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S. Parameswaran, S. Balasubramanian, N. Babai, W. B. Thoreson, I. Ahmad; Induced Pluripotent Stem Cells (iPSCs) Generate Both Early and Late Born Retinal Neurons. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2646.
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The direct reprogramming of somatic cells to a pluripotent state holds significant implications in treating intractable degenerative diseases by ex-vivo cell therapy. These reprogrammed cells can also serve as a model for diseases and discovery of drugs and genes. Here, we examined the depth of retinal potential of mouse iPSCs to determine their usefulness in formulating stem cell approaches to understand and treat retinal degenerative diseases.
Mouse fibroblast iPS cell line, iPS-MEF-Ng-20D-17 (Okita et al., 2007, Nature 448: 313-317) was subjected to previously described, neural differentiation protocol for ES cells (Zhao et al., 2002, BBRC 297(2):177-84). Following neural induction, cells were cultured in the presence of Noggin and FGF2 to enrich retinal progenitors. These cells were cultured in simulated environments of early and late retinal histogenesis to examine their potential to generate a range of retinal cell types on biochemical, molecular and physiological criteria.
The neural induction and expansion significantly altered the global gene expression in iPSCs and caused an up-regulation of transcripts corresponding to eye-field genes. Neurally induced iPSCs when cultured in the E14 retinal cell condition medium responded by down regulating retinal progenitor markers and activating the expression of the regulators and markers of retinal ganglion cells (RGCs). The iPSC-derived RGCs elaborated processes and interacted with cells in the explants of superior colliculus, a target of RGCs in the retina. The cells when cultured with PN1 retinal cell CM responded by activating the expression of regulators and markers of rod photoreceptors. When transplanted intravitreally in neonatal pups, a small subset of these cells incorporated in the outer nuclear layer and expressed rhodopsin. We also observed that induced iPSC possess the potential to differentiate along cone photoreceptor lineage when exposed to the environment simulating early histogenesis.
Mouse fibroblast iPSCs can generate a wide range of retinal cell types. This depth of retinal potential suggests that they may support stem cell approaches to understand and treat a wide range of degenerative retinal diseases, from glaucoma to age-related macular degeneration.
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