SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF

Autores
Atorrasagasti, Maria Catalina; Aquino, Jorge Benjamin; Hofman, Leonardo; Alaniz, Laura Daniela; Malvicini, Mariana; Garcia, Mariana Gabriela; Benedetti, Lorena Gabriela; Friedman, Scott L.; Podhajcer, Osvaldo Luis; Mazzolini Rizzo, Guillermo Daniel
Año de publicación
2011
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Liver fibrosis is an active process that involves changes in cell-cell and cell-extracellular matrix (ECM) interaction. Secreted protein, acidic and rich in cysteine (SPARC) is an ECM protein with many biological functions that is overexpressed in cirrhotic livers and upregulated in activated hepatic stellate cells (aHSCs). We have recently shown that SPARC downregulation ameliorates liver fibrosis in vivo. To uncover the cellular mechanisms involved, we have specifically knocked down SPARC in two aHSC lines [the CFSC-2G (rat) and the LX-2 (human)] and in primary cultured rat aHSCs. Transient downregulation of SPARC in hepatic stellate cells (HSCs) did not affect their proliferation and had only minor effects on apoptosis. However, SPARC knockdown increased HSC adhesion to fibronectin and significantly decreased their migration toward PDFG-BB and TGF-β(1). Interestingly, TGF-β(1) secretion by HSCs was reduced following SPARC small interfering RNA (siRNA) treatment, and preincubation with TGF-β(1) restored the migratory capacity of SPARC siRNA-treated cells through mechanisms partially independent from TGF-β(1)-mediated induction of SPARC expression; thus SPARC knockdown seems to exert its effects on HSCs partially through modulation of TGF-β(1) expression levels. Importantly, collagen-I mRNA expression was reduced in SPARC siRNA-transfected HSCs. Consistent with previous results, SPARC knockdown in aHSCs was associated with altered F-actin expression patterns and deregulation of key ECM and cell adhesion molecules, i.e., downregulation of N-cadherin and upregulation of E-cadherin. Our data together suggest that the upregulation of SPARC previously reported for aHSCs partially mediates profibrogenic activities of TGF-β(1) and PDGF-BB and identify SPARC as a potential therapeutic target for liver fibrosis.
Fil: Atorrasagasti, Maria Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Hofman, Leonardo. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina
Fil: Alaniz, Laura Daniela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Garcia, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Benedetti, Lorena Gabriela. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina
Fil: Friedman, Scott L.. Mount Sinai School of Medicine. Division of Liver Diseases; Estados Unidos
Fil: Podhajcer, Osvaldo Luis. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
Sparc
Cirrhosis
Tgf-B
Pdgf
Hepatic Stellate Cells
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/15266
Acceder
id CONICETDig_7c40740ebe81890a7ad50cabec2c3e82
oai_identifier_str oai:ri.conicet.gov.ar:11336/15266
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGFAtorrasagasti, Maria CatalinaAquino, Jorge BenjaminHofman, LeonardoAlaniz, Laura DanielaMalvicini, MarianaGarcia, Mariana GabrielaBenedetti, Lorena GabrielaFriedman, Scott L.Podhajcer, Osvaldo LuisMazzolini Rizzo, Guillermo DanielSparcCirrhosisTgf-BPdgfHepatic Stellate Cellshttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Liver fibrosis is an active process that involves changes in cell-cell and cell-extracellular matrix (ECM) interaction. Secreted protein, acidic and rich in cysteine (SPARC) is an ECM protein with many biological functions that is overexpressed in cirrhotic livers and upregulated in activated hepatic stellate cells (aHSCs). We have recently shown that SPARC downregulation ameliorates liver fibrosis in vivo. To uncover the cellular mechanisms involved, we have specifically knocked down SPARC in two aHSC lines [the CFSC-2G (rat) and the LX-2 (human)] and in primary cultured rat aHSCs. Transient downregulation of SPARC in hepatic stellate cells (HSCs) did not affect their proliferation and had only minor effects on apoptosis. However, SPARC knockdown increased HSC adhesion to fibronectin and significantly decreased their migration toward PDFG-BB and TGF-β(1). Interestingly, TGF-β(1) secretion by HSCs was reduced following SPARC small interfering RNA (siRNA) treatment, and preincubation with TGF-β(1) restored the migratory capacity of SPARC siRNA-treated cells through mechanisms partially independent from TGF-β(1)-mediated induction of SPARC expression; thus SPARC knockdown seems to exert its effects on HSCs partially through modulation of TGF-β(1) expression levels. Importantly, collagen-I mRNA expression was reduced in SPARC siRNA-transfected HSCs. Consistent with previous results, SPARC knockdown in aHSCs was associated with altered F-actin expression patterns and deregulation of key ECM and cell adhesion molecules, i.e., downregulation of N-cadherin and upregulation of E-cadherin. Our data together suggest that the upregulation of SPARC previously reported for aHSCs partially mediates profibrogenic activities of TGF-β(1) and PDGF-BB and identify SPARC as a potential therapeutic target for liver fibrosis.Fil: Atorrasagasti, Maria Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hofman, Leonardo. