, Eaves C, Cancer stem cell definitions and terminology: The devil is in the details, Nat Rev Cancer. 2012 Nov;12(11):767-75, PMID:23051844 Lichtinger M, Ingram R, Hannah R, Muller D, Clarke D, Assi SA, Lie-A-Ling M, Noailles L, Vijayabaskar MS, Wu M, Tenen DG, Westhead DR, Kouskoff V, Lacaud G, Gottgens B, Bonifer C, RUNX1 reshapes the epigenetic landscape at the onset of haematopoiesis, EMBO J. 2012 Oct 12;31(22):4318-4333, PMID:23064151 Ousset M, Van Keymeulen A, Bouvencourt G, Sharma N, Achouri Y, Simons BD, Blanpain C, Multipotent and unipotent progenitors contribute to prostate postnatal development, Nat Cell Biol. 2012 Nov;14(11):1131-8, PMID:23064263 Wutz A, Agrelo R, Response: The Diversity of Proteins Linking Xist to Gene Silencing, Dev Cell. 2012 Oct 16;23 (4):680, PMID:23079595 Tischler J, Surani MA, Investigating transcriptional states at single-cell-resolution., Curr Opin Biotechnol. 2013 Feb;24(1):69-78. doi: 10.1016/j.copbio.2012.09.013, PMID:23084076 Hoyler T, Klose CSN, Souabni A, Turqueti-Neves A, Pfeifer D, Rawlins EL, Voehringer D, Busslinger M, Diefenbach A, The Transcription Factor GATA3 Controls Cell Fate and Maintenance of Type 2 Innate Lymphoid Cells, Immunity. 2012 Oct 19;37(4):634-48. doi: 10.1016/j.immuni.2012.06.020, PMID:23063333 Bertulat B, De Bonis ML, Della Ragione F, Lehmkuhl A, Milden M, Storm C, Jost KL, Scala S, Hendrich B, D'Esposito M, Cardoso MC, MeCP2 Dependent Heterochromatin Reorganization during Neural Differentiation of a Novel Mecp2-Deficient Embryonic Stem Cell Reporter Line, PLoS One. 2012;7(10):e47848, PMID:23112857 Barker RA, Stem cells and neurodegenerative diseases: where is it all going?, Regen Med. 2012 Nov;7(6 Suppl):2631., PMID:23210808 Rashid ST, Alexander GJ, Induced pluripotent stem cells: from Nobel Prizes to clinical applications., J Hepatol. 2013 Mar;58(3):625-9. doi: 10.1016/j.jhep.2012.10.026, PMID:23131523 Livesey FJ, Stem cell models of Alzheimer's disease and related neurological disorders., Alzheimers Res Ther. 2012 Nov 6;4(5):44, PMID:23131128 Chalut KJ, Hopfler M, Lautenschlaeger F, Boyde L, Chan CJ, Ekpenyong A, Martinez-Arias A, Guck J, Chromatin Decondensation and Nuclear Softening Accompany Nanog Downregulation in Embryonic Stem Cells, Biophys J. 2012 Nov 21;103(10):2060-70, PMID:23200040 Hilcenko C, Simpson PJ, Finch AJ, Bowler FR, Churcher MJ, Jin L, Packman LC, Shlien A, Campbell P, Kirwan M, Dokal I, Warren AJ, Aberrant 3' oligoadenylation of spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia., Blood. 2013 Feb 7;121(6):1028-38., PMID:23190533 Garcia-Ojalvo J, Martinez Arias A, Towards a statistical mechanics of cell fate decisions, Curr Opin Genet Dev. 2012 Dec;22(6):619-26. doi: 10.1016/j.gde.2012.10.004, PMID:23200114 Cho CH, Hannan NR, Docherty FM, Docherty HM, Joรฅo Lima M, Trotter MW, Docherty K, Vallier L, Inhibition of activin/nodal signalling is necessary for pancreatic differentiation of human pluripotent stem cells., Diabetologia. 2012 Dec;55(12):3284-95, PMID:23011350 Geti I, Ormiston ML, Rouhani F, Toshner M, Movassagh M, Nichols J, Mansfield W, Southwood M, Bradley A, Rana AA, Vallier L, Morrell NW, A Practical and Efficient Cellular Substrate for the Generation of Induced Pluripotent Stem Cells from Adults: Blood-Derived Endothelial Progenitor Cells, Stem Cells Transl Med. 2012 Dec;1(12):855-65., PMID:23283547 Yang S-H, Kalkan T, Morrisroe C, Smith A, Sharrocks AD, A Genome-Wide RNAi Screen Reveals MAP Kinase Phosphatases as Key ERK Pathway Regulators during Embryonic Stem Cell Differentiation, PLoS Genet. 2012 Dec;8 (12):e1003112, PMID:23271975 58

