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Stem cells (Dayton, Ohio)
05, 2019;37 (5): 609-622.

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

Joseph Collin, Darin Zerti, Rachel Queen, Tiago Santos-Ferreira, Roman Bauer, Jonathan Coxhead, Rafiqul Hussain, David Steel, Carla Mellough, Marius Ader, Evelyne Sernagor, Lyle Armstrong, Majlinda Lako
Author Information
  1. Joseph Collin: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
  2. Darin Zerti: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
  3. Rachel Queen: Genomics Core Facility, Newcastle University, Newcastle, United Kingdom.
  4. Tiago Santos-Ferreira: CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany.
  5. Roman Bauer: Institute of Neuroscience, Newcastle University, Newcastle, United Kingdom.
  6. Jonathan Coxhead: Genomics Core Facility, Newcastle University, Newcastle, United Kingdom.
  7. Rafiqul Hussain: Genomics Core Facility, Newcastle University, Newcastle, United Kingdom.
  8. David Steel: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
  9. Carla Mellough: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
  10. Marius Ader: CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden, Germany.
  11. Evelyne Sernagor: Institute of Neuroscience, Newcastle University, Newcastle, United Kingdom.
  12. Lyle Armstrong: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
  13. Majlinda Lako: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom. ORCID
PMID: 30681766 DOI: 10.1002/stem.2974

Abstract

Death of photoreceptors is a common cause of age-related and inherited retinal dystrophies, and thus their replenishment from renewable stem cell sources is a highly desirable therapeutic goal. Human pluripotent stem cells provide a useful cell source in view of their limitless self-renewal capacity and potential to not only differentiate into cells of the retina but also self-organize into tissue with structure akin to the human retina as part of three-dimensional retinal organoids. Photoreceptor precursors have been isolated from differentiating human pluripotent stem cells through application of cell surface markers or fluorescent reporter approaches and shown to have a similar transcriptome to fetal photoreceptors. In this study, we investigated the transcriptional profile of CRX-expressing photoreceptor precursors derived from human pluripotent stem cells and their engraftment capacity in an animal model of retinitis pigmentosa (Pde6brd1), which is characterized by rapid photoreceptor degeneration. Single cell RNA-Seq analysis revealed the presence of a dominant cell cluster comprising 72% of the cells, which displayed the hallmarks of early cone photoreceptor expression. When transplanted subretinally into the Pde6brd1 mice, the CRX cells settled next to the inner nuclear layer and made connections with the inner neurons of the host retina, and approximately one-third of them expressed the pan cone marker, Arrestin 3, indicating further maturation upon integration into the host retina. Together, our data provide valuable molecular insights into the transcriptional profile of human pluripotent stem cells-derived CRX photoreceptor precursors and indicate their usefulness as a source of transplantable cone photoreceptors. Stem Cells 2019;37:609-622.

Keywords

CRX Pde6brd1 mice Photoreceptors Pluripotent stem cells Single cell RNA-seq Subretinal transplantation

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Grants

  1. MR/N015037/1/Medical Research Council
  2. MC_PC_15030/MRC
  3. MC_UP_1501/2/Medical Research Council
  4. NC/C016106/1/National Centre for the Replacement, Refinement and Reduction of Animals in Research
  5. MR/M008886/1/MRC
  6. MC_PC_15030/Medical Research Council
  7. #BB/I02333X/1/BBSRC
  8. MR/M008886/1/Medical Research Council
  9. MC_UU_00015/9/Medical Research Council
  10. MR/R011338/1/Medical Research Council

MeSH Term

Animals
Cell Differentiation
Cell Lineage
Humans
Induced Pluripotent Stem Cells
Mice
Organoids
Pluripotent Stem Cells
Retina
Retinal Cone Photoreceptor Cells
Retinal Degeneration
Retinal Rod Photoreceptor Cells
Transcriptome
Journal Article Research Support, Non-U.S. Gov't

Links to CNCB-NGDC Resources

GEN: GEND000039 (Single cell RNA-seq of CRX+ cells obtained at day 90 of retinal organoid differentiation)

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