Restoring Vision with Photoreceptor Regeneration

Zhang C-J and Jin Z-B, J Stem Cell Res Dev 2019, 5: 014 DOI: 10.24966/SRDT-2060/100014

HSOA Journal of Stem Cells Research, Development and Therapy Review Article

Restoring Vision with Photoreceptor Regeneration Chang-Jun Zhang1,2 and Zi-Bing Jin1,2* Laboratory for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research; Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China

1

State Key Laboratory of Ophthalmology, Optometry and Vision Science, National Clinical Research Center for Ophthalmology, National Center for International Research in Regenerative Medicine and Neurogenetics, Wenzhou 325027, China

2

Abstract Neuroretinal diseases are the predominant cause of irreversible blindness worldwide, mainly due to photoreceptor loss. Currently, there are no radical treatments to fully reverse the degeneration or even stop the disease progression. Thus, it is urgent to develop new biological therapeutics for these diseases on the clinical side.

Stem cell-based treatments have become a promising therapeutic for Neuroretinal diseases through replacement of damaged cells with photoreceptors and allied cells. To date, great efforts have been made on regenerate the diseased retina based on stem cell technology. In this review, we overview the current status of stem cell-based treatments for photoreceptor regeneration, including the major cell sources derived from different stem cells in pre-clinical or clinical trial stages. Additionally, we discuss herein the major challenges ahead for and potential new strategy toward photoreceptor regeneration.

Keywords: Delivery strategy; Neuroretinal diseases; Photoreceptor; Regeneration; Stem cell

Abbreviations QOL: Quality of Life CNS: Central Nerve System RD: Retinal Degeneration RP: Retinitis Pigmentosa AMD: Age Related Macular Degeneration

*Corresponding author: Zi-Bing Jin, Laboratory for Stem Cell & Retinal Regeneration, Institute of Stem Cell Research; Division of Ophthalmic Genetics, The Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China, Tel: +86 57788067926; E-mail: jinzb@mail.eye.ac.cn Citation: Zhang C-J, Jin Z-B (2019) Restoring Vision with Photoreceptor Regeneration. Stem Cell Res Dev Ther 4: 014.

Received: July 29, 2019; Accepted: August 12, 2019; Published: August 19, 2019 Copyright: © 2019 Zhang C-J and Jin Z-B. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

BM: Bruch’s Membrane; RPE: Retinal Pigment Epithelium; STGD: Stargardt’s Disease RPCs: Retinal Progenitor Cells hRPCs: human-derived RPC MG: Müller Glia NMDA: N-methyl-D-aspartate CE: Ciliary Epithelium IPE: Iris Pigmented Epithelium ESCs: Embryonic Stem Cells iPSCs: Induced Pluripotent Stem Cells hiESCs: human ESCs hiPSCs: human iPSCs MSCs: Mesenchymal Stem Cells ADSCs: Adipose-Derived Stem Cells AESCs: Amniotic Epithelial Stem Cells BMSCs: Bone Marrow Mesenchymal Stem Cells AFMSCs: Amniotic Fluid Mesenchymal Stem Cells 2D: Two-Dimensional 3D: Three-Dimensional LIF: Leukemia Inhibiting Factor BMP: Bone Morphogenetic Protein IGF-1: Insulin-Like Growth Factor-1 SFEB: Serum-Free Floating Culture System ERG: Electroretinogram FACS: Fluorescence Activated Cell Sorting MACS: Magnetic Activated Cell Sorting INL: Inner Retinal Layer ECM: Extracellular Matrix OKT: Optokinetic Testing SD-OCT: Spectral Domain-Optical Coherence Tomography HAMC: Hyaluronan-Methylcellulose HLAs: Human Leukocyte Antigens RA: Retinoic Acid LCA: Leber Congenital Amaurosis GVHD: Graft Versus Host Disease CSNB: Congenital Stationary Night Blindness

Introduction Human eye, the organ of the visual system, is the most important organ of perception and converts visual signals into neural signals in the brain [1,2]. The structure of the human eye is incredibly complex, comprising the cornea, iris and lens from the anterior segment, and the vitreous humor, retina, choroid and sclera from the posterior segment [3,4]. Healthy and asymptomatic eyes are undoubtedly crucial to Quality of Life (QOL). Unfortunately, there are many different diseases and age-related changes that affecting the eye, ranging from the anterior segment to the posterior segment [5,6]. Apart from

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neuroretinal disorders, a good therapeutic effect can be achieved in most eye diseases in the anterior segment with current medical treatments.

The retina is a part of the Central Nerve System (CNS) and is primarily composed of seven cell types [7-9]. In the mammalian retina, three vital cell types, including photoreceptors, Retinal Pigment Epithelium (RPE) cells and retinal ganglion cells, lack self-regenerative capacity after injury. Thus, neuroretinal disorders, such as Retinal Degeneration (RD) and glaucoma, can lead to irreversible and incurable visual impairment with the loss of photoreceptors, RPE cells, and/or retinal ganglion cells [10].

Retinal degeneration (RD) encompasses a group of major registered blindness-causing diseases accompanied by the death of photoreceptors and/or RPE cells that result in progressive loss of vision and severely impact the quality of patient’s life [11-14]. RD primarily includes Retinitis Pigmentosa (RP) and macular degeneration, which has a high clinical incidence, and these diseases exhibit different symptoms and result from complex disease-causing factors. RP is an inherited retinal disorder involving more than 90 causal genes, and typical symptoms include progressive night blindness and loss of peripheral visual field [15-17]. RP affects more than 1.5 million individuals worldwide with a prevalence rate of approximately 1 in 4000 [15, 18].

Different from inherited and rod-dominated RP, macular degeneration is an over determined and cone-dominated disease caused by both innate and acquired factors and mainly includes Age-Related Macular Degeneration (AMD) and juvenile macular degeneration [19,20]. The thickened Bruch’s Membrane (BM) is the initial characterization of AMD, and subsequently, the loss of RPE cells and photoreceptors gradually occurs in the late stage [21-26]. It is estimated that the number of AMD cases will reach nearly 196 million worldwide by 2020 and 288 million by 2040, leading to an increased social and economic burden [27-29]. Stargardt’s Disease (STGD) is the highest prevalence of juvenile macular degeneration [30-33]. Both diseases are currently incurable in terms of photoreceptor maintanance and disease reversion.

As seen from the foregoing descriptions, traditional therapeutic approaches for neuroretinal diseases can only delay the progression of neuroretinal degeneration and are unable to cure or completely reverse the damage caused by the disease. Unlike the retina in lower vertebrates, the human retina lacks a regenerative capability [34,35].

