Abstract
During chronic liver injury hepatic stellate cells (HSCs), the principal source of extracellular matrix in the fibrotic liver, transdifferentiate into pro-fibrotic myofibroblast-like cells - a process potentially regulated by microRNAs (miRNAs). Recently, we found serum miRNA-25-3p (miR-25) levels were upregulated in children with Cystic Fibrosis (CF) without liver disease, compared to children with CF-associated liver disease and healthy individuals. Here we examine the role of miR-25 in HSC biology. MiR-25 was detected in the human HSC cell line LX-2 and in primary murine HSCs, and increased with culture-induced activation. Transient overexpression of miR-25 inhibited TGF-β and its type 1 receptor (TGFBR1) mRNA expression, TGF-β-induced Smad2 phosphorylation and subsequent collagen1α1 induction in LX-2 cells. Pull-down experiments with biotinylated miR-25 revealed Notch signaling (co-)activators ADAM-17 and FKBP14 as miR-25 targets in HSCs. NanoString analysis confirmed miR-25 regulation of Notch- and Wnt-signaling pathways. Expression of Notch signaling pathway components and endogenous Notch1 signaling was downregulated in miR-25 overexpressing LX-2 cells, as were components of Wnt signaling such as Wnt5a. We propose that miR-25 acts as a negative feedback anti-fibrotic control during HSC activation by reducing the reactivity of HSCs to TGF-β-induced collagen expression and modulating the cross-talk between Notch, Wnt and TGF-β signaling.
RAS ID
28838
Document Type
Journal Article
Date of Publication
6-12-2019
ISSN
2045-2322
Volume
9
Issue
1
Funding Information
Funding information available at: https://doi.org/10.1038/s41598-019-44865-1
PubMed ID
31189969
School
School of Medical and Health Sciences
Grant Number
NHMRC Number : 1048740
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Publisher
Nature Publishing Group
Recommended Citation
Genz, B., Coleman, M. A., Irvine, K. M., Kutasovic, J. R., Miranda, M., Gratte, F. D., Tirnitz-Parker, J. E., Olynyk, J. K., Calvopina, D. A., Weis, A., Cloonan, N., Robinson, H., Hill, M. M., Al-Ejeh, F., & Ramm, G. A. (2019). Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells. DOI: https://doi.org/10.1038/s41598-019-44865-1
Comments
Genz, B., Coleman, M. A., Irvine, K. M., Kutasovic, J. R., Miranda, M., Gratte, F. D., ... Ramm, G. A. (2019). Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells. Scientific Reports, 9(1), Article 8541. Available here