iPSCs-derived insulin-producing cell transplantation is a promising strategy for diabetes therapy. Although there have been many protocols of mature, glucose-responsive β cells induced in vitro over the past few years, many underlying problems remain to be resolved. As a crucial regulator, long noncoding RNAs (lncRNAs) participate in numerous biological processes, including the maintenance of pluripotency, and stem cell differentiation. In this study, we identified a novel lncRNA Gm10451 as a functional regulator for β-like cell differentiation. Localized to the cytoplasm, Gm10451 regulates histone H3K4 methyltransferase complex PTIP to facilitate Insulin+/Nkx6.1+ β-like cell differentiation by targeting miR-338-3p as a competing endogenous RNA (ceRNA). miR-338-3p has also been shown to suppress Nkx6.1+ early-stage β-like cell differentiation by targeting PTIP. Following transplantation into streptozotocin (STZ)-mice, Gm10451 loss in β-like cells prevented the expression of mature β-cell makers, such as Insulin, Nkx6.1, and Mafa. Accordingly, hyperglycemia in the mice was not resolved. Taken together, this study provides an efficient epigenetic target for generating more mature and functional iPSCs-derived β-like cells. We anticipate that pancreatic organoids, which are generated from human stem cells, biological materials, and epigenetic modifications, can be used in the future as a novel diabetes treatment option.
KEYWORDS: Competing endogenous RNA, Differentiation, Long noncoding RNAs, iPSCs, β-like cells