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Differentiation and Transplantation of Embryonic Stem Cell-Derived Cone Photoreceptors into a Mouse Model of End-Stage Retinal Degeneration

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Kamil Kruczek, Anai Gonzalez-Cordero, Debbie Goh, Arifa Naeem, Mindaugas Jonikas, Samuel J.I. Blackford, Magdalena Kloc, Yanai Duran, Anastasios Georgiadis, Robert D. Sampson, Ryea N. Maswood, Alexander J. Smith, Sarah Decembrini, Yvan Arsenijevic, Jane C. Sowden, Rachael A. Pearson, Emma L. West, Robin R. Ali

Original languageEnglish
Pages (from-to)1659-1674
Number of pages16
JournalStem cell reports
Volume8
Issue number6
Early online date25 May 2017
DOIs
Accepted/In press26 Apr 2017
E-pub ahead of print25 May 2017
Published6 Jun 2017

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Abstract

The loss of cone photoreceptors that mediate daylight vision represents a leading cause of blindness, for which cell replacement by transplantation offers a promising treatment strategy. Here, we characterize cone differentiation in retinas derived from mouse embryonic stem cells (mESCs). Similar to in vivo development, a temporal pattern of progenitor marker expression is followed by the differentiation of early thyroid hormone receptor β2-positive precursors and, subsequently, photoreceptors exhibiting cone-specific phototransduction-related proteins. We establish that stage-specific inhibition of the Notch pathway increases cone cell differentiation, while retinoic acid signaling regulates cone maturation, comparable with their actions in vivo. MESC-derived cones can be isolated in large numbers and transplanted into adult mouse eyes, showing capacity to survive and mature in the subretinal space of Aipl1−/− mice, a model of end-stage retinal degeneration. Together, this work identifies a robust, renewable cell source for cone replacement by purified cell suspension transplantation.

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