Referenced in: none

Automatically associated channels: TRP , TRPC , TRPC6

Title: A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo.

Authors: Jennifer Davis, Adam R Burr, Gregory F Davis, Lutz Birnbaumer, Jeffery D Molkentin

Journal, date & volume: Dev. Cell, 2012 Oct 16 , 23, 705-15

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23022034

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.