title: Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation.
abstract: How mechanical cues from the extracellular environment are translated biochemically to modulate the effects of TGF-β on myofibroblast differentiation remains a crucial area of investigation. We report here that the focal adhesion protein, Hic-5 (also known as TGFB1I1), is required for the mechanically dependent generation of stress fibers in response to TGF-β. Successful generation of stress fibers promotes the nuclear localization of the transcriptional co-factor MRTF-A (also known as MKL1), and this correlates with the mechanically dependent induction of α smooth muscle actin (α-SMA) and Hic-5 in response to TGF-β. As a consequence of regulating stress fiber assembly, Hic-5 is required for the nuclear accumulation of MRTF-A and the induction of α-SMA as well as cellular contractility, suggesting a crucial role for Hic-5 in myofibroblast differentiation. Indeed, the expression of Hic-5 was transient in acute wounds and persistent in pathogenic scars, and Hic-5 colocalized with α-SMA expression in vivo. Taken together, these data suggest that a mechanically dependent feed-forward loop, elaborated by the reciprocal regulation of MRTF-A localization by Hic-5 and Hic-5 expression by MRTF-A, plays a crucial role in myofibroblast differentiation in response to TGF-β.
authors.affiliation: Center for Cell Biology and Cancer Research (MC-165), Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Varney
authors.affiliation: Center for Cell Biology and Cancer Research (MC-165), Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
authors.forename: Courtney B
authors.initials: CB
authors.lastname: Betts
authors.affiliation: Center for Cell Biology and Cancer Research (MC-165), Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zheng
authors.affiliation: Center for Cell Biology and Cancer Research (MC-165), Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
authors.affiliation: Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, 150 College Street, FitzGerald Building, Room 234, Toronto, Ontario, Canada M5S 3E2.
authors.forename: Boris
authors.initials: B
authors.lastname: Hinz
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Georgia, Georgia Regents University, CB-3628, 1459 Laney Walker Boulevard, Augusta, GA 30912, USA.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Center for Cell Biology and Cancer Research (MC-165), Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA vandewl@mail.amc.edu.
authors.forename: Livingston
authors.initials: L
authors.lastname: Van De Water
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002454:Cell Differentiation; D002921:Cicatrix / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D060588:LIM Domain Proteins / Q000502:physiology*; D040542:Mechanotransduction, Cellular; D058628:Myofibroblasts / Q000502:physiology*; D051381:Rats; D051900:Smad3 Protein / Q000378:metabolism; D022502:Stress Fibers / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000502:physiology; D014945:Wound Healing
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D051900:Smad3 Protein; C497787:Smad3 protein, rat; C490352:Tgfb1i1 protein, rat; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C557977:myocardin-related transcription factor-A, rat
keywords: Fibrosis; Hic-5; MRTF-A; Mechanotransduction; Myofibroblast; Wound healing