Stem cells are special cell types characterized by the capacity of unlimited self-renew and the ability of multidirectional differentiation into multiple cell types, including photoreceptors, RPE cells, and/or retinal ganglion cells [36]. In recent years, based on these characteristics of stem cells, stem cell transplantation has been well studied and widely used as a feasible approach for maintaining, enhancing and restoring the function and structure of tissues or organs [37]. In particular, the eye has some natural advantages over other tissues and organs in the field of stem cell transplantation therapy; first, the relatively small size only requires a small volume of cells for transplantation; second, because the eye is easily accessible and observable highly invasive methods for surgery or examination can be avoided; third, the immune privileged sites can help to prevent unwanted inflammatory responses and thus promote the survival of donor cells; fourth, the comparatively independent, separated space can minimize J Stem Cell Res Dev Ther ISSN: 2381-2060, Open Access Journal DOI: 10.24966/SRDT-2060/100014

systemic dissemination and maintain the intraocular microenvironment; last, the highly sectionalized structure can permit specific targeted interventions for different ocular tissues [38-41]. During the last two decades, stem cell-based therapy for neuroretinal diseases have become a promising treatment strategy due to the continued advances in generation of appropriate cell sources, development of optimal delivery systems, and exploration of combined cell transplantation.

Stem Cells for Regeneration of the Retina The primary problem facing stem cell transplantation for neuroretinal diseases is identification and characterization of the source of stem cells. Accessible and efficient stem cell sources for neuroretina regeneration are classified into two main categories, endogenous retinal stem cells and exogenous stem cells for retinal regeneration.

Endogenous Retinal Stem Cells The study of restoring vision through retinal transplantation can be traced back to the 1950s, when a donor fetal mouse retina was transplanted into an adult mouse with incomplete integration into the host retina [42]. Subsequently, further studies found that transplantation integration could be increased when the donor or host tissue is at an early stage or the host retina is injured.

Retinal Progenitor Cells (RPCs) have been identified as the effective cellular component of fetal or neonatal retinal transplantation [43-45]; transplantation of isolated RPCs promotes integration with the host retina [46,47]. RPCs have a multipotential differentiation capacity, exhibit expression of the neuroectodermal marker nest in and can potentially differentiate into all retinal cells (e.g., Müller glial cells, rod photoreceptors and bipolar neurons) during development [48,49]. In the early stage of mammal retinal development, RPCs, as the predominant cell type, are easy to isolate from several mammalian species, including rodents, pigs, and humans [50-52]. Surprisingly, in addition to cells from fetal or neonatal epiretinal membrane in the adult human retinas, suggesting that the mature retina may harbor RPCs [53,54]. Mouse-, rat-, cat-, and pig-derived RPCs, as well as human-derived RPCs (hRPCs), have been applied to replace damaged cells in corresponding animal disease models with good differentiation and integration [46,55-59]. However, the low rate of RPC cell proliferation and ethical issues regarding clinical application of RPCs harvested from fetal or neonatal eyes limit their transplantation into human patients.

For the treatment of retinal degenerative diseases, in addition to attempts to replace damaged cells through stem cell transplantation, the endogenous ocular stem cell populations can be reactivated to generate new retinal photoreceptors [60-62]. The well-known endogenous retinal stem cells Müller Glia (MG) are derived from the retinal neuroepithelium and are the major glial unable to the retina [63,64].

MG span the entire length of this structure and function to maintain retinal homeostasis and integrity [65]. Unlike most cell types, the differentiated retinal neurons are incompetent to divide and regenerate once damaged or lost. Surprisingly, MG has a prominent ability to regenerate retinal tissue; however, the capacity for MG regeneration varies greatly among different species. In some non-mammalian species, such as chick, fish and birds, MG have an ability to regenerate neurons [66-68]. In zebrafish, MG generate various retinal neurons and restore visual function through a reprogramming event. In contrast to zebrafish, mammalian MG encounter reactive gliosis and Volume 5 • Issue 1 • 100014

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exhibit hypertrophy after retinal impairment but fail to regenerate novel neurons to replace lost cells under natural circumstances [69]. Specially, mammalian MG can also proliferate and regenerate the adult mammalian retina in response to N-methyl-D-aspartate (NMDA) neurotoxicity in the adult rat retina [70,71]. Further studies showed that the mammalian retina is also capable of regenerating inner retinal neurons after treatment with specific growth factors in mouse retina with intraocular NMDA [72]. Likewise, following NMDA injection in rats, MG started to proliferate mediated by cyclin D1- and D3- related pathways and differentiated exclusively into rhodopsin-positive cells surrounded by synaptophysin, showing the potential for synapse formation [73]. In addition to these neurotoxic substances, axotomy and laser injury can also result in proliferation and differentiation of MG into retinal neurons in vivo [74,75]. Furthermore, molecular fingerprinting showed that MG express genes associated with retinal stem cells in the mouse retina [76].

Although the differentiation potential of endogenous human MG has not yet been shown, in vitro, MG isolated from adult human retinas was shown to possess an ability to differentiate into rod photoreceptors for the first time [77]. Moreover, human MG-derived photoreceptors and MG-derived retinal ganglion cells were transplanted into deficient rodent retinas, resulting in the functional restoration of rod or retinal ganglion cells [78-80]. Although some previous studies have shown that the newly generated neurons are functional and can partially restore visual function, neurogenesis is still limited, evidenced by the low number of regenerated cells. Thus, novel strategies are required to maintain adequate numbers of MG and promote their effective trans-differentiation to regenerate newly formed retinal neurons in vivo.

As with MG, many previous studies showed that some other ocular stem cells, including RPE [81,82], the Ciliary Epithelium (CE) [83,84], and Iris Pigmented Epithelium (IPE) [85-87], also retain some restricted regenerative capacities. However, the efficiency of reprogramming and the potential of produced new cells derived from these endogenous stem cells are so low that they do not achieve extensive replacement of mature mammalian eyes after injury or disease. Based on the advancement of in vitro culture techniques, they may also be promising as a source of donor cells for cell replacement therapy. Moreover, the development of new techniques to induce reactivation and differentiation of endogenous stem cells is another breakthrough in the treatment of neuroretinal diseases.

Exogenous Stem Cells Exogenous stem cells for retinal regeneration are primarily non-ocular stem cells. The non-ocular stem cells that can generate retinal cells are mainly divided into three types, Embryonic Stem Cells (ESCs) [88], induced Pluripotent Stem Cells (iPSCs) induced from mature somatic cells [89], and Mesenchymal Stem Cells (MSCs) [90]. MSCs can be obtained from various sources, including Adipose-Derived Stem Cells (ADSCs) [91], Amniotic Epithelial Stem Cells (AESCs) [92], Bone Marrow Mesenchymal Stem Cells (BMSCs) [93], and Amniotic Fluid Mesenchymal Stem Cells (AFMSCs) [94]. ESCs and iPSCs are currently widely used and have been selected as prospective therapeutic strategies for neuroretinal diseases; thus, they are our next narrative focus.

