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CRX Expression in Pluripotent Stem Cell Derived Photoreceptors Marks a Transplantable Subpopulation of Early Cones

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CRX Expression in Pluripotent Stem Cell Derived Photoreceptors Marks a Transplantable Subpopulation of Early Cones EMBRYONIC STEM CELLS/INDUCED PLURIPOTENT STEM CELLS CRX Expression in Pluripotent Stem Cell-Derived Photoreceptors Marks a Transplantable Subpopulation of Early Cones JOSEPH COLLIN,a,* DARIN ZERTI,a,* RACHEL QUEEN,b TIAGO SANTOS-FERREIRA,c ROMAN BAUER,d b b a a c JONATHAN COXHEAD, RAFIQUL HUSSAIN, DAVID STEEL, CARLA MELLOUGH, MARIUS ADER, d a a EVELYNE SERNAGOR, LYLE ARMSTRONG, MAJLINDA LAKO Key Words. Photoreceptors • Pluripotent stem cells • CRX • Single cell RNA-seq • Pde6brd1 mice • Subretinal transplantation a Institute of Genetic Medicine, ABSTRACT Newcastle University, Newcastle, United Kingdom; Death of photoreceptors is a common cause of age-related and inherited retinal dystrophies, bGenomics Core Facility, thus their replenishment from renewable stem cell sources is a highly desirable therapeutic goal. Newcastle University, Human pluripotent stem cells provide a useful cell source in view of their limitless self-renewal Newcastle, United Kingdom; capacity and potential to differentiate not only into cells of the retina but also self-organize into cCRTD/Center for tissue with structure akin to the human retina as part of three-dimensional retinal organoids. Regenerative Therapies Photoreceptor precursors have been isolated from differentiating human pluripotent stem cells Dresden, Center for Molecular through application of cell surface markers or fluorescent reporter approaches and shown to and Cellular Bioengineering, have a similar transcriptome to fetal photoreceptors. In this study, we investigated the transcrip- Technische Universität tional profile of CRX-expressing photoreceptor precursors derived from human pluripotent stem Dresden, Dresden, Germany; cells and their engraftment capacity in an animal model of retinitis pigmentosa (Pde6brd1), which dInstitute of Neuroscience, is characterized by rapid photoreceptor degeneration. Single cell RNA-Seq analysis revealed the Newcastle University, presence of a dominant cell cluster comprising 72% of the cells, which displayed the hallmarks of Newcastle, United Kingdom early cone photoreceptor expression. When transplanted subretinally into the Pde6brd1 mice, the CRX+ cells settled next to the inner nuclear layer, made connections with the inner neurons of the *Contributed equally. host retina and approximately one-third expressed the pan cone marker, Arrestin 3, indicating Correspondence: Majlinda Lako, further maturation upon integration into the host retina. Together, our data provide valuable + Ph.D., Institute of Genetic molecular insights into the transcriptional profile of human pluripotent stem cells-derived CRX Medicine, International Centre photoreceptor precursors and indicate their usefulness as a source of transplantable cone pho- for Life, Newcastle University, toreceptors. STEM CELLS 2019;00:1–15 Newcastle upon Tyne NE1 3BZ, United Kingdom. Telephone: 44-191-241-8688; e-mail: SIGNIFICANCE STATEMENT [email protected] Diseases affecting the retina, the light-sensitive extension of the central nervous system, account Received June 23, 2018; for approximately 26% of global blindness. Human pluripotent stem cells have been shown to accepted for publication December 3, 2018; first differentiate into various retinal cell types, including photoreceptors, which can be enriched by published online in STEM CELLS cell surface or fluorescent molecule tagging approaches. Molecular heterogeneity of photorecep- EXPRESS January 25, 2019. tor precursors derived from human pluripotent stem cells and their capacity to engraft into a fast degenerative model of retinitis pigmentosa have been investigated. Data show that photorecep- http://dx.doi.org/ 10.1002/stem.2974 tor precursors characterized by CRX expression are largely homogenous and committed to an early cone phenotype. Upon transplantation into degenerated retinae, these precursors settle This is an open access article into the appropriate layer, make connections with the host interneurons, and mature into cones. under the terms of the Creative Future work is needed to assess at the functional level whether the transplanted cells are able Commons Attribution License, which permits use, distribution to restore vision in degenerative models of retinal disease. and reproduction in any medium, provided the original work is properly cited. INTRODUCTION and partially sighted people in Europe with an average of 1 in 30 individuals experiencing sight Blindness represents an increasing global prob- loss. The major causes of blindness are cata- lem which is closely correlated with old age. racts, glaucoma, and age-related macular degen- One in 3 people over 65 are at