Hepatocyte growth factor (HGF) inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction.

<h4>Background</h4>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-β (TGF-β) is a crucial event in liver fibrogenesis due to its...

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Autores principales:	Monika Kwiecinski, Andrea Noetel, Natalia Elfimova, Jonel Trebicka, Stephanie Schievenbusch, Ingo Strack, Levente Molnar, Melanie von Brandenstein, Ulrich Töx, Roswitha Nischt, Oliver Coutelle, Hans Peter Dienes, Margarete Odenthal
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e0d98e2590fe47cead544574a88526b9
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spelling	oai:doaj.org-article:e0d98e2590fe47cead544574a88526b92021-11-04T06:08:54ZHepatocyte growth factor (HGF) inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction.1932-620310.1371/journal.pone.0024568https://doaj.org/article/e0d98e2590fe47cead544574a88526b92011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21931759/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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-β (TGF-β) 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-β on the miR-29 collagen axis in HSC.<h4>Methodology</h4>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-β, HGF, collagen-I and -IV mRNA, in addition to miR-29a and miR-29b were determined after HGF and TGF-β 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.<h4>Principal findings</h4>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-β stimulation of HSC, in vitro. Finally, we show that during myofibroblastic transition and TGF-β exposure the HGF-receptor, Met, is upregulated in HSC. Thus, whereas TGF-β 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.<h4>Conclusions</h4>Upregulation of miRNA-29 by HGF and downregulation by TGF-β take part in the anti- or profibrogenic response of HSC, respectively.Monika KwiecinskiAndrea NoetelNatalia ElfimovaJonel TrebickaStephanie SchievenbuschIngo StrackLevente MolnarMelanie von BrandensteinUlrich TöxRoswitha NischtOliver CoutelleHans Peter DienesMargarete OdenthalPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 9, p e24568 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Monika Kwiecinski Andrea Noetel Natalia Elfimova Jonel Trebicka Stephanie Schievenbusch Ingo Strack Levente Molnar Melanie von Brandenstein Ulrich Töx Roswitha Nischt Oliver Coutelle Hans Peter Dienes Margarete Odenthal Hepatocyte growth factor (HGF) inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction.
description	<h4>Background</h4>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-β (TGF-β) 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-β on the miR-29 collagen axis in HSC.<h4>Methodology</h4>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-β, HGF, collagen-I and -IV mRNA, in addition to miR-29a and miR-29b were determined after HGF and TGF-β 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.<h4>Principal findings</h4>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-β stimulation of HSC, in vitro. Finally, we show that during myofibroblastic transition and TGF-β exposure the HGF-receptor, Met, is upregulated in HSC. Thus, whereas TGF-β 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.<h4>Conclusions</h4>Upregulation of miRNA-29 by HGF and downregulation by TGF-β take part in the anti- or profibrogenic response of HSC, respectively.
format	article
author	Monika Kwiecinski Andrea Noetel Natalia Elfimova Jonel Trebicka Stephanie Schievenbusch Ingo Strack Levente Molnar Melanie von Brandenstein Ulrich Töx Roswitha Nischt Oliver Coutelle Hans Peter Dienes Margarete Odenthal
author_facet	Monika Kwiecinski Andrea Noetel Natalia Elfimova Jonel Trebicka Stephanie Schievenbusch Ingo Strack Levente Molnar Melanie von Brandenstein Ulrich Töx Roswitha Nischt Oliver Coutelle Hans Peter Dienes Margarete Odenthal
author_sort	Monika Kwiecinski
title	Hepatocyte growth factor (HGF) inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction.
title_short	Hepatocyte growth factor (HGF) inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction.
title_full	Hepatocyte growth factor (HGF) inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction.
title_fullStr	Hepatocyte growth factor (HGF) inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction.
title_full_unstemmed	Hepatocyte growth factor (HGF) inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction.
title_sort	hepatocyte growth factor (hgf) inhibits collagen i and iv synthesis in hepatic stellate cells by mirna-29 induction.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/e0d98e2590fe47cead544574a88526b9
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Hepatocyte growth factor (HGF) inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction.

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