J Stem Cell Res Dev Ther ISSN: 2381-2060, Open Access Journal DOI: 10.24966/SRDT-2060/100014

Differentiation of ESCs and iPSCs into Photoreceptors and RPE Cells The first pluripotential cells from mouse embryos were established

by Martin, Evans and Kaufman in 1981 [95]. Subsequently, Tomson and colleagues isolated ESCs from primate and human embryos in 1998 [88]. ESCs and iPSCs are capable of differentiation into various retinal cell types using Two-Dimensional (2D) or Three-Dimensional (3D) culture systems, including photoreceptors [96,97], RPE cells [98,99], and retinal ganglion cells [97,100].

Deriving Photoreceptors from ESCs and iPSCs Direct differentiation of ESCs into neural and retinal cell types can be guided by manipulation of signaling pathways in vivo, sequentially followed by the withdrawal of Wnt signaling, Leukemia Inhibiting Factor (LIF), and Bone Morphogenetic Protein (BMP) and the activation of Insulin-Like Growth Factor 1 (IGF-1) and Activin/Nodal signaling pathways [96,101-109]. Mouse ESC-derived neuroretinal cells have been induced in vivo by using certain factors for neural and retinal induction [106]. Mouse ESCs successfully generated retinal progenitors in the presence of FBS at reasonable efficiency (26%) after treatment in A Serum-Free Floating Culture System (SFEB) with addition of Dkk1 (a Wnt antagonist), Lefty A (a nodal antagonist), serum and activin, successively. However, only in co-culture with embryonic retinal cells can these retinal progenitors efficiently differentiate into photoreceptor precursors [106,110]. Subsequently, human ESCs were reported to produce neural progenitors in vitro, but their differentiation into retinal cells needs to be performed via intraocular transplantation into adult rats [111]. Similarly, human ESC-derived retinal progenitors were induced under the addition of dkk1, noggin and IGF-1 in Matrigel and continued to generate photoreceptors in co-culture with adult mouse retinal cells [112]. A groundbreaking work showed that mouse, monkey and human ESC-derived photoreceptor precursors was realized under optimized culture conditions in vitro, with elimination of the need for animal-derived substances or retinal tissue [113].

Ethical issues and immune rejection are major constraints in clinical application of hESCs [114]. In 2006 and 2007, mouse and human somatic cells were induced for the first time to form the pluripotent stem cells via reprogramming using the “Yamanaka factors”, Oct3/4, c-Myc, Sox2, and Klf4 [89,117]. These iPSCs pose identical self-renewal and multi-differentiation properties as ESCs and serve as a prospective source of donor cells to eliminate or reduce the immune rejection by using the iPSC-derived retinal cells from the patients.

Mouse and human iPSCs can differentiate into photoreceptors with defined factors in vitro through the stepwise differentiation process used in differentiation of ESCs [105]. In summary, the 2D-based protocols used in differentiation of ESCs or iPSCs toward photoreceptors all proceed through an analogous regulatory pathway, including suppression of endogenous BMP/TGFβ, Activin/Nodal and Wnt signaling pathways with the addition of IGF-1 or Insulin and combination with various regulatory factors (such as FGF1/FGF2/T3/ COCO), retinoic acid (RA) and taurine [105,107,113,116-123].

To change the low differentiation efficacy observed in 2D culture systems and establish robust protocols that provide a sufficient number of donor cells, mouse and human ESC-derived optic cups were first generated in the Sasai lab using a 3D culture system; these optic Volume 5 • Issue 1 • 100014

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cups are a significantly multilayered retinal tissue composed of major neural retinal components, generally referred to as retinal organoids [124,125]. Moreover, hiPSC-derived optic vesicle-like structures or retinal organoids grown using 3D culture systems have also been established [126-125]. On the basis of 3D retinal organoid technology, many researchers have cultivated and produced a large number of ESC/iPSC-derived photoreceptor cells for transplantation research [129-146]. In this review, we will not go into too much detail.

In addition to generating transplantable cells or tissue, 3D retinal organoid technology also holds great potential for in vitro disease model, large-scale drug screening and testing, and cell development exploration [147,148]. Patient iPSC-derived optic cups were used to investigate the disease mechanism of hereditary blindness with the common CEP290 mutation [146]. Most recently, our lab generated iPSC-derived retinal organoids from RP patient with RPGR gene mutations, which can monitor photoreceptor degeneration similar to retinal morphology of the RP patient [149]. Interestingly, these defects were partially rescued byCRISPR-Cas9-mediated correction of RPGR mutation.

Derivation of Photoreceptor-Supportive RPE Cells from Pluripotent Stem Cells Considerable progress has been made in developing efficient protocols to direct differentiation of both ESCs and iPSCs into RPE cells, and thus, a plentiful and controllable source of RPE cells can be serviceable for cell transplantation therapy. An early study showed that mouse ESCs were efficiently induced to differentiate into melanocytes in vitro [150]. Subsequent studies demonstrated that RPE cells could also be derived from mouse and primate ESCs [151,152]. The first hESC-derived RPE was generated using the original protocol, a differentiation system without coculture using certain cells or factors developed by Klimanskaya’s group [153]. Transcriptomics analysis of hESC-derived RPE, mature RPE and human fetal RPE confirmed that they are more similar to native RPE tissue than the existing human RPE cell lines. Vugler and colleagues found that hESC-derived RPE cells express several markers associated with the development and maturity of RPE cells, including Pax6, OTX1/2, RPE65 and PMEL17 [154]. Although ESC-derived RPE cells have features very similar to those of typical RPE cells in morphology and function, the differences of in vitro cell maturity require further analysis to obtain optimal transplant cell populations for transplantation. Theoretically, an unlimited source of RPE cells can be harvested utilizing this culture system.

Since then, different labs have optimized the protocol to derive pure and safe RPE cells from hESCs and iPSCs [116,155-167]. As described earlier, iPSCs possess regenerative capability equivalent to those of hESCs and thus are also used as another pluripotent cell source for cell and tissue regeneration [89,115,167]. The process of iPSC-derived RPE cell differentiation can be greatly promoted directed by inhibiting the signaling pathways of Wnt and Nodal in RPE cells with the addition of factors such as Dkk1 and Lefty-A [172,173].

Morphologically and functionally, iPSC-derived RPE cells have the similarity with native RPE and express RPE-specific markers.

In view of the fact iPSCs can be generated from any differentiated somatic cells by induction with “Yamanaka factors” [89,174], patient-specific iPSCs afford a potential cell replacement therapy that theoretically may circumvent immune rejection [175-177].

