Matrix-driven myosin II mediates the pro-fibrotic fibroblast phenotype

Brian D. Southern, Lisa M. Grove, Shaik O. Rahaman, Susamma Abraham, Rachel G. Scheraga, Kathryn A. Niese, Huanxing Sun, Erica L. Herzog, Fei Liu, Daniel J Tschumperlin, Thomas T. Egelhoff, Steven Rosenfeld, Mitchell A. Olman

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Pro-fibrotic mesenchymal cells are known to be the key effector cells of fibroproliferative disease, but the specific matrix signals and the induced cellular responses that drive the fibrogenic phenotype remain to be elucidated. The key mediators of the fibroblast fibrogenic phenotype were characterized using a novel assay system that measures fibroblast behavior in response to actual normal and fibrotic lung tissue. Using this system, we demonstrate that normal lung promotes fibroblast motility and polarization, while fibrotic lung immobilizes the fibroblast and promotes myofibroblast differentiation. These context-specific phenotypes are surprisingly both mediated by myosin II. The role of myosin II is supported by the observation of an increase in myosin phosphorylation and a change in intracellular distribution in fibroblasts on fibrotic lung, as compared with normal lung. Moreover, loss of myosin II activity has opposing effects on protrusive activity in fibroblasts on normal and fibrotic lung. Loss of myosin II also selectively inhibits myofibroblast differentiation in fibroblasts on fibrotic lung. Importantly, these findings are recapitulated by varying the matrix stiffness of polyacrylamide gels in the range of normal and fibrotic lung tissue. Comparison of the effects of myosin inhibition on lung tissue with that of polyacrylamide gels suggests that matrix fiber organization drives the fibroblast phenotype under conditions of normal/soft lung, while matrix stiffness drives the phenotype under conditions of fibrotic/stiff lung. This work defines novel roles for myosin II as a key regulatory effector molecule of the pro-fibrotic phenotype, in response to biophysical properties of the matrix.

Original languageEnglish (US)
Pages (from-to)6083-6095
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number12
DOIs
StatePublished - Mar 18 2016

Fingerprint

Myosin Type II
Fibroblasts
Phenotype
Lung
Stiffness matrix
Myosins
Tissue
Myofibroblasts
Phosphorylation
Assays
Polarization
Molecules
Reference Values
Fibers

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Southern, B. D., Grove, L. M., Rahaman, S. O., Abraham, S., Scheraga, R. G., Niese, K. A., ... Olman, M. A. (2016). Matrix-driven myosin II mediates the pro-fibrotic fibroblast phenotype. Journal of Biological Chemistry, 291(12), 6083-6095. https://doi.org/10.1074/jbc.M115.712380

Matrix-driven myosin II mediates the pro-fibrotic fibroblast phenotype. / Southern, Brian D.; Grove, Lisa M.; Rahaman, Shaik O.; Abraham, Susamma; Scheraga, Rachel G.; Niese, Kathryn A.; Sun, Huanxing; Herzog, Erica L.; Liu, Fei; Tschumperlin, Daniel J; Egelhoff, Thomas T.; Rosenfeld, Steven; Olman, Mitchell A.

In: Journal of Biological Chemistry, Vol. 291, No. 12, 18.03.2016, p. 6083-6095.

Research output: Contribution to journalArticle

Southern, BD, Grove, LM, Rahaman, SO, Abraham, S, Scheraga, RG, Niese, KA, Sun, H, Herzog, EL, Liu, F, Tschumperlin, DJ, Egelhoff, TT, Rosenfeld, S & Olman, MA 2016, 'Matrix-driven myosin II mediates the pro-fibrotic fibroblast phenotype', Journal of Biological Chemistry, vol. 291, no. 12, pp. 6083-6095. https://doi.org/10.1074/jbc.M115.712380
Southern BD, Grove LM, Rahaman SO, Abraham S, Scheraga RG, Niese KA et al. Matrix-driven myosin II mediates the pro-fibrotic fibroblast phenotype. Journal of Biological Chemistry. 2016 Mar 18;291(12):6083-6095. https://doi.org/10.1074/jbc.M115.712380
Southern, Brian D. ; Grove, Lisa M. ; Rahaman, Shaik O. ; Abraham, Susamma ; Scheraga, Rachel G. ; Niese, Kathryn A. ; Sun, Huanxing ; Herzog, Erica L. ; Liu, Fei ; Tschumperlin, Daniel J ; Egelhoff, Thomas T. ; Rosenfeld, Steven ; Olman, Mitchell A. / Matrix-driven myosin II mediates the pro-fibrotic fibroblast phenotype. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 12. pp. 6083-6095.
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