Experimental and Molecular Medicine

Korean Society for Biochemistry and Molecular Biongy (생화학분자생물학회)
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Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases

  • Bansal, Ruchi (Targeted Therapeutics, Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente) ;
  • Nakagawa, Shigeki (Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute) ;
  • Yazdani, Saleh (Targeted Therapeutics, Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente) ;
  • van Baarlen, Joop (Laboratorium Pathologie Oost-Nederland) ;
  • Venkatesh, Anu (Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute) ;
  • Koh, Anna P (Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute) ;
  • Song, Won-Min (Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute) ;
  • Goossens, Nicolas (Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute) ;
  • Watanabe, Hideo (Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School) ;
  • Beasley, Mary B (Department of Medicine, Icahn School of Medicine at Mount Sinai) ;
  • Powell, Charles A (Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai) ;
  • Storm, Gert (Targeted Therapeutics, Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente) ;
  • Kaminski, Naftali (Yale School of Medicine, Pulmonary, Critical Care and Sleep Medicine) ;
  • van Goor, Harry (Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen) ;
  • Friedman, Scott L (Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute) ;
  • Hoshida, Yujin (Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute) ;
  • Prakash, Jai (Targeted Therapeutics, Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente)
  • Received : 2016.12.09
  • Accepted : 2017.05.14
  • Published : 2017.11.30
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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 ${\alpha}$-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 ${\beta}$-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.

Keywords

References

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