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- Title
Hepatocyte Growth Factor (HGF) Inhibits Collagen I and IV Synthesis in Hepatic Stellate Cells by miRNA-29 Induction.
- Authors
Kwiecinski, Monika; Noetel, Andrea; Elfimova, Natalia; Trebicka, Jonel; Schievenbusch, Stephanie; Strack, Ingo; Molnar, Levente; Brandenstein, Melanie von; Töx, Ulrich; Nischt, Roswitha; Coutelle, Oliver; Dienes, Hans Peter; Odenthal, Margarete
- Abstract
Background: In chronic liver disease, hepatic stellate cells (HSC) transdifferentiate into myofibroblasts, promoting extracellular matrix (ECM) synthesis and deposition. Stimulation of HSC by transforming growth factor-&bgr; (TGF-&bgr;) is a crucial event in liver fibrogenesis due to its impact on myofibroblastic transition and ECM induction. In contrast, hepatocyte growth factor (HGF), exerts antifibrotic activities. Recently, miR-29 has been reported to be involved in ECM synthesis. We therefore studied the influence of HGF and TGF-&bgr; on the miR-29 collagen axis in HSC. Methodology: HSC, isolated from rats, were characterized for HGF and Met receptor expression by Real-Time PCR and Western blotting during culture induced myofibroblastic transition. Then, the levels of TGF-b, HGF, collagen-I and -IV mRNA, in addition to miR-29a and miR-29b were determined after HGF and TGF-&bgr; stimulation of HSC or after experimental fibrosis induced by bile-duct obstruction in rats. The interaction of miR-29 with 39-untranslated mRNA regions (UTR) was analyzed by reporter assays. The repressive effect of miR-29 on collagen synthesis was studied in HSC treated with miR-29-mimicks by Real-Time PCR and immunoblotting. Principal Findings: The 39-UTR of the collagen-1 and 24 subtypes were identified to bind miR-29. Hence, miR-29a/b overexpression in HSC resulted in a marked reduction of collagen-I and -IV synthesis. Conversely, a decrease in miR-29 levels is observed during collagen accumulation upon experimental fibrosis, in vivo, and after TGF-b stimulation of HSC, in vitro. Finally, we show that during myofibroblastic transition and TGF-&bgr; exposure the HGF-receptor, Met, is upregulated in HSC. Thus, whereas TGF-&bgr; stimulation leads to a reduction in miR-29 expression and de-repression of collagen synthesis, stimulation with HGF was definitely associated with highly elevated miR-29 levels and markedly repressed collagen-I and -IV synthesis. Conclusions: Upregulation of miRNA-29 by HGF and downregulation by TGF-b take part in the anti- or profibrogenic response of HSC, respectively.
- Subjects
HEPATOCYTE growth factor; COLLAGEN; KUPFFER cells; NON-coding RNA; MYOFIBROBLASTS; WESTERN immunoblotting; MESSENGER RNA; LABORATORY rats
- Publication
PLoS ONE, 2011, Vol 6, Issue 9, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0024568