title: Matrix-driven Myosin II Mediates the Pro-fibrotic Fibroblast Phenotype.
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.
authors.affiliation: From the Department of Pathobiology and Respiratory Institute.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Southern
authors.affiliation: From the Department of Pathobiology and.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Grove
authors.affiliation: From the Department of Pathobiology and.
authors.forename: Shaik O
authors.initials: SO
authors.lastname: Rahaman
authors.affiliation: From the Department of Pathobiology and.
authors.forename: Susamma
authors.initials: S
authors.lastname: Abraham
authors.affiliation: From the Department of Pathobiology and Respiratory Institute.
authors.forename: Rachel G
authors.initials: RG
authors.lastname: Scheraga
authors.affiliation: From the Department of Pathobiology and.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Niese
authors.affiliation: Yale ILD Center of Excellence, Yale School of Medicine, New Haven, Connecticut 06520.
authors.forename: Huanxing
authors.initials: H
authors.lastname: Sun
authors.affiliation: Yale ILD Center of Excellence, Yale School of Medicine, New Haven, Connecticut 06520.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Herzog
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts 02115, and.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tschumperlin
authors.affiliation: Department of Cellular and Molecular Medicine, and.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Egelhoff
authors.affiliation: Department of Cancer Biology, Cleveland Clinic, Lerner Research Institute, Cleveland, Ohio 44195.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Rosenfeld
authors.affiliation: From the Department of Pathobiology and Respiratory Institute, olmanm@ccf.org.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Olman
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D016764:Cell Polarity; D048430:Cell Shape; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D024462:Myosin Type II / Q000502:physiology*; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology
chemical_list: D024462:Myosin Type II
keywords: fibroblast; fibroblast migration; fibrosis; lung; myofibroblast; myofibroblast differentiation; myosin; non-muscle myosin II