Rac1 expression by fibroblasts is required for tissue repair in vivo.
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 alpha-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.
Department of Physiology and Pharmacology, Division of Oral Biology, Schulich School of Medicine and Dentistry, Canadian Institute of Health Research Group in Skeletal Development and Remodeling, University of Western Ontario, London, Ontario, Canada.
Shangxi
S
Liu
Mohit
M
Kapoor
Andrew
A
Leask
D000199:Actins / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006909:Hydroxyproline / Q000378:metabolism; D007124:Immunoenzyme Techniques; D051379:Mice; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D009479:Neuropeptides / Q000502:physiology*; D016877:Oxidants / Q000494:pharmacology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000293:injuries / Q000378:metabolism*; D012871:Skin Diseases / Q000378:metabolism / Q000517:prevention & control*; D014945:Wound Healing / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000502:physiology*; D020830:rac1 GTP-Binding Protein
D000199:Actins; D009479:Neuropeptides; D016877:Oxidants; D012333:RNA, Messenger; C484602:Rac1 protein, mouse; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D006909:Hydroxyproline