Exp Mol Med.
2017 Nov;49(11):e396. 10.1038/emm.2017.213.
Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases
- Bansal R
- Nakagawa S
- Yazdani S
- van Baarlen J
- Venkatesh
- Koh AP
- Song WM
- Goossens N
- Watanabe H
- Beasley MB
- Powell CA
- Storm G
- Kaminski N
- van Goor H
- Friedman S
- Hoshida Y
- Prakash J
- Affiliations
-
- 1Targeted 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. R.Bansal@utwente.nl, J.Prakash@utwente.nl
- 2Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, New York, NY, USA.
- 3Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- 4Laboratorium Pathologie Oost-Nederland, Hengelo, The Netherlands.
- 5Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
- 6Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- 7Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- 8Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
- 9Yale School of Medicine, Pulmonary, Critical Care and Sleep Medicine, New Haven, CT, USA.
- 10Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
- 11Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
- 12ScarTec Therapeutics BV, Enschede, The Netherlands.
- KMID: 2396801
- DOI: http://doi.org/10.1038/emm.2017.213
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.
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