J Stem Cell Res Dev Ther ISSN: 2381-2060, Open Access Journal DOI: 10.24966/SRDT-2060/100014

In summary, iPSC-derived RPE cells are a promising cell source to replace defective RPE cells in retinal degeneration.

Transplantation of Stem Cell-Derived Photoreceptors, RPE for Retinal Repair Above, we have introduced stem cell sources of photoreceptors from stem cells above that are considered efficient cell sources for photoreceptor transplantation target to neuroretinal degenerative diseases. From the first attempts at transplantation of human ESC-derived neural progenitors into immunodeficient rats intravitreally and subretinally, which showed an insufficient sources for photoreceptor transplantation [178], to the preliminary successful research showing that human ESC/iPSC-derived neural progenitors could effectively protect vision in RCS rats (an AMD-like rat model) [179,180], the cumulative findings during the past few decades have encouraged researchers to further explore transplantation of retinal specific cell types.

Transplantation of Stem Cell-Derived RPE Cells: Preclinical Studies and Clinical Trials Previous studies of allogeneic and xenogeneic replacement therapy using autologous or mature RPE cells showed an unstable phenotype and a limited source of RPE cells, which provided a space for development of cell replacement therapies using stem cell-derived RPE [153,181-197]. Stem cell-derived RPE cells have been the focus of replacement therapy for AMD and STGD, which are assigned to macular disorders characterized by early loss of the RPE cells that maintain the survival of photoreceptors.

ESC-derived RPE cells were first transplanted as a monolayer to treat RPE dysfunction in RCS rats using primate ESCs and enhanced the survival of the host photoreceptors [198]. Subsequently, hESC-derived RPE cells were also utilized for subretinal transplantation in RCS rats and Elovl4 mutant mice (a STGD-like mouse model) and safely prompted preservation of visual function and production of more photoreceptors [154,155,199-201]. Likewise, hiPSC-derived RPE cells were also able to rescue vision in animal models of retinal degeneration [185,202-205]. These preclinical studies have set an encouraging and solid foundation for clinical trials of human ESC/ iPSC-derived RPE transplantation.

In 2011, the U.S. Food and Drug Administration approved phase I/II clinical trials for ESC-derived RPE transplantation in the treatment of macular degeneration [206]. According to the current registered clinical trials using stem cell-based therapies for STGD or AMD (https://clinicaltrials.gov/), phase I and II clinical trials are in progress for RPE replacement using hESC/iPSC-derived RPE cells in single-cell suspensions or in monolayers seeded on scaffolds. The preclinical study and clinical trial of hESC-derived RPE cell suspension (named MA09-RPE, forming a master cell bank of hESCs) for treatment of non-neovascular AMD and advanced STGD was first launched in America and primarily demonstrated the safety of subretinal transplantation of hESC-derived RPE cell suspension [206208]. In addition, the potential efficacy has also been confirmed by clinical trials (NCT02463344, NCT02563782) for non-neovascular AMD using a cell suspension with immunosuppressive therapy as resistance to rejection. Moreover, the same MA09-RPE cell suspension was used to treat non-neovascular AMD and STGD in a phase I/IIa Volume 5 • Issue 1 • 100014

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clinical trial in South Korea without abnormal proliferation and tumor formation [209].

In addition to the above therapeutic strategies using a stem cell-derived RPE cell suspension, an alternative optimized approach is to grow RPE cells on a bioengineered scaffold to form an RPE monolayer before transplantation, which can improve resistance to adverse events and produce polarized RPE cells in a highly functionalized cell monolayer [210-214]. As with CPCB-RPE1, hESC-derived RPE cells are seeded on a biosynthetic scaffold designed to mimic BM, produced as described previously [215,226]. Several preclinical studies were performed to evaluate the transplantation effects of CPCB-RPE1 into the RCS rats and Yucatan mini pigs, and the results indicated that CPCB-RPE1 implants survived in an intact monolayer without development of intraocular or systemic tumors [215-217]. Then, the safety and efficacy of CPCB-RPE1 transplantation was confirmed in a phase I/II a clinical trial for non-neovascular AMD in America, and visual improvement in the short term was observed in some patients. In England, an RPE patch named PF-05206388, composed of hESC-derived RPE monolayer on a coated and synthetic basement membrane, was implanted into the subretinal space of severe neovascular AMD patients, resulting in an increase in visual acuity over 12 months. Unwilling to lag behind, China has initiated two phase 0/I clinical trials for treatment of AMD conducted by Beijing Tongren hospital (NCT02755428) and Southwest hospital (NCT02749734).

The phase I clinical trials for neovascular AMD (NCT02749734) using a hESC-derived RPE cell suspension showed a limited functional improvement in vision, albeit to different degrees between patients [205].

Implantation studies of hiPSC-derived RPE cells have lagged behind those of hESC-derived RPE cells. However, allograft transplantation of hESC-derived RPE requires lifelong immunosuppressive therapy, and in contrast, iPSCs do not provoke an immune reaction [218,219]. Due to allowance for autologous transplantation, reduction of ethical issues and potentially unlimited cell sources, hiPSC-derived RPE cells have become widely used. Moreover, particularly, patient iPSC-derived RPE is considered the best in vitro disease modeling candidate to visually and accessibly monitor progression of human disease progression [197,220-222].

A preclinical study in Rpe65rd12/Rpe65rd12 mice showed that implantation of hiPSC-derived RPE cell suspension into this mouse model safely presented colocalization with the host native RPE cells and restored modest vision detected by Electroretinogram (ERG) [223]. Another preclinical study in RCS rats demonstrate that hiPSC-derived RPE cells have the ability to phagocytose photoreceptor material and maintain long-term visual function after transplantation of a cell suspension [185]. The other preclinical studies in RCS rats reported that transplantation of hiPSC-derived RPE cell suspension exhibited protective effects and restored visual function.

[197,202,214,224].

To optimize the beneficial effects to host retinal function, an intact donor hiPSC-derived RPE monolayer grown on biomaterial scaffolds was implanted, similar to hESC-derived RPE. This novel approach for hESC-derived RPE cells as apolarized monolayer on a thick synthetic scaffold was first transplanted into RCS rats [225], and subsequently, hESC-derived RPE cell patch or sheets on biodegradable scaffolds were used for AMD treatment in rodents and pigs and provided positive results for clinical trials [226-228].

J Stem Cell Res Dev Ther ISSN: 2381-2060, Open Access Journal DOI: 10.24966/SRDT-2060/100014

The progress in iPSC replacement therapy is cruising to the clinic.

