title: A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo.
abstract: After injury or cytokine stimulation, fibroblasts transdifferentiate into myofibroblasts, contractile cells that secrete extracellular matrix for wound healing and tissue remodeling. Here, a genome-wide screen identified TRPC6, a Ca(2+) channel necessary and sufficient for myofibroblast transformation. TRPC6 overexpression fully activated myofibroblast transformation, while fibroblasts lacking Trpc6 were refractory to transforming growth factor β (TGF-β) and angiotensin II-induced transdifferentiation. Trpc6 gene-deleted mice showed impaired dermal and cardiac wound healing after injury. The profibrotic ligands TGF-β and angiotensin II induced TRPC6 expression through p38 mitogen-activated protein kinase (MAPK) serum response factor (SRF) signaling via the TRPC6 promoter. Once induced, TRPC6 activates the Ca(2+)-responsive protein phosphatase calcineurin, which itself induced myofibroblast transdifferentiation. Moreover, inhibition of calcineurin prevented TRPC6-dependent transdifferentiation and dermal wound healing. These results demonstrate an obligate function for TRPC6 and calcineurin in promoting myofibroblast differentiation, suggesting a comprehensive pathway for myofibroblast formation in conjunction with TGF-β, p38 MAPK, and SRF.
authors.affiliation: Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Davis
authors.forename: Adam R
authors.initials: AR
authors.lastname: Burr
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Davis
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D051379:Mice; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism*; D000074287:TRPC6 Cation Channel; D014945:Wound Healing
chemical_list: D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse