Format

Send to

Choose Destination
Exp Mol Med. 2017 Nov 17;49(11):e396. doi: 10.1038/emm.2017.213.

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

Author information

1
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.
2
Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, New York, NY, USA.
3
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4
Laboratorium Pathologie Oost-Nederland, Hengelo, The Netherlands.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
6
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7
Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8
Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
9
Yale School of Medicine, Pulmonary, Critical Care and Sleep Medicine, New Haven, CT, USA.
10
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
11
Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
12
ScarTec Therapeutics BV, Enschede, The Netherlands.

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.

PMID:
29147013
PMCID:
PMC5704196
DOI:
10.1038/emm.2017.213
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center