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; ArgentinaFil: Alaniz, Laura Daniela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garcia, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Benedetti, Lorena Gabriela. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaFil: Friedman, Scott L.. Mount Sinai School of Medicine. Division of Liver Diseases; Estados UnidosFil: Podhajcer, Osvaldo Luis. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaAmerican Physiological Society2011-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/15266Atorrasagasti, Maria Catalina; Aquino, Jorge Benjamin; Hofman, Leonardo; Alaniz, Laura Daniela; Malvicini, Mariana; et al.; SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF; American Physiological Society; American Journal Of Physiology-gastrointestinal And Liver Physiology; 300; 5; 5-2011; G739-G7481522-1547enginfo:eu-repo/semantics/altIdentifier/url/http://ajpgi.physiology.org/content/300/5/G739.longinfo:eu-repo/semantics/altIdentifier/doi/10.1152/ajpgi.00316.2010info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:41:15Zoai:ri.conicet.gov.ar:11336/15266instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:41:15.327CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF
title SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF
spellingShingle SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF
Atorrasagasti, Maria Catalina
Sparc
Cirrhosis
Tgf-B
Pdgf
Hepatic Stellate Cells
title_short SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF
title_full SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF
title_fullStr SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF
title_full_unstemmed SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF
title_sort SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF
dc.creator.none.fl_str_mv Atorrasagasti, Maria Catalina
Aquino, Jorge Benjamin
Hofman, Leonardo
Alaniz, Laura Daniela
Malvicini, Mariana
Garcia, Mariana Gabriela
Benedetti, Lorena Gabriela
Friedman, Scott L.
Podhajcer, Osvaldo Luis
Mazzolini Rizzo, Guillermo Daniel
author Atorrasagasti, Maria Catalina
author_facet Atorrasagasti, Maria Catalina
Aquino, Jorge Benjamin
Hofman, Leonardo
Alaniz, Laura Daniela
Malvicini, Mariana
Garcia, Mariana Gabriela
Benedetti, Lorena Gabriela
Friedman, Scott L.
Podhajcer, Osvaldo Luis
Mazzolini Rizzo, Guillermo Daniel
author_role author
author2 Aquino, Jorge Benjamin
Hofman, Leonardo
Alaniz, Laura Daniela
Malvicini, Mariana
Garcia, Mariana Gabriela
Benedetti, Lorena Gabriela
Friedman, Scott L.
Podhajcer, Osvaldo Luis
Mazzolini Rizzo, Guillermo Daniel
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Sparc
Cirrhosis
Tgf-B
Pdgf
Hepatic Stellate Cells
topic Sparc
Cirrhosis
Tgf-B
Pdgf
Hepatic Stellate Cells
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Liver fibrosis is an active process that involves changes in cell-cell and cell-extracellular matrix (ECM) interaction. Secreted protein, acidic and rich in cysteine (SPARC) is an ECM protein with many biological functions that is overexpressed in cirrhotic livers and upregulated in activated hepatic stellate cells (aHSCs). We have recently shown that SPARC downregulation ameliorates liver fibrosis in vivo. To uncover the cellular mechanisms involved, we have specifically knocked down SPARC in two aHSC lines [the CFSC-2G (rat) and the LX-2 (human)] and in primary cultured rat aHSCs. Transient downregulation of SPARC in hepatic stellate cells (HSCs) did not affect their proliferation and had only minor effects on apoptosis. However, SPARC knockdown increased HSC adhesion to fibronectin and significantly decreased their migration toward PDFG-BB and TGF-β(1). Interestingly, TGF-β(1) secretion by HSCs was reduced following SPARC small interfering RNA (siRNA) treatment, and preincubation with TGF-β(1) restored the migratory capacity of SPARC siRNA-treated cells through mechanisms partially independent from TGF-β(1)-mediated induction of SPARC expression; thus SPARC knockdown seems to exert its effects on HSCs partially through modulation of TGF-β(1) expression levels. Importantly, collagen-I mRNA expression was reduced in SPARC siRNA-transfected HSCs. Consistent with previous results, SPARC knockdown in aHSCs was associated with altered F-actin expression patterns and deregulation of key ECM and cell adhesion molecules, i.e., downregulation of N-cadherin and upregulation of E-cadherin. Our data together suggest that the upregulation of SPARC previously reported for aHSCs partially mediates profibrogenic activities of TGF-β(1) and PDGF-BB and identify SPARC as a potential therapeutic target for liver fibrosis.
