Platelet-derived growth factor-beta receptor activation is essential for fibroblast and pericyte recruitment during cutaneous wound healing

Am J Pathol. 2006 Dec;169(6):2254-65. doi: 10.2353/ajpath.2006.060196.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Benzamides
  • Cell Movement
  • Cell Proliferation
  • Collagen Type I / biosynthesis
  • Collagen Type I / genetics
  • Female
  • Fibroblasts / physiology*
  • Imatinib Mesylate
  • Mice
  • Mice, Transgenic
  • Neovascularization, Physiologic / drug effects
  • Pericytes / physiology*
  • Piperazines / pharmacology*
  • Promoter Regions, Genetic
  • Pyrimidines / pharmacology*
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Skin / injuries*
  • Wound Healing / drug effects*

Substances

  • Benzamides
  • Collagen Type I
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Receptor, Platelet-Derived Growth Factor beta