Journal
STEM CELL REPORTS
Volume 13, Issue 4, Pages 761-774Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2019.08.014
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Funding
- Japan Agency for Medical Research and Development (AMED) [JP16am0101059, JP18am0101103]
- Japan Society for the Promotion of Science (JSPS) KAKENHI [17H06305]
- Grants-in-Aid for Scientific Research [17H06305] Funding Source: KAKEN
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The first-in-human trial of induced pluripotent stem cell (iPSC)-based autologous transplantation was successfully performed on a female patient with age-related macular degeneration. Here we delineated the base-resolution methylome of the iPSC-derived retinal pigment epithelium (iRPE) used in this trial. The methylome of iRPE closely resembled that of native RPE (nRPE), although partially methylated domains (PMDs) emerged in iRPE but not nRPE. Most differentially methylated regions between iRPE and nRPE appeared to originate from (de)methylation errors during differentiation, whereas errors at reprogramming resulted in aberrant genomic imprinting and X chromosome reactivation. Moreover, non-CpG methylation was prominent in nRPE but not iRPE. Intriguingly, xenotransplantation to mouse remodeled the iRPE methylome to demethylate a subset of suppressed genes and accumulate non-CpG methylation, but failed to resolve PMDs and hypermethylated CpG islands. Although the impacts of these alterations remain elusive, our findings should provide a useful guide for methylome analyses of other iPSC-derived cells.
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