Fibronectin protects from excessive liver fibrosis by modulating the availability of and responsiveness of stellate cells to active TGF-β
Fibrotic tissue in the liver is mainly composed of collagen. Fibronectin, which is also present in fibrotic matrices, is required for collagen matrix assembly in vitro. It also modulates the amount of growth factors and their release from the matrix. We therefore examined the effects of the absence...
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| description | Fibrotic tissue in the liver is mainly composed of collagen. Fibronectin, which is also present in fibrotic matrices, is required for collagen matrix assembly in vitro. It also modulates the amount of growth factors and their release from the matrix. We therefore examined the effects of the absence of fibronectin on the development of fibrosis in mice.Conditional deletion of fibronectin in the liver using the Mx promoter to drive cre expression resulted in increased collagen production and hence a more pronounced fibrosis in response to dimethylnitrosamine in mice. Exclusive deletion of fibronectin in hepatocytes or normalization of circulating fibronectin in Mx-cKO mice did not affect the development of fibrosis suggesting a role for fibronectin production by other liver cell types. The boosted fibrosis in fibronectin-deficient mice was associated with enhanced stellate cell activation and proliferation, elevated concentrations of active TGF-β, and increased TGF-β-mediated signaling.In vitro experiments revealed that collagen-type-I production by fibronectin-deficient hepatic stellate cells stimulated with TGF-β was more pronounced, and was associated with augmented Smad3-mediated signaling. Interfering with TGF-β signaling using SB431542 normalized collagen-type-I production in fibronectin-deficient hepatic stellate cells. Furthermore, precoating culture plates with fibronectin, but not collagen, or providing fibronectin fibrils unable to interact with RGD binding integrins via the RGD domain significantly diminished the amount of active TGF-β in fibronectin-deficient stellate cells and normalized collagen-type-I production in response to TGF-β stimulation. Thus, excessive stellate cell activation and production of collagen results from increased active TGF-β and TGF-β signaling in the absence of fibronectin.In conclusion, our data indicate that fibronectin controls the availability of active TGF-β in the injured liver, which impacts the severity of the resulting fibrosis. We therefore propose a novel role for locally produced fibronectin in protecting the liver from an excessive TGF-β-mediated response. |
| doi_str_mv | 10.1371/journal.pone.0028181 |
| format | Article |
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Fibronectin, which is also present in fibrotic matrices, is required for collagen matrix assembly in vitro. It also modulates the amount of growth factors and their release from the matrix. We therefore examined the effects of the absence of fibronectin on the development of fibrosis in mice.Conditional deletion of fibronectin in the liver using the Mx promoter to drive cre expression resulted in increased collagen production and hence a more pronounced fibrosis in response to dimethylnitrosamine in mice. Exclusive deletion of fibronectin in hepatocytes or normalization of circulating fibronectin in Mx-cKO mice did not affect the development of fibrosis suggesting a role for fibronectin production by other liver cell types. The boosted fibrosis in fibronectin-deficient mice was associated with enhanced stellate cell activation and proliferation, elevated concentrations of active TGF-β, and increased TGF-β-mediated signaling.In vitro experiments revealed that collagen-type-I production by fibronectin-deficient hepatic stellate cells stimulated with TGF-β was more pronounced, and was associated with augmented Smad3-mediated signaling. Interfering with TGF-β signaling using SB431542 normalized collagen-type-I production in fibronectin-deficient hepatic stellate cells. Furthermore, precoating culture plates with fibronectin, but not collagen, or providing fibronectin fibrils unable to interact with RGD binding integrins via the RGD domain significantly diminished the amount of active TGF-β in fibronectin-deficient stellate cells and normalized collagen-type-I production in response to TGF-β stimulation. Thus, excessive stellate cell activation and production of collagen results from increased active TGF-β and TGF-β signaling in the absence of fibronectin.In conclusion, our data indicate that fibronectin controls the availability of active TGF-β in the injured liver, which impacts the severity of the resulting fibrosis. We therefore propose a novel role for locally produced fibronectin in protecting the liver from an excessive TGF-β-mediated response.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0028181</identifier><identifier>PMID: 22140539</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Active control ; Animals ; Apoptosis ; Biochemistry ; Biology ; Cell activation ; Cell culture ; Cell cycle ; Clonal deletion ; Collagen ; Collagen - biosynthesis ; Collagen - genetics ; Deoxyribonucleic acid ; Dimethylnitrosamine ; DNA ; Endothelial Cells - metabolism ; Endothelial Cells - pathology ; Extracellular matrix ; Extracellular Matrix - metabolism ; Fibrils ; Fibronectin ; Fibronectins - metabolism ; Fibrosis ; Gastroenterology ; Gene Deletion ; Gene Expression Regulation ; Growth factors ; GTP-Binding Proteins - genetics ; Hepatic Stellate Cells - metabolism ; Hepatic Stellate Cells - pathology ; Hepatocytes ; Hepatocytes - metabolism ; Hepatocytes - pathology ; Immunology ; Integrins ; Kinases ; Kupffer Cells - metabolism ; Kupffer Cells - pathology ; Liver ; Liver Cirrhosis - metabolism ; Liver Cirrhosis - pathology ; Liver Cirrhosis - prevention & control ; Medicine ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myxovirus Resistance Proteins ; N-Nitrosodimethylamine ; Pathogenesis ; Proteins ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Rodents ; Signal Transduction ; Signaling ; Smad3 protein ; Stellate cells ; Studies ; Transforming Growth Factor beta - metabolism ; Trends</subject><ispartof>PloS one, 2011-11, Vol.6 (11), p.e28181</ispartof><rights>2011 Kawelke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Kawelke et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c525t-137bf67239c04088cf4b164b07dc68b2d9b41d7b24709b2203c7dc247f12e4443</citedby><cites>FETCH-LOGICAL-c525t-137bf67239c04088cf4b164b07dc68b2d9b41d7b24709b2203c7dc247f12e4443</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225392/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225392/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22140539$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Feghali-Bostwick, Carol</contributor><creatorcontrib>Kawelke, Nina</creatorcontrib><creatorcontrib>Vasel, Matthaeus</creatorcontrib><creatorcontrib>Sens, Carla</creatorcontrib><creatorcontrib>Au, Anja von</creatorcontrib><creatorcontrib>Dooley, Steven</creatorcontrib><creatorcontrib>Nakchbandi, Inaam A</creatorcontrib><title>Fibronectin protects from excessive liver fibrosis by modulating the availability of and responsiveness of stellate cells to active TGF-β</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Fibrotic tissue in the liver is mainly composed of collagen. Fibronectin, which is also present in fibrotic matrices, is required for collagen matrix assembly in vitro. It also modulates the amount of growth factors and their release from the matrix. We therefore examined the effects of the absence of fibronectin on the development of fibrosis in mice.Conditional deletion of fibronectin in the liver using the Mx promoter to drive cre expression resulted in increased collagen production and hence a more pronounced fibrosis in response to dimethylnitrosamine in mice. Exclusive deletion of fibronectin in hepatocytes or normalization of circulating fibronectin in Mx-cKO mice did not affect the development of fibrosis suggesting a role for fibronectin production by other liver cell types. The boosted fibrosis in fibronectin-deficient mice was associated with enhanced stellate cell activation and proliferation, elevated concentrations of active TGF-β, and increased TGF-β-mediated signaling.In vitro experiments revealed that collagen-type-I production by fibronectin-deficient hepatic stellate cells stimulated with TGF-β was more pronounced, and was associated with augmented Smad3-mediated signaling. Interfering with TGF-β signaling using SB431542 normalized collagen-type-I production in fibronectin-deficient hepatic stellate cells. Furthermore, precoating culture plates with fibronectin, but not collagen, or providing fibronectin fibrils unable to interact with RGD binding integrins via the RGD domain significantly diminished the amount of active TGF-β in fibronectin-deficient stellate cells and normalized collagen-type-I production in response to TGF-β stimulation. Thus, excessive stellate cell activation and production of collagen results from increased active TGF-β and TGF-β signaling in the absence of fibronectin.In conclusion, our data indicate that fibronectin controls the availability of active TGF-β in the injured liver, which impacts the severity of the resulting fibrosis. We therefore propose a novel role for locally produced fibronectin in protecting the liver from an excessive TGF-β-mediated response.</description><subject>Active control</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biochemistry</subject><subject>Biology</subject><subject>Cell activation</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Clonal deletion</subject><subject>Collagen</subject><subject>Collagen - biosynthesis</subject><subject>Collagen - genetics</subject><subject>Deoxyribonucleic acid</subject><subject>Dimethylnitrosamine</subject><subject>DNA</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelial Cells - pathology</subject><subject>Extracellular matrix</subject><subject>Extracellular Matrix - metabolism</subject><subject>Fibrils</subject><subject>Fibronectin</subject><subject>Fibronectins - metabolism</subject><subject>Fibrosis</subject><subject>Gastroenterology</subject><subject>Gene Deletion</subject><subject>Gene Expression Regulation</subject><subject>Growth factors</subject><subject>GTP-Binding Proteins - genetics</subject><subject>Hepatic Stellate Cells - metabolism</subject><subject>Hepatic