Base-Resolution Methylome of Retinal Pigment Epithelial Cells Used in the First Trial of Human Induced Pluripotent Stem Cell-Based Autologous Transplantation

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. •The methylome of iPSC-derived RPE closely resembled that of native RPE•Most methylomic differences originated from errors during differentiation•Errors at reprogramming induced loss of imprinting and X chromosome reactivation•Some of the differences were mitigated by xenotransplantation to mouse In this article, Ito and colleagues delineated the base-resolution methylome of iPSC-derived retinal pigment epithelial (RPE) cell used in the first-in-human trial of autologous transplantation. The methylome closely resembled that of native RPE cell. Intriguingly, it became even closer to its natural counterpart upon xenotransplantation to mouse, demonstrating its plasticity to respond appropriately to the in vivo environment.