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Recapitulation of Human Retinal Development from Human Pluripotent Stem Cells Generates Transplantable Populations of Cone Photoreceptors

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Anai Gonzalez-Cordero, Kamil Kruczek, Arifa Naeem, Milan Fernando, Magdalena Kloc, Joana Ribeiro, Debbie Goh, Yanai Duran, Samuel J.I. Blackford, Laura Abelleira-Hervas, Robert D. Sampson, Ian O. Shum, Matthew J. Branch, Peter J. Gardner, Jane C. Sowden, James W.B. Bainbridge, Alexander J. Smith, Emma L. West, Rachael A. Pearson, Robin R. Ali

Original languageEnglish
Pages (from-to)820-837
Number of pages18
JournalStem cell reports
Volume9
Issue number3
Early online date24 Aug 2017
DOIs
Accepted/In press27 Jul 2017
E-pub ahead of print24 Aug 2017
Published12 Sep 2017

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Abstract

Transplantation of rod photoreceptors, derived either from neonatal retinae or pluripotent stem cells (PSCs), can restore rod-mediated visual function in murine models of inherited blindness. However, humans depend more upon cone photoreceptors that are required for daylight, color, and high-acuity vision. Indeed, macular retinopathies involving loss of cones are leading causes of blindness. An essential step for developing stem cell-based therapies for maculopathies is the ability to generate transplantable human cones from renewable sources. Here, we report a modified 2D/3D protocol for generating hPSC-derived neural retinal vesicles with well-formed ONL-like structures containing cones and rods bearing inner segments and connecting cilia, nascent outer segments, and presynaptic structures. This differentiation system recapitulates human photoreceptor development, allowing the isolation and transplantation of a pure population of stage-matched cones. Purified human long/medium cones survive and become incorporated within the adult mouse retina, supporting the potential of photoreceptor transplantation for treating retinal degeneration.

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