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Peter D. Westenskow, Tim U. Krohne, Toshihide Kurihara, Edith Aguilar, Saiyong Zhu, Oscar Yanes, Gary Siuzdak, Sheng Ding, Martin Friedlander; hiPS-RPE Derived With OCT4 And Small Molecules Resemble Fetal hRPE And Prevent Photoreceptor Degeneration In RCS Rats. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3192.
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The potential to generate autologous grafts for transplantation in patients with blinding disorders such as AMD can be realized by reprogramming somatic cells to pluripotency and directing them into RPE fates. Conventional reprogramming involves lentiviral-delivered Yamanaka or Thomson factors. However, safety and regulatory concerns persist and hiPS-RPE may have unique transcriptional profiles that make their clinical usefulness questionable until functional genomic analyses (i.e. metabolomic assays) are completed.
OCT4 transduction and small biomicking molecules effectively convert human keratinocytes to iPS (referred to as 1F-iPS). 1F-iPS-RPE were derived and compared with primary fetal (hfRPE), adult (hRPE), and immortalized (ARPE-19) RPE using different techniques. Protein expression of RPE markers was quantified using in-cell westerns and ELISAs. Metabolomic profiles were generated using a large-scale untargeted mass-spectrometry based approach. Finally, 1F-iPS-RPE were transplanted in RCS rat eyes and monitored over several months with OCT imaging and histology.
1F-iPS-RPE exhibit classic morphologies, express RPE-specific markers at similar levels as hfRPE, and have very similar metabolomic profiles as hfRPE. The metabolomic profiles of conventional hiPS-RPE, however, are dramatically unlike any of the RPE cell-types examined. 1F-iPS-RPE are functional in vivo, and once implanted prevent retinal degeneration in RCS rats up to 18 weeks after the procedure; importantly, no tumors were observed.
Many of the safety and regulatory concerns about the use of iPS cells may be alleviated by using 1F-iPS. However, the strongest rationale for the use of these cells is that 1F-iPS-RPE most strongly resemble hfRPE while conventional hiPS-RPE have a distinct metabolomic profile that may preclude their use in the clinic. Furthermore, 1F-iPS-RPE function in vivo and mediate anatomical rescue of photoreceptors in RCS rats making them excellent potential substitutions for diseased RPE.
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