CircVapa promotes the abnormal differentiation of small intestinal epithelial stem cells in diabetic state.

Abstract

Diabetic enteropathy (DE) is a common complication of diabetes mellitus (DM), yet its underlying molecular mechanisms remain poorly understood. Emerging evidence suggests that abnormal differentiation of intestinal epithelial stem cells (IESCs) contributes to early intestinal dysfunction in DM. In this study, we aimed to investigate the role of CircVapa in regulating IESC differentiation and to elucidate the underlying molecular mechanism involving the miR-212-3p/Smoc2 axis. In this study, IESCs were extracted from BKS.CgDock7m+/+Lepr db/JNju (DM) mice models. A circular RNA molecule, CircVapa, was identified as being markedly enriched in IESCs. Experimental suppression of CircVapa in diabetic mice attenuated abnormal differentiation of intestinal epithelial cells (IECs). Notably, CircVapa was identified as a critical mediator of Lgr5+ stem cell functionality in hyperglycemic conditions. Mechanistically, microarray analysis, bioinformatics analysis, and luciferase reporter assays demonstrated that CircVapa serves as a competitive endogenous RNA (ceRNA) by directly binding miR-212-3p, thereby regulating Smoc2 expression. Furthermore, CircVapa regulated abnormal IESC differentiation via the miR-212-3p/Smoc2 regulatory network in diabetic mice. Collectively, this study demonstrates an important role of CircVapa in regulating IEC differentiation during DM progression.