Integrin alpha 11 in the regulation of the myofibroblast phenotype: Implications for fibrotic diseases

Ruchi Bansal, Shigeki Nakagawa, Saleh Yazdani, Joop van Baarlen, Anu Venkatesh, Anna P. Koh, Won Min Song, Nicolas Goossens, Hideo Watanabe, Mary B. Beasley, Charles A. Powell, Gert Storm, Naftali Kaminski, Harry van Goor, Scott L. Friedman, Yujin Hoshida, Jai Prakash

Research output: Contribution to journalArticle

15 Scopus citations

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 β-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.

Original languageEnglish (US)
Article numbere396
JournalExperimental and Molecular Medicine
Volume49
Issue number11
DOIs
StatePublished - Nov 3 2017
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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    Bansal, R., Nakagawa, S., Yazdani, S., van Baarlen, J., Venkatesh, A., Koh, A. P., Song, W. M., Goossens, N., Watanabe, H., Beasley, M. B., Powell, C. A., Storm, G., Kaminski, N., van Goor, H., Friedman, S. L., Hoshida, Y., & Prakash, J. (2017). Integrin alpha 11 in the regulation of the myofibroblast phenotype: Implications for fibrotic diseases. Experimental and Molecular Medicine, 49(11), [e396]. https://doi.org/10.1038/emm.2017.213