Platelet-derived growth factor-beta receptor activation is essential for fibroblast and pericyte recruitment during cutaneous wound healing.
Connective tissue remodeling provides mammals with a rapid mechanism to repair wounds after injury. Inappropriate activation of this reparative process leads to scarring and fibrosis. Here, we studied the effects of platelet-derived growth factor receptor-beta blockade in vivo using the platelet-derived growth factor receptor (PDGFR)-beta inhibitor imatinib mesylate on tissue repair. After 7 days, healing of wounds was delayed with significantly reduced wound closure and concomitant reduction in myofibroblast frequency, expression of fibronectin ED-A, and collagen type I. Using a collagen type I transgenic reporter mouse, we showed that inhibiting PDGFR-beta activation restricted the distribution of collagen-synthesizing cells to wound margins and dramatically reduced cell proliferation in vivo. By 14 days, treated wounds were fully closed. Blocking PDGFR-beta signaling did not prevent the differentiation of myofibroblasts in vitro but potently inhibited fibroblast proliferation and migration. In addition, PDGFR-beta inhibition in vivo was accompanied by abnormal microvascular morphogenesis reminiscent of that observed in PDGFR-beta-/- mice with significantly reduced immunostaining of the pericyte marker NG2. Imatinib treatment also inhibited pericyte proliferation and migration in vitro. This study highlights the significance of PDGFR-beta signaling for the recruitment, proliferation, and functional activities of fibro-blasts and pericytes during the early phases of wound healing.
Rajkumar
Vineeth S
VS
Centre for Rheumatology and Connective Tissue Disease, Department of Medicine, University College London NW3 2PF, UK, and the Clinical Research Center, University Hospital, Orebro, Sweden.
Shiwen
Xu
X
Bostrom
Maria
M
Leoni
Patricia
P
Muddle
John
J
Ivarsson
Mikael
M
Gerdin
Bengt
B
Denton
Christopher P
CP
Bou-Gharios
George
G
Black
Carol M
CM
Abraham
David J
DJ
D000818:Animals; D017209:Apoptosis; D001549:Benzamides; D002465:Cell Movement; D049109:Cell Proliferation; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D000068877:Imatinib Mesylate; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020286:Pericytes / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D012867:Skin / Q000293:injuries*; D014945:Wound Healing / Q000187:drug effects*
D001549:Benzamides; D024042:Collagen Type I; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta