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Guiding non‐neural, retinal pigment epithelium (RPE) to produce retinal neurons may offer a source of developing neurons for cell‐replacement.  Sox2  plays important roles in maintaining neural progenitor/stem cell properties and in converting fibroblasts into pluripotent stem cells. This study tests the possibility of using  Sox2  to reprogram RPE to differentiate toward retinal neurons in vivo and in vitro. Expression of  Sox2  in the chick retina was detected in progenitor cells, in cells at a discrete location in the layers of amacrine and ganglion cells, and in Műller glia. Overexpression of  Sox2  in the developing eye resulted in hypopigmentation of the RPE. In the affected regions, expression of retinal ganglion cell markers became apparent in the RPE layer. In RPE cell culture,  Sox2  promoted the expression of retinal ganglion and amacrine markers, and suppressed the expression of genes associated with RPE properties. Mechanistic investigation using the developing retina revealed a coexpression of  Sox2  and basic fibroblast growth factor ( bFGF ), a growth factor commonly used in stem cell culture and capable of inducing RPE‐to‐retina transdifferentiation (or reprogramming) during early development. Similar patterns of changes in  Sox2  expression and in  bFGF  expression were observed in atrophic retina and in injured retina. In RPE cell culture,  Sox2  and  bFGF  mutually enhanced one another's expression. Upregulation of  bFGF  expression by  Sox2  also occurred in the retina. These results suggest that  Sox2  can initiate a reprogramming of RPE cells to differentiate toward retinal neurons and may engage  bFGF  during the process. S TEM  C ELLS  2009;27:1376–1387

Reprogramming Retinal Pigment Epithelium to Differentiate Toward Retinal Neurons with Sox2