Platelet-Derived Growth Factor-β Receptor Activation Is Essential for Fibroblast and Pericyte Recruitment during Cutaneous Wound Healing

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-␤ blockade in vivo using the platelet-derived growth factor receptor (PDGFR)-␤ 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-␤ 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-␤ signaling did not prevent the differentiation of myofibroblasts in vitro but potently inhibited fibroblast proliferation and migration. In addition, PDGFR-␤ inhibition in vivo was accompanied by abnormal microvascular morphogenesis reminiscent of that observed in PDGFR-␤ ؊/؊ 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-␤ signaling for the recruitment, proliferation, and functional activities of fibroblasts and pericytes during the early phases of wound healing.

Pericytes and Perivascular Fibroblasts Are the Primary Source of Collagen-Producing Cells in Obstructive Fibrosis of the Kidney

“…PDGF secretion has been implicated as an autocrine growth factor for myofibroblasts in vitro, but its role in vivo in the initiation and progression of fibrosis in the kidney is less clear, 37 although in skin wound-healing, PDGFR␤ blockade has been reported to delay wound closure. 38 Macrophages are necessary for proliferation of kidney fibroblasts and induction of matrix deposition. 39 Future studies should determine whether macrophage delivered PDGF is important in the initiation of fibrosis and pericyte differentiation.…”

Concise Review: Wharton's Jelly: The Rich, but Enigmatic, Source of Mesenchymal Stromal Cells

“…One possible mechanism for this, as mentioned above, is through the PDGF/PDGFRβ axis. Signaling through this pathway results in a potent chemotactic and mitogenic response seen in pericyte recruitment, both during development 69, 70, and following tissue injury 71, 72. In cell culture, it has been reported that amniotic epithelial cells produce PDGF‐B 73, 74, and therefore, could potentially serve as a stimulus for perivascular migration in vivo.…”

MFG-E8 Regulates Angiogenesis in Cutaneous Wound Healing

“…PDGF receptor b (PDGFRb) signaling is essential for angiogenesis and for recruitment, proliferation, and normal function of fibroblasts and pericytes during the tissue-formation phase. 3 Blockade of VEGF receptor signaling and PDGFRb signaling inhibits angiogenesis and results in delayed wound healing, 3,4 indicating that angiogenesis is critical for normal wound healing.…”