Universität zu Köln

Kwiecinski, Monika, Noetel, Andrea, Elfimova, Natalia, Trebicka, Jonel ORCID: 0000-0002-7028-3881, Schievenbusch, Stephanie, Strack, Ingo, Molnar, Levente, von Brandenstein, Melanie, Toex, Ulrich, Nischt, Roswitha, Coutelle, Oliver, Dienes, Hans Peter and Odenthal, Margarete (2011). Hepatocyte Growth Factor (HGF) Inhibits Collagen I and IV Synthesis in Hepatic Stellate Cells by miRNA-29 Induction. PLoS One, 6 (9). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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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-beta (TGF-beta) 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-beta 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-beta, HGF, collagen-I and -IV mRNA, in addition to miR-29a and miR-29b were determined after HGF and TGF-beta stimulation of HSC or after experimental fibrosis induced by bile-duct obstruction in rats. The interaction of miR-29 with 3'-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 3'-UTR of the collagen-1 and -4 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-beta stimulation of HSC, in vitro. Finally, we show that during myofibroblastic transition and TGF-beta exposure the HGF-receptor, Met, is upregulated in HSC. Thus, whereas TGF-beta 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-beta take part in the anti-or profibrogenic response of HSC, respectively.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kwiecinski, Monika UNSPECIFIED UNSPECIFIED UNSPECIFIED Noetel, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Elfimova, Natalia UNSPECIFIED UNSPECIFIED UNSPECIFIED Trebicka, Jonel UNSPECIFIED orcid.org/0000-0002-7028-3881 UNSPECIFIED Schievenbusch, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Strack, Ingo UNSPECIFIED UNSPECIFIED UNSPECIFIED Molnar, Levente UNSPECIFIED UNSPECIFIED UNSPECIFIED von Brandenstein, Melanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Toex, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Nischt, Roswitha UNSPECIFIED UNSPECIFIED UNSPECIFIED Coutelle, Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Dienes, Hans Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-489144
DOI:	10.1371/journal.pone.0024568
Journal or Publication Title:	PLoS One
Volume:	6
Number:	9
Date:	2011
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BETA GENE-EXPRESSION; FAT-STORING CELLS; RAT-LIVER; TRANSFORMING GROWTH-FACTOR-BETA-1; TGF-BETA; FACTOR SUPPRESSES; FIBROSIS; ACTIVATION; MICRORNAS; TRANSDIFFERENTIATION Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48914