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MiR-181a-5p mediates the effects of BMP4 on intestinal cell proliferation and differentiation

ABSTRACT: The intestinal mucosa undergoes a dynamic process of continual proliferation, differentiation and apoptosis. Delineating the mechanisms involved in intestinal epithelial cell (IEC) differentiation is crucial to our understanding of not only normal gut adaptation but also aberrant intestinal growth. BMP signaling is a crucial regulator of intestinal proliferation and differentiation. However, the molecular underpinnings of the BMP pathway in this context are not entirely known. Here we showed a key role for BMP4/miR-181/glycolysis signaling pathway in the maintenance of intestinal epithelial cell proliferation and differentiation. Treatment with BMP4 increased expression of enterocyte markers and decreased proliferation of IECs, and importantly, decreased the expression of miR-181a-5p in mouse and human intestinal organoids. Inhibition of miR-181a-5p, a member of miR-181 with highest expression in intestinal cells, significantly increased enterocyte differentiation as noted by increased expression of enterocyte markers in human and mouse intestinal organoids. In addition, miR-181a-5p miRCURY LNA inhibitor repressed the expression of endogenous miR-181a-5p and decreased intestinal stem cell self-renewal as noted by the decreased expression of Ki67, cyclin D1 and OLFM4 and organoid forming efficiency. In contrast, overexpression of miR-181a-5p mimics decreased the expression of enterocyte markers. Moreover, BMP4 treatment or inhibition of miR-181a-5p repressed HK1 expression and inhibited glycolysis. In line of this, knockdown of HK1 or inhibition of glycolysis using 2-DG promoted enterocyte maturation and inhibited proliferation of IECs. Together, we provide evidence showing that miR-181a-5p inhibits intestinal enterocyte differentiation and promotes IEC proliferation thorough HK1-dependent glycolysis. Importantly, our findings identified miR-181a-5p as downstream in mediating BMP4 induction of enterocyte differentiation and inhibition of proliferation in IECs.

ORGANISM(S): Mus musculus

PROVIDER: GSE266339 | GEO | 2025/04/30

REPOSITORIES: GEO

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Project description:High levels of factor XI (FXI) increase the risk of thromboembolic disease. However, the genetic and environmental factors regulating FXI expression are still largely unknown. The aim of our study was to evaluate the regulation of FXI by microRNAs (miRNAs) in the human liver. In silico prediction yielded four miRNA candidates that might regulate FXI expression. HepG2 cells were transfected with miR-181a-5p, miR- 23a-3p, miR-16-5p and miR-195-5p. We used mir-494, which was not predicted to bind to F11, as a negative control. Only miR-181a-5p caused a significant decrease both in FXI protein and F11 mRNA levels. In addition, transfection with a miR-181a-5p inhibitor in PLC/PRF/5 hepatic cells increased both the levels of F11 mRNA and extracellular FXI. Luciferase assays in human colon cancer cells deficient for Dicer (HCT-DK) demonstrated a direct interaction between miR-181a-5p and 3'untranslated region of F11. Additionally, F11 mRNA levels were inversely and significantly correlated with miR-181a-5p levels in 114 healthy livers, but not with miR-494. This study demonstrates that FXI expression is directly regulated by a specific miRNA, miR-181a-5p, in the human liver. Future studies are necessary to further investigate the potential consequences of miRNA dysregulation in pathologies involving FXI. In the study presented here, we report arrays including 1,898 human mature miRNAs (LCSciences, Houston, TX; Sanger mirBase Release 18.0) using total RNA extracted from a healthy human liver sample E122; a Caucasian donor that gave informed consent were provided by biobanc CIBERehd. Human liver studies were apporved by Local Ethics Committee from Hospital Universitario Morales Meseguer in Murcia. In the study presented here, we report arrays including 2,019 human mature miRNAs (LCSciences, Houston, TX; Sanger mirBase Release 19.0) using total RNA extracted from 3 healthy human liver samples (662, 664, 771) from Caucasian donors that gave informed consent were provided by St. Jude Liver Resource at St. Distribution System and by cooperative Human Tissue Network. Human liver studies were apporved by Local Ethics Committee from Hospital Universitario Morales Meseguer in Murcia

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MiR-181a-5p mediates the effects of BMP4 on intestinal cell proliferation and differentiation

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