A TRPC6-Dependent Pathway for Myofibroblast Transdifferentiation and Wound Healing In Vivo

被引：296

作者：

Davis, Jennifer ^{[1
]}

Burr, Adam R. ^{[1
]}

Davis, Gregory F. ^{[1
]}

Birnbaumer, Lutz ^{[2
]}

Molkentin, Jeffery D. ^{[1
,3
]}

机构：

[1] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA

[2] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA

[3] Howard Hughes Med Inst, Cincinnati, OH 45229 USA

来源：

DEVELOPMENTAL CELL | 2012年 / 23卷 / 04期

基金：

美国国家卫生研究院;

关键词：

SERUM RESPONSE FACTOR; ACTIVATED T-CELLS; TGF-BETA; TRANSCRIPTION FACTOR; CARDIAC-HYPERTROPHY; NUCLEAR FACTOR; TRPC CHANNELS; UP-REGULATION; DIFFERENTIATION; FIBROSIS;

D O I：

10.1016/j.devcel.2012.08.017

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 Ca2+ channel necessary and sufficient for myofibroblast transformation. TRPC6 overexpression fully activated myofibroblast transformation, while fibroblasts lacking Trpc6 were refractory to transforming growth factor beta (TGF-beta) and angiotensin II-induced transdifferentiation. Trpc6 gene-deleted mice showed impaired dermal and cardiac wound healing after injury. The profibrotic ligands TGF-beta 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 Ca2+-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-beta, p38 MAPK, and SRF.

引用

页码：705 / 715

页数：11

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