miR‐27a‐3p regulates intestinal cell proliferation and differentiation through Wnt/β‐catenin signalling

Abstract Intestinal stem cells differentiate into absorptive enterocytes, characterised by increased brush border enzymes such as intestinal alkaline phosphatase (IAP), making up the majority (95%) of the terminally differentiated cells in the villus. Loss of integrity of the intestinal epithelium plays a key role in inflammatory diseases and gastrointestinal infection. Here, we show that the intestinal microRNA (miR)‐27a‐3p is an important regulator of intestinal epithelial cell proliferation and enterocyte differentiation. Repression of endogenous miR‐27a‐3p leads to increased enterocyte differentiation and decreased intestinal epithelial cell proliferation in mouse and human small intestinal organoids. Mechanistically, miR‐27a‐3p regulates intestinal cell differentiation and proliferation at least in part through the regulation of retinoic acid receptor α (RXRα), a modulator of Wnt/β‐catenin signalling. Repression of miR‐27a‐3p increases the expression of RXRα and concomitantly, decreases the expression of active β‐catenin and cyclin D1. In contrast, overexpression of miR‐27a‐3p mimic decreases the expression of RXRα and increases the expression of active β‐catenin and cyclin D1. Moreover, overexpression of the miR‐27a‐3p mimic results in impaired enterocyte differentiation and increases intestinal epithelial cell proliferation. These alterations were attenuated or blocked by Wnt inhibition. Our study demonstrates an miR‐27a‐3p/RXRα/Wnt/β‐catenin pathway that is important for the maintenance of enterocyte homeostasis in the small intestine.