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Rac1 Expression by Fibroblasts Is Required for Tissue Repair in Vivo

https://doi.org/10.2353/ajpath.2009.080779Get rights and content

Tissue repair requires that fibroblasts migrate into the wound to produce and remodel extracellular matrix, a process that requires adhesion. Failure to suppress the tissue repair program results in fibrotic disorders that are characterized by excessive adhesive signaling. The role of specific components of adhesive signaling in fibrogenic responses is unclear, but may involve small GTPases such as Rac1. To address the functions of Rac1 in fibroblasts, we generated mice containing a fibroblast-specific deletion of Rac1. These mice show delayed cutaneous wound closure, including reduced collagen production and myofibroblast formation. In cultured Rac1-deficient fibroblasts, adhesion, spreading, and migration were significantly inhibited. Rac1-deficient fibroblasts possessed impaired myofibroblast formation and function as visualized by reduced α-smooth muscle actin expression as well as matrix contraction. Both in vivo and in vitro, Rac1- deficient fibroblasts showed a reduced generation of reactive oxygen species; in vitro, hydrogen peroxide alleviated the phenotype of Rac1-deficient fibroblasts. Thus, Rac1 is an essential signaling integrator that is required for normal wound healing and dermal homeostasis.

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Supported by grants from the Canadian Foundation for Innovation and the Canadian Institutes of Health Research and the Ontario Thoracic Society. A.L. is a New Investigator of the Arthritis Society (Scleroderma Society of Ontario), the recipient of an Early Researcher Award and a member of the Canadian Scleroderma Research Group New Emerging Team. M.K. is the recipient of postdoctoral fellowships from the Canadian Arthritis Network and the Ontario Ministry of Innovation.

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