Fil: Atorrasagasti, Maria Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Hofman, Leonardo. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina
Fil: Alaniz, Laura Daniela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Garcia, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Benedetti, Lorena Gabriela. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina
Fil: Friedman, Scott L.. Mount Sinai School of Medicine. Division of Liver Diseases; Estados Unidos
Fil: Podhajcer, Osvaldo Luis. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina
Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Investigaciones Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Liver fibrosis is an active process that involves changes in cell-cell and cell-extracellular matrix (ECM) interaction. Secreted protein, acidic and rich in cysteine (SPARC) is an ECM protein with many biological functions that is overexpressed in cirrhotic livers and upregulated in activated hepatic stellate cells (aHSCs). We have recently shown that SPARC downregulation ameliorates liver fibrosis in vivo. To uncover the cellular mechanisms involved, we have specifically knocked down SPARC in two aHSC lines [the CFSC-2G (rat) and the LX-2 (human)] and in primary cultured rat aHSCs. Transient downregulation of SPARC in hepatic stellate cells (HSCs) did not affect their proliferation and had only minor effects on apoptosis. However, SPARC knockdown increased HSC adhesion to fibronectin and significantly decreased their migration toward PDFG-BB and TGF-β(1). Interestingly, TGF-β(1) secretion by HSCs was reduced following SPARC small interfering RNA (siRNA) treatment, and preincubation with TGF-β(1) restored the migratory capacity of SPARC siRNA-treated cells through mechanisms partially independent from TGF-β(1)-mediated induction of SPARC expression; thus SPARC knockdown seems to exert its effects on HSCs partially through modulation of TGF-β(1) expression levels. Importantly, collagen-I mRNA expression was reduced in SPARC siRNA-transfected HSCs. Consistent with previous results, SPARC knockdown in aHSCs was associated with altered F-actin expression patterns and deregulation of key ECM and cell adhesion molecules, i.e., downregulation of N-cadherin and upregulation of E-cadherin. Our data together suggest that the upregulation of SPARC previously reported for aHSCs partially mediates profibrogenic activities of TGF-β(1) and PDGF-BB and identify SPARC as a potential therapeutic target for liver fibrosis.
publishDate 2011
dc.date.none.fl_str_mv 2011-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/15266
Atorrasagasti, Maria Catalina; Aquino, Jorge Benjamin; Hofman, Leonardo; Alaniz, Laura Daniela; Malvicini, Mariana; et al.; SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF; American Physiological Society; American Journal Of Physiology-gastrointestinal And Liver Physiology; 300; 5; 5-2011; G739-G748
1522-1547
url http://hdl.handle.net/11336/15266
identifier_str_mv Atorrasagasti, Maria Catalina; Aquino, Jorge Benjamin; Hofman, Leonardo; Alaniz, Laura Daniela; Malvicini, Mariana; et al.; SPARC downregulation attenuates the profibrogenic response of hepatic stellate cells induced by TGF-β1 and PDGF; American Physiological Society; American Journal Of Physiology-gastrointestinal And Liver Physiology; 300; 5; 5-2011; G739-G748
1522-1547
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://ajpgi.physiology.org/content/300/5/G739.long
info:eu-repo/semantics/altIdentifier/doi/10.1152/ajpgi.00316.2010
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
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dc.publisher.none.fl_str_mv American Physiological Society
publisher.none.fl_str_mv American Physiological Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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