Format

Send to

Choose Destination
See comment in PubMed Commons below
Dev Cell. 2012 Oct 16;23(4):705-15. doi: 10.1016/j.devcel.2012.08.017. Epub 2012 Sep 27.

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

Author information

1
Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

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.

Comment in

PMID:
23022034
PMCID:
PMC3505601
DOI:
10.1016/j.devcel.2012.08.017
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center