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Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases.
Bansal, Ruchi; Nakagawa, Shigeki; Yazdani, Saleh; van Baarlen, Joop; Venkatesh, Anu; Koh, Anna P; Song, Won-Min; Goossens, Nicolas; Watanabe, Hideo; Beasley, Mary B; Powell, Charles A; Storm, Gert; Kaminski, Naftali; van Goor, Harry; Friedman, Scott L; Hoshida, Yujin; Prakash, Jai.
Afiliação
  • Bansal R; Targeted Therapeutics, Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
  • Nakagawa S; Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, New York, NY, USA.
  • Yazdani S; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • van Baarlen J; Targeted Therapeutics, Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
  • Venkatesh A; Laboratorium Pathologie Oost-Nederland, Hengelo, The Netherlands.
  • Koh AP; Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, New York, NY, USA.
  • Song WM; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Goossens N; Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, New York, NY, USA.
  • Watanabe H; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Beasley MB; Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, New York, NY, USA.
  • Powell CA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Storm G; Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, New York, NY, USA.
  • Kaminski N; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • van Goor H; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • Friedman SL; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Hoshida Y; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Prakash J; Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Exp Mol Med ; 49(11): e396, 2017 11 17.
Article em En | MEDLINE | ID: mdl-29147013
ABSTRACT
Tissue fibrosis, characterized by excessive accumulation of aberrant extracellular matrix (ECM) produced by myofibroblasts, is a growing cause of mortality worldwide. Understanding the factors that induce myofibroblastic differentiation is paramount to prevent or reverse the fibrogenic process. Integrin-mediated interaction between the ECM and cytoskeleton promotes myofibroblast differentiation. In the present study, we explored the significance of integrin alpha 11 (ITGA11), the integrin alpha subunit that selectively binds to type I collagen during tissue fibrosis in the liver, lungs and kidneys. We showed that ITGA11 was co-localized with α-smooth muscle actin-positive myofibroblasts and was correlatively induced with increasing fibrogenesis in mouse models and human fibrotic organs. Furthermore, transcriptome and protein expression analysis revealed that ITGA11 knockdown in hepatic stellate cells (liver-specific myofibroblasts) markedly reduced transforming growth factor ß-induced differentiation and fibrotic parameters. Moreover, ITGA11 knockdown dramatically altered the myofibroblast phenotype, as indicated by the loss of protrusions, attenuated adhesion and migration, and impaired contractility of collagen I matrices. Furthermore, we demonstrated that ITGA11 was regulated by the hedgehog signaling pathway, and inhibition of the hedgehog pathway reduced ITGA11 expression and fibrotic parameters in human hepatic stellate cells in vitro, in liver fibrosis mouse model in vivo and in human liver slices ex vivo. Therefore, we speculated that ITGA11 might be involved in fibrogenic signaling and might act downstream of the hedgehog signaling pathway. These findings highlight the significance of the ITGA11 receptor as a highly promising therapeutic target in organ fibrosis.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenótipo / Cadeias alfa de Integrinas / Miofibroblastos Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Exp Mol Med Assunto da revista: BIOLOGIA MOLECULAR / BIOQUIMICA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenótipo / Cadeias alfa de Integrinas / Miofibroblastos Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Exp Mol Med Assunto da revista: BIOLOGIA MOLECULAR / BIOQUIMICA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Holanda