In 2013, a clinical trial authority for hiPSC-derived RPE into patient treatment was approved in Japan [229]. In 2014, Takahashi’s group from the RIKEN Institute safely performed the first transplantation of autologous iPSC-derived RPE sheets for a female neovascular AMD patient in clinical trial. However, in 2015, RIKEN suspended the clinical trial for another patient due to genomic variations in iPSCs [230]. The landmark research results were finally published in 2017 and showed that the best visual acuity correction had not been improved or worsened 1 year after transplantation [137]. Currently, a novel clinical trial for autologous hiPSC-derived RPE transplantation in AMD is ongoing by Moor fields eye hospital (NCT02464956).

Transplantation of Stem Cell-Derived Photoreceptors The initial studies of photoreceptor replacement focused on photoreceptors derived from donor tissues [231-233], which are known as a very limited cell sources for clinical application. It was demonstrated that the development stage of donor cells influenced the grafting outcomes, and post-mitotic photoreceptor precursors isolated from P4 mouse retina were an optimal donor cell [231,234]. Then, transplantation of these photoreceptor cells successfully restored functional rod-mediated vision in Gnat1−/− mice [233], a model of congenital stationary night blindness with dysfunctional rods [235]. The fact that less mature photoreceptor precursors derived from mouse ESCs helped to improve transplantation success was again confirmed [132,236].

Numerous transplantation studies [129,132,135,139,224,241-239] have been subsequently performed with retinal cells differentiated from mouse ESCs and iPSCs generated using the differentiation protocol reported by Eiraku and Tucker [124,224] (Table 1). To obtain abundant photoreceptors derived from mouse ESC and iPSC and minimize potential tumor genesis from undifferentiated cells, cell-sorting strategies have been used to purify miscellaneous cell populations prior to transplantation [224,237]. These cell-sorting strategies via Fluorescence Activated Cell Sorting (FACS) and Magnetic Activated Cell Sorting (MACS) were established based on the expression of photoreceptor-specific fluorescent reporters or cell surface markers [233, 240-242]. They have been successfully used to purify mouse ESC- and iPSC-derived photoreceptors before transplantation [132,135,139,236,237]. These studies from different groups demonstrated that mouse ESC- and iPSC-derived photoreceptors have the competence to partially recover visual function in various mouse models associated with RD. In 1997, for the first time, a human photoreceptor obtained from adult human cadaveric eyes was successfully implanted into two RP patients but was unable to improve vision [243]. And transplantation of human fetal retinal sheets into RP patients showed that they are capable of surviving and improving vision partially with no rejection of the allogeneic transplant [244-246]. However, ethical issues and the limited source of fetal tissue-derived retinal sheets are bound to make it impossible to be used on a large scale.

Early, neural progenitors deriving from differentiation of hESCs were implanted into immune-suppressed rats and non-immunosuppressed mouse retinas, and the results indicated that they could survive for a long time without tumor formation but differentiated into photoreceptor-like cells with a low-level of efficiency [103,247].

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Subsequently, following transplantation into RCS rats, neural progenitors deriving human ESC and iPSC continued to present uncommitted progenitors with Nestin expression but no expression of specific retinal markers [248,249]. However, vision loss was significantly retarded in RCS rats although not completely halted, which may be mediated by phagotrophic capacity toward photoreceptor outer segments or secretion of neurotrophic factors from the injected neural progenitors [250].

In the earliest transplantation studies of human ESC- derived retinal cells (80%), they were transplanted into the subretinal space of Crx-/- mice (a mouse model of Leber’s Congenital Amaurosis) [251] and differentiated into functional photoreceptors and restored light responses in the mouse model 2–3 weeks after injection [107]. Moreover, human iPSC-derived photoreceptors purified via FACS in combination with a photoreceptor-specific GFP marker could integrate into the host ONL of adult wild-type mice, similar to normal mouse photoreceptors and human ESC-derived rod photoreceptors [107].

Similarly, human ESC- and iPSC-derived photoreceptor progenitors, following FACS or MACS sorting, differentiated into photoreceptors after transplantation into rd1 mice, and integrated into the host retinal neural circuit, restoring partial visual function [240]. In a recent study, human iPSC-derived mature photoreceptors brought mild recovery of host light perception when transplanted into rhodopsin mutant nude rats and primate models of retinal degeneration [252].

For the rod-dominated mouse retina, transplantation of donor rod photoreceptors into murine models of retinal disease improved vision to different degrees [233,234,240,253]. Theoretically, for cone-dominated human retinas, cone photoreceptor replacement should be the optimal strategy for treatment of human retinal degeneration. Several reports of cone transplantation showed a detectable restoration of visual function using a variety of cone and cone-like donor cells in degenerative hosts [238,254-256], which resulted from donor cone integration into degenerative retina. Meanwhile, a significant proportion of material transfer between donor cells and the host retina was observed in non-degenerative hosts [238, 254-261].

These clinical trials mentioned above for treating RD using stem cell-derived RPE have aroused a strong interest in promoting stem cell-derived photoreceptors toward clinical applications. One landmark step is that human ESC lines for therapeutic purposes have been derived from Good Manufacturing Practices (GMP)-compliant xeno-free and feeder-free protocols [262]. Moreover, fullly GMP-compliant human iPSC lines have been generated from adult fibroblasts with different inherited retinal diseases in patients [263]. Then, human ESC- and iPSC-derived photoreceptors were generated using feeder-free and xeno-free GMP conditions [125,127, 263-265].

Strategies for Delivering Stem Cell-Derived Photoreceptors, RPE Cells Stem cell-derived retinal cells are often injected into the eye via direct injection intravitreally or subretinally. Intravitreal injection is easier and less invasive and provides a more access to the Inner Retinal Layer (INL). However, this delivery route is associated with a risk of short-term complications, including retinal detachment, endophthalmitis, and hemorrhage [266,267].

Subretinal injection offers a direct and effective route to deliver donor cells with more precise localization via a minimally invasive J Stem Cell Res Dev Ther ISSN: 2381-2060, Open Access Journal DOI: 10.24966/SRDT-2060/100014

injection [206,268]. To avoid the complications and improve the injection effectiveness, subretinal delivery requires skill and stability until mastered. The routes of subretinal injection can be classified into three types: a trans-corneal route passing the lens and vitreous humor [269-272], a trans-scleral route entering the pars plana at the limbus or ora serrata [273-276]; and a transscleral route through the choroid and BM without penetrating the retina [277-279]. The choice of different routes depends on the anatomy of the eyeball according to the species and age. Bleb formation in the subretinal space, come down to retinal detachment that creates a space between the outer segment of the photoreceptor and the RPE, is defined as a successful sign of injection.

Delivering Stem Cell-Derived RPE Stem cell-derived RPE is implanted into the subretinal space as an isolated cell suspension or monolayer on a scaffold [285,286].

