Abstract
SummaryThe 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.
Highlights
Cone photoreceptors mediate high acuity and color vision in daylight
Postmitotic photoreceptor precursors isolated from donor mice injected subretinally as a suspension are capable of driving visual function in models of retinal degeneration (Barnea-Cramer et al, 2016; MacLaren et al, 2006; Pearson et al, 2012; Santos-Ferreira et al, 2015; Singh et al, 2013)
We have reported transplantation of a mixed population of embryonic cone rod homeobox-positive (CRX+) photoreceptors, enriched for cones compared with postnatal stages (Lakowski et al, 2010), while Ader and colleagues used cone-like cells from mice lacking NRL, a transcription factor essential for rod genesis, reporting an improvement in light-evoked responses in mice lacking cone function (Santos-Ferreira et al, 2015)
Summary
Cone photoreceptors mediate high acuity and color vision in daylight. Cones are a rare subtype in most mammals, constituting approximately 3% of photoreceptors in mice and 5% in humans (Jeon et al, 1998). Retinal sheet transplantation has the advantage of supplying a structured tissue, injection of a flat, thick sheet of cells with the correct polarity into the subretinal space is surgically challenging (Reh, 2016; Seiler and Aramant, 2012). Postmitotic photoreceptor precursors isolated from donor mice injected subretinally as a suspension are capable of driving visual function in models of retinal degeneration (Barnea-Cramer et al, 2016; MacLaren et al, 2006; Pearson et al, 2012; Santos-Ferreira et al, 2015; Singh et al, 2013)
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