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The fibroblast integrin alpha11beta1 is induced in a mechanosensitive manner involving activin A and regulates myofibroblast differentiation.

ABSTRACT: Fibrotic tissue is characterized by an overabundance of myofibroblasts. Thus, understanding the factors that induce myofibroblast differentiation is paramount to preventing fibrotic healing. Previous studies have shown that mechanical stress derived from the integrin-mediated interaction between extracellular matrix and the cytoskeleton promotes myofibroblast differentiation. Integrin alpha11beta1 is a collagen receptor on fibroblasts. To determine whether alpha11beta1 can act as a mechanosensor to promote the myofibroblast phenotype, mouse embryonic fibroblasts and human corneal fibroblasts were utilized. We found that alpha11 mRNA and protein levels were up-regulated in mouse embryonic fibroblasts grown in attached three-dimensional collagen gels and conversely down-regulated in cells grown in floating gels. alpha11 up-regulation could be prevented by manually detaching the collagen gels or by cytochalasin D treatment. Furthermore, SB-431542, an inhibitor of signaling via ALK4, ALK5, and ALK7, prevented the up-regulation of alpha11 and the concomitant phosphorylation of Smad3 under attached conditions. In attached gels, TGF-beta1 was secreted in its inactive form but surprisingly not further activated, thus not influencing alpha11 regulation. However, inhibition of activin A attenuated the up-regulation of alpha11. To determine the role of alpha11 in myofibroblast differentiation, human corneal fibroblasts were transfected with small interfering RNA to alpha11, which decreased alpha-smooth muscle actin expression and myofibroblast differentiation. Our data suggest that alpha11beta1 is regulated by cell/matrix stress involving activin A and Smad3 and that alpha11beta1 regulates myofibroblast differentiation.

SUBMITTER: Carracedo S

PROVIDER: S-EPMC2856250 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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The fibroblast integrin alpha11beta1 is induced in a mechanosensitive manner involving activin A and regulates myofibroblast differentiation.

Carracedo Sergio S Lu Ning N Popova Svetlana N SN Jonsson Roland R Eckes Beate B Gullberg Donald D

The Journal of biological chemistry 20100202 14

Fibrotic tissue is characterized by an overabundance of myofibroblasts. Thus, understanding the factors that induce myofibroblast differentiation is paramount to preventing fibrotic healing. Previous studies have shown that mechanical stress derived from the integrin-mediated interaction between extracellular matrix and the cytoskeleton promotes myofibroblast differentiation. Integrin alpha11beta1 is a collagen receptor on fibroblasts. To determine whether alpha11beta1 can act as a mechanosensor ...[more]

PMID: 20129924

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Project description:Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin-induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double-transgenic (DTG) mice with doxycycline-inducible overexpression of human FGF2 (SPC-rtTA;TRE-hFGF2) or single-transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild-type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline-induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFβ1-induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad-dependent gene expression, FGF2 inhibited TGFβ1-induced stress fiber formation and serum response factor-dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin-induced pulmonary fibrosis in vivo and reverses TGFβ1-induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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The fibroblast integrin alpha11beta1 is induced in a mechanosensitive manner involving activin A and regulates myofibroblast differentiation.

Publications

The fibroblast integrin alpha11beta1 is induced in a mechanosensitive manner involving activin A and regulates myofibroblast differentiation.

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