肠干细胞分化为吸收性肠上皮细胞，其特征是刷状缘酶（例如肠碱性磷酸酶（IAP））增加，构成绒毛中终末分化细胞的大部分（95%）。肠上皮完整性的丧失在炎症性疾病和胃肠道感染中起着关键作用。在这里，我们证明肠道微小RNA（miR）-27a-3p是肠上皮细胞增殖和肠上皮细胞分化的重要调节因子。抑制内源性 miR-27a-3p 会导致小鼠和人小肠类器官中肠上皮细胞分化增加并减少肠上皮细胞增殖。从机制上讲，miR-27a-3p 至少部分通过调节视黄酸受体 α (RXRα)（Wnt/β-catenin 信号传导调节剂）来调节肠细胞分化和增殖。抑制 miR-27a-3p 会增加 RXRα 的表达，同时降低活性 β-catenin 和细胞周期蛋白 D1 的表达。相反，miR-27a-3p模拟物的过度表达会降低RXRα的表达并增加活性β-连环蛋白和细胞周期蛋白D1的表达。此外，miR-27a-3p模拟物的过度表达会导致肠上皮细胞分化受损并增加肠上皮细胞增殖。这些改变被 Wnt 抑制减弱或阻断。我们的研究表明 miR-27a-3p/RXRα/Wnt/β-catenin 通路对于维持小肠肠上皮细胞稳态非常重要。© 2024 作者。北京干细胞与再生医学研究院和John Wiley联合出版的《细胞增殖》

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.© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.