risk for devel- eration [2]. The latter accounts for 50% of blind oping sight loss and 90% of visually impaired and partially sighted registration with an esti- people are over the age of 65 [1]. Overall, mated prevalence of ~600,000 significantly visually there are estimated to be over 30 million blind impaired people in the U.K. and over 8 million STEM CELLS 2019;00:1–15 www.StemCells.com ©2019 The Authors. STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press 2019 2 Pluripotent Stem Cells-Derived CRX+ Photoreceptors worldwide. Antioxidants, neuronal survival agents and vascu- labeled hESC line, in which expression of the green fluorescent lar endothelial growth factor inhibitors have been shown to protein (GFP) was controlled by CRX, a key transcription factor slow disease progression; however, to date there are no in retinal development with predominant expression in post- treatments to restore lost retinal cells and improve visual mitotic precursors [17]. We have differentiated this cell line to function; thus, there is a pressing need for research into the retinal organoids and have enriched the postmitotic CRX expres- replacement and/or reactivation of dysfunctional photorecep- sing photoreceptor precursors by fluorescence activated cell + tors and the adjoining retinal pigment epithelium (RPE) cells, sorting. We have performed single cell RNA-seq of the CRX both of which are essential for normal retinal function. precursors to assess intercellular heterogeneity and in parallel Human embryonic stem cells (hESC) and induced pluripo- we have tested their engraftment into an animal model of early onset severe retinal degeneration (Pde6brd1). Our data suggest tent stem cells (hiPSC) have an intrinsic capacity to differentiate + into self-organized laminated retinal organoids which contain all that the 72% of CRX precursors are characterized by the the key retinal cell types that form synaptic connections, respond expression of early cone markers, with a small minority (28%) to light and electrophysiological stimuli and engraft in animal expressing genes involved in cholesterol and mitochondrial bio- + models of retinal degeneration [3–10]. These retinal organoids genesis. Furthermore, we show that the CRX photoreceptor have been shown to recapitulate human retinal development precursors integrate into the correct retinal layer and make syn- [8] and moreover to yield a population of cone photoreceptors aptic connections with the host bipolar cells of Pde6brd1 mice. which are able to both integrate and undergo material transfer in an environment-dependent manner [11]. A growing number of recent publications have also indicated the usefulness of MATERIALS AND METHODS fi patient speci c retinal organoids for disease modeling and tox- Human Pluripotent Stem Cell Culture – icology studies [12 14]. and Differentiation fi Despite this progress, there is a need to improve the ef - 0 ciency and scalability of retinal organoid production, optimize The hESC line harboring the GFP reporter at the 3 UTR of CRX locus was expanded in mTeSR1 (Stem Cell Technologies, Vancouver, the differentiation protocols, and characterize the retinal cell types generated within the organoids. For cell based therapies, it BC, Canada) at 37 Cand5%CO2 on 6-well plates precoated with is important to generate and enrich defined populations of reti- Low Growth Factor Matrigel (Corning Life Sciences, Acton, MA). nal cells of interest (e.g., photoreceptors, RPE cells) and assess Differentiation to retinal organoids was performed as described fi their transplantation into the context of host retinal environ- in Mellough et al. [5] with minor modi cations which included fi ment. Various approaches have been used to selectively enrich addition of 10 μM Y27632 dihydrochloride for the rst 48 hours of retinal cell types from these complex organoids including immu- differentiation and 10% fetal calf serum, T3 (40 ng/ml), taurine nostaining with cell surface markers [15, 16] or flow activated cell (0.1 mM), and retinoic acid (0.5 μM) from day 18 of differentia- sorting using reporter labeled cell lines [17, 18], which harbor tion. Retinal organoids were collected on day 90 for single cell fluorescent markers of key photoreceptor transcription factors RNA-Seq studies and day 90 and 120 for subretinal transplants. such as cone rod homeobox (CRX) or neural retina leucine zipper (NRL) genes. Enrichment of photoreceptors is, however, not suffi- Single Cell RNA-Seq cient for ensuring successful engraftment into an adult retina. Generation of Single Cell cDNA Library for mRNA Sequencing. Work performed in animal models has shown that the maturity Retinal organoids at day 90 of differentiation were dissociated to of stem cell-derived photoreceptor precursors is critical for single cells using the Embryoid Body Dissociation Kit (Miltenyi ensuring the directed engraftment of cells into the correct
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