Vascular manipulations
that boost adult neurogenesis
Evidence shows the vasculature plays a key role in maintaining organ homeostasis, alongside its established function of tissue perfusion. We spoke to Professor Eli Keshet about the VASNICHE project’s work in investigating how blood vessels affect stem cell properties and maintenance, research which could lead to new insights into adult neurogenesis The sole function of blood vessels in the body has long been thought to be perfusion, namely supplying tissues with oxygen, nutrients, hormones and other blood-borne substances. While this is indeed a central part of the vasculature’s function, recent research suggests that blood vessels also play additional roles in the body. “Over recent years the idea has emerged that blood vessels, in addition to their established role in providing perfusion, also have additional roles in maintaining organ well-being, what we call organ homeostasis,” explains Professor Eli Keshet. Based at the
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Hebrew University of Jerusalem, Professor Keshet is exploring this area further in the ERC-backed VASNICHE project, using mice to study blood vessels in association with adult stem cells. “The latter are cells with stem cell properties that reside in normal adult tissues, including in the brain,” he explains. The old view was that the adult brain loses its capacity to produce new neurons over time, yet it has since become clear that new neurons can in fact be added in the adult brain via repeated divisions of resident stem cells in a process known as ‘adult
neurogenesis’. However, these neurons can be born anew only in the two regions of the brain where neural stem cells reside. Of these two regions, Professor Keshet is focusing his attention on the hippocampus. “The hippocampus has many functions, some of which are related to learning and memory, functions which in part rely on newly-added neurons,” he outlines. Unfortunately however, the capacity to generate new neurons in the hippocampus is known to decline with age, thus calling for some ways to attenuate age-related decline of adult hippocampal neurogenesis.
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Vascular stem cell niche Stem cells, in general, need to communicate constantly with their surrounding environment, known as the ‘stem cell niche’, in order to function effectively. The stem cell niche is the major focus of the VASNICHE project, with researchers aiming to gain new insights into the structure and composition of stem cell niches. “What cell types make the niche? Which cell types control the performance and maintenance of the stem cells?” says Professor Keshet. There is an increasing body of evidence to suggest that blood vessels are an integral component of stem cell niches at large, and of neuronal stem cells specifically. “The proposition here is that vascular cells must communicate constantly with neuronal stem cells in order to secure their proper function,” explains Professor Keshet. The apparent close physical proximity between blood vessels and neuronal stem cells is consistent with this proposition, yet this is not on its own sufficient to
manoeuvre, we can dramatically boost adult neurogenesis and improve cognitive functioning of the mice,” says Professor Keshet.
Attenuation of age-related neurogenic decline The capacity to make new neurons in the brain is known to also deteriorate with age in humans. Debate continues around the underlying cause of age-related deterioration in adult neurogenesis; Professor Keshet and his colleagues have put forward the proposition that it is not only the stem cells themselves that are aging. “Possibly the ability of the stem cell niche to support proper stem cell function is also deteriorating with age,” he explains. “Rejuvenating the vasculature could have an even greater impact on neurogenesis in the elderly.” The researchers have indeed found that rejuvenating the niche vasculature in aged mice - at a time where hippocampal neurogenesis has already substantially decreased - results in a highly significant
We have developed a very sophisticated transgenic mouse system, where we can manipulate blood vessels in mice at will. This includes both expanding or reducing the vasculature in the brain region of choice and recording the effect of these vascular manipulations on stem cell-driven neurogenesis prove a causal relationship. The project aims to build a stronger evidence base supporting the idea that blood vessels play an indispensable role in the control of stem cell function by harnessing the research group’s unique expertise in vascular manipulations. “We have developed a very sophisticated transgenic mouse system, where we can manipulate blood vessels in mice at will,” outlines Professor Keshet. “This includes both expanding or reducing the vasculature in the brain region of choice and recording the effect of these vascular manipulations on stem cell-driven neurogenesis.” To reinforce and rejuvenate the vasculature in the region where hippocampal stem cells reside, the researchers ‘switch on’ production of the protein known as Vascular Endothelial Growth Factor (VEGF), which promotes and orchestrates the generation of new blood vessels. Researchers have found that when more blood vessels are induced at the stem cell niche, more and more neurons are produced. “By using this
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increase in the rate of new neuron formation. Could a similar approach be harnessed to boost neurogenesis in humans and help maintain cognitive function for longer? While Professor Keshet is keen to stress that the project’s approach has been experimental, and the findings are not directly applicable to humans, he believes that this research could help lay the foundations for further investigation into treatments aimed at boosting adult neurogenesis via manipulating the stem cell niche. “Maybe we can consider other, more realistic ways of region-specific blood vessels rejuvenation for which this study could be regarded as a proof-ofconcept,” he says. The next question, which is currently being explored in Professor Keshet’s laboratory under the VASNICHE project, is which molecules produced by the vasculature contribute to improved neurogenesis. “We are still in the process of trying to see what the blood vessels produce to achieve this increased neurogenesis,” he says.
At a glance Full Project Title The vascular stem cell niche and the neuromuscular unit (VASNICHE) Project Objectives Generation of new neurons in the hippocampus of the adult brain declines with age rendering its contemplated ‘rejuvenation’ highly desirable. Assuming that age-related neurogenic decline us due to aging of the stem cell microenvironment and, specifically, the niche vasculature, attempts were made to boost neurogenesis through ‘rejuvenation’ of the niche vasculature. Project Funding ERC-AG-LS4 - ERC Advanced Grant Physiology, Pathophysiology and Endocrinology. EU contribution: EUR 2 499 980. Project Partner • Dr. Tamar Licht, The Hebrew University of Jerusalem Contact Details Project Coordinator, Professor Eli Keshet THE HEBREW UNIVERSITY OF JERUSALEM EIN KEREM CAMPUS 91120 JERUSALEM Israel T: +972 2 675 8496 E: elik@ekmd.huji.ac.il W: http://www.cordis.europa.eu/project/ rcn/106989_en.html Licht T, Rothe G, Kreisel T, Wolf B, Benny O, Rooney A, Ffrench-Constant C, Enikolopov G, Keshet E. VEGF pre-conditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis Proc. Natl. Acad. Sci. USA, Published online November 14, 2016, E7828-E7836
Professor Eli Keshet
Professor Eli Keshet is a professor of Molecular Biology at the faculty of Medicine of the Hebrew University of Jerusalem. He received his PhD from the Hebrew university in 1975, conducted post-doctoral research at the University of Wisconsin and advanced research at American National Cancer Institute, USA. His research focuses on the vascular system and the mechanisms of blood vessel formation. Professor Keshet is a member of the Israel Academy of Sciences.
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