After subretinal injection, the scattered RPE cell suspension forms aggregates without an intact monolayer, initiates an immune response [282], and causes severe complications, such as proliferative vitreoretinopathy [215,283]. The use of biocompatible scaffolds [283-287] could avoid these issues and enables proper subretinal delivery of stem cell-derived RPE cells as a monolayer structure for transplantation [288]. Thus, monolayer RPE sheets can be constructed with naturally occurring polymers or synthetic scaffolds. Natural materials are reported to potentially cause a series of issues, such as risk of infection, difficulties controlling the consistency of the material, and mechanical instability [289,290]. Synthetic scaffolds are widely used due to their biocompatibility, ability to imitate the native Extracellular Matrix (ECM), and biodegradability [291-293]. Particularly, parylene, an undegradable synthetic material, is widely used in RPE sheet construction to aid in an intact formation of polarized monolayer without disruption of host RPE structure [210,216,294], which can promote donor RPE cells to survive and integrate into the host RPE [216]. As mentioned above, CPCB-RPE1, an hESC-derived RPE monolayer seeded on an ultrathin polymeric parylene-C scaffold, has been tested in a clinical trial [215,216]. Studies of other synthetic materials (i.e., PLGA, PET, and PCL) are also ongoing [225,295-297]. In addition, RPE sheet can be generated on a collagen coating without an additional scaffold and then released from the digested collagen coating [226]. Furthermore, a human iPSC-derived RPE sheet generated using this strategy has been transplanted onto one AMD patient [137].

Scaffold-based subretinal delivery requires a larger retinotomy into the subretinal space compared with dispersed cell delivery, and some efforts have to be made for more subtle manipulation and smaller microfabrication.

Delivering Stem Cell-Derived Photoreceptors The challenges of photoreceptor transplantation primarily involve how to improve the survival rate of transplanted photoreceptors and promote integration of transplanted cells with the host retina to restore vision function. The key step in photoreceptor transplantation is to guarantee effective delivery of donor photoreceptors into the host subretinal space. The strategies for donor photoreceptor delivery can primarily be divided into three approaches: injection of photoreceptor cell suspensions, transplantation of intact retinal or photoreceptor sheets and transplantation of photoreceptors seeded onto engineered scaffolds. Although these approaches have been applied for treatment Volume 5 • Issue 1 • 100014

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of photoreceptor degeneration and achieved an encouraging result, there is no single approach that perfectly solves all the problems [236,283,298-303].

Before transplantation studies toward stem cell-derived photoreceptors, transplantation of primary photoreceptors achieved considerable progress using a single-cell suspension approach [233,253,255,304].

Then, cell suspension transplantation of ESC- and iPSC-derived photoreceptors into mouse models of RD improved vision function as measured by ERG [107,109,224,305]. Notwithstanding the tactic of cell suspension transplantation has some crucial advantages, including precise control of the number of transplanted cells and minimally invasive delivery via subretinal injection [107,109,224,305], it also has some unexpected disadvantages, including high incidence of cell death of transplanted cells and low rates of cell survival and integration [129,306-309].

Transplantation of retinal sheets has been studied as an alternative tactics for photoreceptor replacement in RD. Many previous studies of photoreceptor replacement focused on the usage of intact retinal or photoreceptor sheets [232,243,246,310-312], but these individuals with these transplants presented large variations in visual function recovery. Similarly, mouse ESC- and iPSC-derived retinal sheets differentiated into mature photoreceptors with OSs and integrated into the host retina, restoring partial vision after transplantation into rd1 mice [129,239]; but hESC-derived retinal sheets were successfully transplanted into monkey and rat models of retinal degeneration, and then matured into structured grafts without positive functional changes in monkeys and resulted in visual function recovery as measured by Optokinetic Testing (OKT) in rats [313,314]. In addition to variations in visual function recovery, retinal sheet transplantation relatively highly invasive for the patient and often leads to an immune response to the transplants [315,316] compared with single-cell suspension.

To further improve photoreceptor transplantation, biomaterial scaffolds designed for photoreceptor delivery have been developed.

They can enhance cell survival and promote cell integration into the host retina. Many biomaterial scaffolds have been constructed using multiple polymers alone or jointly, such as PHBV8, PLLA, PLGA, PMMA, PGS, PCL, HA, PDMS, and MC, and have been applied in transplantation of mouse or porcine RPCs [288,306-308,317-322].

Biodegradable scaffolds with high permeability have an insurmountable advantage in promoting photoreceptor survival with nutrient and oxygen diffusion [225,304,318].

Future Directions and Challenges Ahead for Photoreceptor Regeneration As described above, stem cell-based therapies for neuroretinal diseases have achieved unprecedented progress in the last decades. With the progress in cell transplantation therapies, perhaps in the next 10 years, some neuroretinal diseases will be completely cured. Currently, transplantation studies of different stem cell-derived retinal cells are at different stages of development. Stem cell-derived RPE transplantation has been pushed into clinical trials and produced positive preclinical data. Due to the complex circuitry of photoreceptors within the inner retina or optic nerve, stem cell-derived photoreceptor replacement still lies at the preclinical study level with positive results.

In short, different grand challenges exist for the two cell transplantation therapies and remain to be overcome in the future.

Stem Cell-Derived RPE Transplantation ESC- and iPSC-derived RPE transplantation has been performed in numerous preclinical studies [154,155,185,197-199,215217,225,226,228,324,325] and clinical trials [137,206-208,326,327].

After human ESC-derived RPE transplantation into AMD or STGD patients, no tumor formation or immunological rejection was observed, confirming the safety [326,328]. However, no significant visual improvement was observed despite visible pigmentation and thickening of the RPE layer in the host retina detected by noninvasive fundus photography and Spectral Domain Optical Coherence Tomography (SD-OCT). Therefore, it is especially urgent to explore new strategies to promote curative effects.

The viability of RPE cells was significantly promoted by culture in Hyaluronan-Methylcellulose (HAMC) hydrogel combined with IGF-1 factor, which was illuminated by a study in which dual-use biocompatible materials can be used as drug delivery platforms or to encapsulate cells [329,330], indicating that strategies for co-delivery of growth factors and retinal cells to improve the curative effects of stem cell-derived RPE transplantation are promising. Future research needs to focus on this interesting point.

Furthermore, recent studies showed that 3D micro structured scaffolds promote efficient polarization of human iPSC-derived photoreceptors and basal axon extensions [323]. And two-photon polymerized polycaprolactone successfully supported human iPSC-derived retinal progenitor cells for implantation into a porcine model of retinitis pigmentosa [297]. These pioneering studies on the delivery of stem cell-derived photoreceptors combined with biomaterial scaffolds pave the way for future photoreceptor transplantation therapies.

