title: Myocardin-related transcription factors A and B are key regulators of TGF-β1-induced fibroblast to myofibroblast differentiation.
abstract: Myofibroblasts are contractile, smooth muscle-like cells that are characterized by the de novo expression of smooth muscle α-actin (SMαA) and normally function to assist in wound closure, but have been implicated in pathological contractures. Transforming growth factor β-1 (TGF-β1) helps facilitate the differentiation of fibroblasts into myofibroblasts, but the exact mechanism by which this differentiation occurs, in response to TGF-β1, remains unclear. Myocardin-related transcription factors A and B (MRTFs, MRTF-A/B) are transcriptional co-activators that regulate the expression of smooth muscle-specific cytoskeletal proteins, including SMαA, in smooth muscle cells and fibroblasts. In this study, we demonstrate that TGF-β1 mediates myofibroblast differentiation and the expression of a contractile gene program through the actions of the MRTFs. Transient transfection of a constitutively active MRTF-A induced an increase in the expression of SMαA and other smooth muscle-specific cytoskeletal proteins, and an increase in myofibroblast contractility, even in the absence of TGF-β1. MRTF-A/B knockdown, in TGF-β1-differentiated myofibroblasts, resulted in decreased smooth muscle-specific cytoskeletal protein expression levels and reduced contractile force generation, as well as a decrease in focal adhesion size and number. These results provide direct evidence that the MRTFs are mediators of myofibroblast differentiation in response to TGF-β1.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Biomedical Research Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: Crider
authors.forename: George M
authors.initials: GM
authors.lastname: Risinger
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Haaksma
authors.forename: Eric W
authors.initials: EW
authors.lastname: Howard
authors.forename: James J
authors.initials: JJ
authors.lastname: Tomasek
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C508962:Tgfb1 protein, rat; C557977:myocardin-related transcription factor-A, rat; C569168:myocardin-related transcription factor-B, rat; C498862:Acta2 protein, rat