2012 Publications continued Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P, Askenase P, Bond VC, Borràs FE, Breakefield X, Budnik V, Buzas E, Camussi G, Clayton A, Cocucci E, Falcon-Perez JM, Gabrielsson S, Gho YS, Gupta D, Harsha HC, Hendrix A, Hill AF, Inal JM, Jenster G, Krämer-Albers EM, Lim SK, Llorente A, Lötvall J, Marcilla A, Mincheva-Nilsson L, Nazarenko I, Nieuwland R, Nolte-'t Hoen EN, Pandey A, Patel T, Piper MG, Pluchino S, Prasad TS, Rajendran L, Raposo G, Record M, Reid GE, Sánchez-Madrid F, Schiffelers RM, Siljander P, Stensballe A, Stoorvogel W, Taylor D, Thery C, Valadi H, van Balkom BW, Vázquez J, Vidal M, Wauben MH, Yáñez-Mó M, Zoeller M, Mathivanan S., Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation., PLoS Biol. 2012 Dec;10 (12):e1001450., PMID:23271954 Muñoz Descalzo S, Rué P, Garcia-Ojalvo J, Martinez Arias A, Correlations between the levels of Oct4 and Nanog as a signature for naïve pluripotency in mouse embryonic stem cells., Stem Cells. 2012 Dec;30(12):2683-91. doi: 10.1002/stem.1230., PMID:22969005 Göttgens B, Genome-scale technology driven advances to research into normal and malignant haematopoiesis, Scientifica Volume 2012 (2012), Article ID 437956, 11 pages, Volume 2012 (2012), Article ID 437956, 11 pages, PMID:None Silva J, Reprogramming: The Next Generation, Cell Stem Cell. Volume 11, Issue 6, 7 December 2012, Pages 740–743, PMID:None Joshi A, Hannah R, Diamanti E, Göttgens B, Gene set control analysis(GSCA) predicts haematopoietic control mechanisms from genome-wide transcription factor binding data., Exp Hematol. 2013 Apr;41(4):354-66.e14. doi: 10.1016/j.exphem.2012.11.008, PMID:23220237 Hackett JA, Sengupta R, Zylicz JJ, Murakami K, Lee C, Down TA, Surani MA, Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine., Science. 2013 Jan 25;339(6118):448-52. doi: 10.1126/ science.1229277, PMID:23223451 Surani MA, Cellular Reprogramming in Pursuit of Immortality, Cell Stem Cell. 2012 Dec 7;11(6):748-50, PMID:23217420 Pasque V, Radzisheuskaya A, Gillich A, Halley-Stott RP, Panamarova M, Zernicka-Goetz M, Surani MA, Silva JC, Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency., J Cell Sci. 2012 Oct 17, PMID:23077180 Drouin-Ouellet J, Barker RA, Parkinson's disease in a dish: What patient specific-reprogrammed somatic cells can tell us about Parkinson's disease, if anything?, Stem Cells Int. 2012;2012:926147. doi: 10.1155/2012/926147, PMID:23316244 Lange S, Trost A, Tempfer H, Bauer H-C, Bauer H, Rohde E, Reitsamer HA, Franklin RJM, Aigner L, Rivera FJ, Brain pericyte plasticity as a potential drug target in CNS repair, Drug Discov Today. 2013 May;18(9-10):456-63. doi: 10.1016/j.drudis.2012.12.007, PMID:23266366

On the Cover Volocity速-based 3D reconstruction of the expression of the Hyaluronate (HA) receptor CD44 in a mouse neurosphere in vitro. Systemically injected neural stem/precursor cells (NPCs) use CD44 to establish therapeutically relevant intercellular communication programmes - and ultimately enter the inflamed central nervous system (CNS) - with HA-expressing activated endothelial and ependymal cells in vivo. The type III intermediate filament vimentin is shown in red, CD44 in green, and the mitosis protein phospho-histone H3 in white. Nuclei (blue) are labelled with Dapi. The expression of CD44 was deconvolved from a total of n= 40 Z-stacks of optical slices in 0.5- mm intervals. Image: Stefano Pluchino The cover image is reproduced with permission of John Wiley & Sons, Inc. Journal: Glia, 2013 Sep;61(9):1379-401. Copyright: Stefano Pluchino, 2013

2012