Additionally, human iPSC-derived RPE has been reported [331] to exhibit differential expression of ES-associated miRNAs compared with human fetal RPE, and thus underscoring the importance of assessing human iPSC-derived RPE completely before transplantation.

Moreover, a clinical trial was suspended due to genomic variations found in the transplanted human allogeneic iPSCs [230], which may have a potential risk of tumorigenicity. To improve the reliability of stem cell-based treatment, donor iPSCs or iPSC-derived RPE cells must be subjected to extensive testing. Donor iPSCs induced from autologous somatic cells will be a good choice for stem cell-based treatment. For future allogeneic trials, a GMP-compliant bank of iPSCs, similar to that of ESCs, should be gradually established in all qualified medical institutions [230]. And these cells should be matched with patient Human Leukocyte Antigens (HLAs), thereby reducing the risk of immunological rejection [332-335].

Taken together, these strategies for delivering stem cell-derived retinal cells in combination with biodegradable scaffolds are very promising advanced techniques to treat and even cure neuroretinal diseases in the future.

In addition to the above burning problems, standardized cell differentiation, high-efficiency cell delivery, preferable safety evaluation, most suitable phase for transplantation therapies and therapeutic analysis are all unremitting pursuits for future clinical trials.

J Stem Cell Res Dev Ther ISSN: 2381-2060, Open Access Journal DOI: 10.24966/SRDT-2060/100014

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Stem Cell-Derived Photoreceptor Transplantation A number of transplantation studies using stem cell-derived photoreceptors have been carried out in many photoreceptor-deficient animal models (Table 1). Although the integration of transplanted photoreceptors into host retinas has been reported in some previous studies [107,237,240,336], vision improvement was not significantly observed due to insufficient integration of cells. Therefore, the first issue is how to obtained sufficient donor cells in an efficient and reliable manner. To overcome this issue, on the basis of fully GMP-compliant generation of human ESC- and iPSC-derived photoreceptors [125,127,263,265,337], an efficient and reliable cell sorting strategy could be added to the GMP guidelines. Certain cell-specific surface antigens (CD73 or C-Kit) have been used as markers for sorting photoreceptors from human fetal retinas or stem cell-derived organoids via MACS or FACS [205,338-340]. In the future, achievement of a GMP-compliant photoreceptor sorting strategy will lay the foundation for acquiring appropriate donor cells.

The second outstanding issue is how to interpret and identify material transfer or cell integration between donor cells and host retina after photoreceptor transplantation into animal models. Before material transfer (RNA and/or protein) was found in donor cells and host photoreceptors [257,258,341], the therapeutic efficiency of photoreceptor replacement was attributed to its integration into the host retina and differentiation of rods [107,109,233,234]. Human ESC- and iPSC-derived photoreceptors have been confirmed to integrate and form synaptic connections with host cells that result in vision improvement [129,239,305], and material transfer and cell integration could occur at the same time at different ratios [339,342-345]. However, more work needs to be performed to illuminate the cellular mechanisms of this phenomenon.

The third general issue is how to improve the effectiveness of treatments based on human iPSC-derived photoreceptor transplantation. As is known, autologous transplantation of photoreceptors derived from the patient’s own iPSCs will evade immunological rejection. However, iPSCs from patients still carry the disease-causing gene mutations, leading to potential risk of pathopoiesis after transplantation. CRISPR-Cas9 gene editing technology allows modification of the gene mutations in patient iPSCs during in vitro culture [346]. Our group has corrected an RPGR mutation in patient iPSCs using CRISPR/Cas9 gene editing technology in vitro, which rescued photoreceptor structure and electrophysiological property in retinal organoids derived from these iPSCs [149]. Therefore, human iPSC-derived photoreceptors with CRISPR-Cas9-mediated correction will be a promising strategy for treatment of inherited retinal disorders.

How to definitively solve cone transplantation is also a worthy concern. Previously, the vast majority of studies primarily focused on rod transplantation and demonstrated that transplanted donor rod photoreceptors possess the ability to rescue vision impairment in rodent models of retinal diseases [109,190,231,234,236,240,256,303,339,342345,347]. Notwithstanding, cone transplantation has also been reported recently [254-256], and these transplanted donor cones were characterized by rod-like morphological features, which were deemed J Stem Cell Res Dev Ther ISSN: 2381-2060, Open Access Journal DOI: 10.24966/SRDT-2060/100014

to result from cell integration and/or material transfer determined by the different host microenvironments [238], but detailed mechanisms need to be further explored to improve the efficiency of cone transplantation.

Actually, the influencing factors in photoreceptor transplantation are more than those mentioned above. Suitable preclinical animal models, immune rejection, tumor formation, cell survival, and delivery systems should all be further optimized carefully and continuously before clinical trials.

The Expected Role of Retinal Glial Cells in Stem Cell-Based Therapy for Neuroretinal Diseases Not only that, a new strategy for stem cell-based combined transplantation has been developed to treat various no-ocular diseases or injury such as severe aplastic anemia [348], acute blood loss [349], Graft Versus Host Disease (GVHD) [350], myocardial infarction [351], diabetes [352], and cavernous nerve injury-related erectile dysfunction [33]. And these studies of combined transplantation confirmed a more positive and encouraging result than that of single transplantation. Previous studies have demonstrated that MSCs were able to promote the survival and functionalization of retinal cells after single transplantation through secretion of neuroprotective factors and deactivation of inflammatory pathway [354-356]. As expected, combined transplantation of human RPCs and MSCs into subretinal space of RCS rats presented better therapeutic effect in functional maintenance and structural integration than that of single transplantation [357]. Likewise, in vivo intravitreal combined transplantation of human iPSCs and mouse RGCs facilitated RGC neurites into longer extension than single transplantation of mouse RGCs [358]. Therefore, for treating neuroretinal diseases effectively, a new co transplantation tactics in combination with stem cell-derived photoreceptors or RPE cells appears to be a promising way to give full play to the effects of transplanted cells. Microglia is selected as targeted cells for combined transplantation with stem cell-derived photoreceptors or RPE cells.

Microglia are a group of highly specialized immune cells and widely exist in CNS, including retina, which play a pivotal role in immune surveillance and maintaining homeostasis of retinal microenvironment [359,360]. Microglia has been confirmed to have neuroprotective effects against neuronal death in ischemic brain injury [361,362]. And microglia is also capable of phagocytizing injured photoreceptors and preventing the death of photoreceptors in acute retinal detachment [363]. Recent studies further demonstrated that subretinal microglia in photoreceptor degeneration played an important role in protection of RPE structural integrity [364]. Therefore, microglia should be able to improve subretinal microenvironment prior to transplantation suitable for the survival of transplanted photoreceptors or RPE cells. In addition, microglia can be generated from induction of human ESCs and iPSC [365,366], providing sufficient cell sources for combined transplantation studies. Taken together, combined transplantation of stem cell-derived microglia and photoreceptors or RPE cells will become the next another target to treat neuroretinal diseases.

