Cited by 530Cellular Mechanics and InteractionsInterstitial Lung Diseases and Idiopathic Pulmonary FibrosisProtein Kinase Regulation and GTPase Signaling

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Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction

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Huang, Xiangwei, Yang, Naiheng, Fiore, Vincent F., Barker, Thomas H., Sun, Yi, Morris, Stephan W., Ding, Qiang, Thannickal, Victor J., Zhou, Yong·2012·American Journal of Respiratory Cell and Molecular Biology

DOI 10.1165/rcmb.2012-0050ocPMC PMC3488695

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Abstract

The mechanical properties of the extracellular matrix have recently been shown to promote myofibroblast differentiation and lung fibrosis. Mechanisms by which matrix stiffness regulates myofibroblast differentiation are not fully understood. The goal of this study was to determine the intrinsic mechanisms of mechanotransduction in the regulation of matrix stiffness–induced myofibroblast differentiation. A well established polyacrylamide gel system with tunable substrate stiffness was used in this study. Megakaryoblastic leukemia factor-1 (MKL1) nuclear translocation was imaged by confocal immunofluorescent microscopy. The binding of MKL1 to the α-smooth muscle actin (α-SMA) gene promoter was quantified by quantitative chromatin immunoprecipitation assay. Normal human lung fibroblasts responded to matrix stiffening with changes in actin dynamics that favor filamentous actin polymerization. Actin polymerization resulted in nuclear translocation of MKL1, a serum response factor coactivator that plays a central role in regulating the expression of fibrotic genes, including α-SMA, a marker for myofibroblast differentiation. Mouse lung fibroblasts deficient in Mkl1 did not respond to matrix stiffening with increased α-SMA expression, whereas ectopic expression of human MKL1 cDNA restored the ability of Mkl1 null lung fibroblasts to express α-SMA. Furthermore, matrix stiffening promoted production and activation of the small GTPase RhoA, increased Rho kinase (ROCK) activity, and enhanced fibroblast contractility. Inhibition of RhoA/ROCK abrogated stiff matrix–induced actin cytoskeletal reorganization, MKL1 nuclear translocation, and myofibroblast differentiation. This study indicates that actin cytoskeletal remodeling–mediated activation of MKL1 transduces mechanical stimuli from the extracellular matrix to a fibrogenic program that promotes myofibroblast differentiation, suggesting an intrinsic mechanotransduction mechanism.

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Authors: Huang, X., Yang, N., Fiore, V. F., Barker, T. H., Sun, Y., Morris, S. W., Ding, Q., Thannickal, V. J., & Zhou, Y.
Affiliations: University of Alabama at Birmingham (US)
Georgia Institute of Technology (US)
St. Jude Children's Research Hospital (US)
Corresponding author: Zhou, Yong
ORCID: Fiore, Vincent F.
Barker, Thomas H.
Sun, Yi
Ding, Qiang
Thannickal, Victor J.
Zhou, Yong
Venue: American Journal of Respiratory Cell and Molecular Biology
Publisher: Oxford University Press (OUP)
Published: 2012-09-01
Volume: 47
Issue: 3
Pages: 340-348
ISSN: 1044-1549 (ISSN-L)
1535-4989
DOI: 10.1165/rcmb.2012-0050oc
PMC: PMC3488695
OpenAlex: W2172237567
Cited by: 530
References: 65
Citations by year: 2026: 39 · 2025: 35 · 2024: 44 · 2023: 45 · 2022: 35 · 2021: 44 · 2020: 41 · 2019: 34 · 2018: 47 · 2017: 36 · 2016: 22 · 2015: 39 · 2014: 26 · 2013: 32 · 2012: 11
FWCI: 16.35
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: American Journal of Respiratory Cell and Molecular Biology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Science Foundation
American Heart Association
St. Jude Children's Research Hospital
American Lebanese Syrian Associated Charities
National Institutes of Health
National Heart, Lung, and Blood Institute (R21HL097215, HL107181, HL 067967, P50HL107181, R01HL067967, R01HL085324, HL097215)
National Cancer Institute (R01CA087064, CA87064)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: extracellular matrix stiffness, myofibroblast differentiation, mechanotransduction, MKL1, RhoA/ROCK signaling, actin cytoskeleton remodeling, alpha-smooth muscle actin, pulmonary fibrosis, lung fibroblasts
MeSH terms: Animals, Base Sequence, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Electrophoresis, Polyacrylamide Gel, Extracellular Matrix, Humans, Phosphorylation, Oncogene Proteins, Fusion, Trans-Activators, Extracellular Matrix Proteins, DNA Primers, Mice, Knockout, Mechanotransduction, Cellular, Mice, Myofibroblasts

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Matrix stiffness-induced myofibroblast differentiation is mediated by intrinsic mechanotransduction

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