Stellate Cells - pathology</subject><subject>Hepatocytes</subject><subject>Hepatocytes - metabolism</subject><subject>Hepatocytes - pathology</subject><subject>Immunology</subject><subject>Integrins</subject><subject>Kinases</subject><subject>Kupffer Cells - metabolism</subject><subject>Kupffer Cells - pathology</subject><subject>Liver</subject><subject>Liver Cirrhosis - metabolism</subject><subject>Liver Cirrhosis - pathology</subject><subject>Liver Cirrhosis - prevention & control</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myxovirus Resistance Proteins</subject><subject>N-Nitrosodimethylamine</subject><subject>Pathogenesis</subject><subject>Proteins</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Smad3 protein</subject><subject>Stellate cells</subject><subject>Studies</subject><subject>Transforming Growth Factor beta - 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Fibronectin, which is also present in fibrotic matrices, is required for collagen matrix assembly in vitro. It also modulates the amount of growth factors and their release from the matrix. We therefore examined the effects of the absence of fibronectin on the development of fibrosis in mice.Conditional deletion of fibronectin in the liver using the Mx promoter to drive cre expression resulted in increased collagen production and hence a more pronounced fibrosis in response to dimethylnitrosamine in mice. Exclusive deletion of fibronectin in hepatocytes or normalization of circulating fibronectin in Mx-cKO mice did not affect the development of fibrosis suggesting a role for fibronectin production by other liver cell types. The boosted fibrosis in fibronectin-deficient mice was associated with enhanced stellate cell activation and proliferation, elevated concentrations of active TGF-β, and increased TGF-β-mediated signaling.In vitro experiments revealed that collagen-type-I production by fibronectin-deficient hepatic stellate cells stimulated with TGF-β was more pronounced, and was associated with augmented Smad3-mediated signaling. Interfering with TGF-β signaling using SB431542 normalized collagen-type-I production in fibronectin-deficient hepatic stellate cells. Furthermore, precoating culture plates with fibronectin, but not collagen, or providing fibronectin fibrils unable to interact with RGD binding integrins via the RGD domain significantly diminished the amount of active TGF-β in fibronectin-deficient stellate cells and normalized collagen-type-I production in response to TGF-β stimulation. Thus, excessive stellate cell activation and production of collagen results from increased active TGF-β and TGF-β signaling in the absence of fibronectin.In conclusion, our data indicate that fibronectin controls the availability of active TGF-β in the injured liver, which impacts the severity of the resulting fibrosis. We therefore propose a novel role for locally produced fibronectin in protecting the liver from an excessive TGF-β-mediated response.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22140539</pmid><doi>10.1371/journal.pone.0028181</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1310424914 |
| source | PubMed Central Free; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; Free Full-Text Journals in Chemistry |
| subjects | Active control Animals Apoptosis Biochemistry Biology Cell activation Cell culture Cell cycle Clonal deletion Collagen Collagen - biosynthesis Collagen - genetics Deoxyribonucleic acid Dimethylnitrosamine DNA Endothelial Cells - metabolism Endothelial Cells - pathology Extracellular matrix Extracellular Matrix - metabolism Fibrils Fibronectin Fibronectins - metabolism Fibrosis Gastroenterology Gene Deletion Gene Expression Regulation Growth factors GTP-Binding Proteins - genetics Hepatic Stellate Cells - metabolism Hepatic Stellate Cells - pathology Hepatocytes Hepatocytes - metabolism Hepatocytes - pathology Immunology Integrins Kinases Kupffer Cells - metabolism Kupffer Cells - pathology Liver Liver Cirrhosis - metabolism Liver Cirrhosis - pathology Liver Cirrhosis - prevention & control Medicine Mice Mice, Inbred C57BL Mice, Knockout Myxovirus Resistance Proteins N-Nitrosodimethylamine Pathogenesis Proteins RNA, Messenger - genetics RNA, Messenger - metabolism Rodents Signal Transduction Signaling Smad3 protein Stellate cells Studies Transforming Growth Factor beta - metabolism Trends |
| title | Fibronectin protects from excessive liver fibrosis by modulating the availability of and responsiveness of stellate cells to active TGF-β |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-03T08%3A28%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Fibronectin%20protects%20from%20excessive%20liver%20fibrosis%20by%20modulating%20the%20availability%20of%20and%20responsiveness%20of%20stellate%20cells%20to%20active%20TGF-%CE%B2&rft.jtitle=PloS%20one&rft.au=Kawelke,%20Nina&rft.date=2011-11-28&rft.volume=6&rft.issue=11&rft.spage=e28181&rft.pages=e28181-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0028181&rft_dat=%3Cproquest_plos_%3E2900323481%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1310424914&rft_id=info:pmid/22140539&rft_doaj_id=oai_doaj_org_article_ec15ff925fd9489cb51764db7b41a69e&rfr_iscdi=true |