Moreover, as mentioned above, Müller Glia (MG) are also promising targeted cells to be directly reactivated and differentiate into new retinal neurons in vivo with the development of induced techniques.

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Donor cell sources

Human MG-derived photoreceptors

Human RPCs and MSCs

Host animal models

Transgenic P23H rats [367]

RCS rats with Mertk mutation [368]

Target diseases

Cell dose

Retinitis Pigmentosa (RP)

Total 2 μl containing 1 μl cell suspension and 4 × 104 photoreceptor differentiated cells

RP

Rho−/− mice [373]

RP

Gucy2e-/-mice [371]

Leber congenital amaurosis (LCA)

Subretinal injection

Subretinal injection

Gnat1−/− mice [235]

2× 10 cells/1 μl sorted by FACS 5

CSNB

Rho−/− mice [373]

Reference

4 weeks after transplantation

Transplanted cells migrated and integrated into the ONL Significant rod function improvement measured by scotopic flash ERG

[80]

3 weeks after transplantation

Combined transplantation has a higher ratio of photoreceptor differentiation and low immunoreaction than single transplantation

[357]

3-6 months after transplantation

Preserve visual function measured

by OKR

[376]

Subretinal injection via superior sclera

2-3 weeks after transplantation

No robust integration and maturation of photoreceptors Increased cell death and gliosis

[96]

8-12 weeks Subretinal injection by trans-scleral route

2× 10 cells/1 μl sorted by FACS

mice Prph2 [374]

Effects of transplantation

Congenital stationary night blindness(CSNB)

5

rd2/rd2

Time point for evaluation

6-12weeks

Rho−/− mice [379]

Mouse iPSC-derived photoreceptor precursors using 2D culture

3 weeks

8-12weeks Gnat-/- mice [235]

Mouse ESC-derived rod photoreceptors using 3D culture

3 weeks

Delivery methods

5× 104-1× 105 cells/2 μL

Human RPCs

Mouse ESC-derived rod photoreceptors using 2D culture

Total 4 × 105 cells/5 μl separately and together

Time window (postnatal)

3 weeks after transplantation

3-4 weeks RP

RP

4-6 week

Subretinal injection

3 weeks after transplantation

1.1.6 × 105 integrated cells 2. Increased b-wave amplitude measured by ERG

[224]

[239]

[129]

Mouse iPSC-derived retinal sheets using 3D culture

Pde6brd1 mouse [375]

RP

0.5 mm × 2 mm retinal sheets

6-9 weeks

Subretinal injection

2-4 weeks after transplantation

Photoreceptor responses recorded by ex vivo micro-ERG and ganglion cell responses recorded MEA

Mouse ESC/ iPSC derived retinal sheet using 3D culture

Pde6brd1 mouse [375]

RP

0.5 mm x 1.5-2 mm retinal sheets

6-8 weeks

Subretinal injection

2 weeks to 6 months after transplantation

Form synaptic connections

J Stem Cell Res Dev Ther ISSN: 2381-2060, Open Access Journal DOI: 10.24966/SRDT-2060/100014

[372]

Form shorter segments

8 weeks

2.5× 105 cells/lμl

2.5 × 104 integrated cells form long outer segments Vision restoration measured by water maze and optometry system

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Mouse ESC-derived cone photoreceptors using 3D culture

Human ESC-derived photoreceptor precursors using 2D culture

Human ESC- and iPSC-derived photoreceptor progenitors

Nrl−/− mice [376]

“Cod” hybrid phenotype

Prph2rd2/rd2 [374]

RP

RPE65R91W/R91W [377]

Cone degeneration

Crx -/- mice [379]

Pde6brd1 mouse [375]

LCA

RP

Significant material transfer 2× 105 cells/1 μL sorted by FACS

Immunodeficient rho S334ter-3 rat [380]

5× 104-8× 104 cells/1 μL

2 × 105 cells/2μL

0-3 days (intravitreal) and 4-6 weeks (subretinal)

10-12 weeks

Intravitreal and subretinal injections

Subretinal injection by trans-scleral route

4,5,6,9,11 years

RP

Retinal sheets

26-38 days

Immunodeficient NOG-rd1-2J and NOG-rd10 [382]

Human iPSC-derived retinal sheets using 3D culture

Subretinal injection by trans-scleral route

Subretinal injection

8 weeks

Immunodeficient SD-Foxn1 Tg(S334ter)3LavRrrc nude rats [383]

2-5 months

RP

2-3 weeks after transplantation

Significant cones integration

[238]

Significant material transfer

RP-like monkey model induced by cobalt chloride or laser photocoagulation [313]

Human ESC-derived retinal sheets using 3D culture

2-3 months

[107]

3 weeks after transplantation

Survival and maturation in vivo of few transplanted cells Partial vision recovery measured by optomotor response (OMR) and light avoidance behavior

[109]

35, 88, 123, and 148 days after transplantation

Lack positive functional results Differentiation into various retinal cells

[313]

2 weeks after transplantation

Produce functional photoreceptor Visual improvements measured

by OKR and SC electrophysiologic recording

[381]

4 weeks after transplantation

Long-term survival Functional integration Light responses measured by MEA

[382]

3-5 months after transplantation

Formation of outer segments and integration into host bipolar cells Observed RGC light responses by MEA

Subretinal injection by trans-vitreal route

Retinal sheets

RP-like monkey model induced by cobalt chloride or laser photocoagulation [313]

2 weeks after transplantation

1.3 × 103Nrl+ integrated human cells 2. A small, significant ERG response

9 months

6-7 months after transplantation

[252]

Mild vision recovery measured by Visually-Guided Saccades (VGS)

Table 1: Representative stem cell transplantation studies in animal models of photoreceptor-defective diseases.

Conclusion

Competing Interest

In terms of depth and breadth, translational medicine studies on stem cell transplantation for treatment of neuroretinal diseases have made considerable progress. Although these encouraging advances have brought great hope to the treatment of neuroretinal diseases, there are still big challenges ahead that need to be further explored and overcome. The new techniques of stem cell-based transplantation are also worthy of unwearied pursuit.

The author declares that has no competing interests.

J Stem Cell Res Dev Ther ISSN: 2381-2060, Open Access Journal DOI: 10.24966/SRDT-2060/100014

Acknowledgment This work was partly supported by Zhejiang Provincial Natural Science Foundation of China (LQ17H120005); National Key Research and Development Program of China (2017YFA0105300); Ministry of Education 111 project (D16011).

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