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

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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 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
Pages (from-to)e396
Number of pages16
JournalExperimental and Molecular Medicine
Volume49
Issue number11
DOIs
Publication statusPublished - Nov 2017

Fingerprint

Integrin alpha Chains
Myofibroblasts
Phenotype
Liver
Hedgehogs
Hepatic Stellate Cells
Liver Cirrhosis
Extracellular Matrix
Fibrosis
Tissue
Transforming Growth Factors
Collagen Type I
Cytoskeleton
Transcriptome
Integrins
Smooth Muscle
Muscle
Actins
Collagen
Adhesion

Cite this

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. / Integrin alpha 11 in the regulation of the myofibroblast phenotype : implications for fibrotic diseases. In: Experimental and Molecular Medicine. 2017 ; Vol. 49, No. 11. pp. e396.
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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 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.",
author = "Ruchi Bansal and Shigeki Nakagawa and Saleh Yazdani and {van Baarlen}, Joop and Anu Venkatesh and Koh, {Anna P} and Won-min Song and Nicolas Goossens and Hideo Watanabe and Beasley, {Mary B} and Powell, {Charles A} and Gert Storm and Naftali Kaminski and {van Goor}, Harry and Friedman, {Scott L} and Yujin Hoshida and Jai Prakash",
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Bansal, R, Nakagawa, S, Yazdani, S, van Baarlen, J, Venkatesh, A, Koh, AP, Song, W, Goossens, N, Watanabe, H, Beasley, MB, Powell, CA, Storm, G, Kaminski, N, van Goor, H, Friedman, SL, Hoshida, Y & Prakash, J 2017, 'Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases' Experimental and Molecular Medicine, vol. 49, no. 11, pp. e396. https://doi.org/10.1038/emm.2017.213

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.

In: Experimental and Molecular Medicine, Vol. 49, No. 11, 11.2017, p. e396.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Integrin alpha 11 in the regulation of the myofibroblast phenotype

T2 - implications for fibrotic diseases

AU - Bansal, Ruchi

AU - Nakagawa, Shigeki

AU - Yazdani, Saleh

AU - van Baarlen, Joop

AU - Venkatesh, Anu

AU - Koh, Anna P

AU - Song, Won-min

AU - Goossens, Nicolas

AU - Watanabe, Hideo

AU - Beasley, Mary B

AU - Powell, Charles A

AU - Storm, Gert

AU - Kaminski, Naftali

AU - van Goor, Harry

AU - Friedman, Scott L

AU - Hoshida, Yujin

AU - Prakash, Jai

N1 - Open Access

PY - 2017/11

Y1 - 2017/11

N2 - 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.

AB - 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.

U2 - 10.1038/emm.2017.213

DO - 10.1038/emm.2017.213

M3 - Article

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JO - Experimental and Molecular Medicine

JF - Experimental and Molecular Medicine

SN - 1226-3613

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