Rajkumar Vineeth S, Shiwen Xu, Bostrom Maria, Leoni Patricia, Muddle John, Ivarsson Mikael, Gerdin Bengt, Denton Christopher P, Bou-Gharios George, Black Carol M, Abraham David J
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.
Am J Pathol. 2006 Dec;169(6):2254-65. doi: 10.2353/ajpath.2006.060196.
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.
结缔组织重塑为哺乳动物提供了一种在受伤后快速修复伤口的机制。这种修复过程的不适当激活会导致瘢痕形成和纤维化。在此，我们使用血小板衍生生长因子受体（PDGFR）-β抑制剂甲磺酸伊马替尼在体内研究了血小板衍生生长因子受体-β阻断对组织修复的影响。7天后，伤口愈合延迟，伤口闭合明显减少，同时肌成纤维细胞频率、纤连蛋白ED-A表达和I型胶原减少。使用I型胶原转基因报告小鼠，我们发现抑制PDGFR-β激活将胶原合成细胞的分布限制在伤口边缘，并显著降低体内细胞增殖。到14天时，处理过的伤口完全闭合。阻断PDGFR-β信号传导在体外并未阻止肌成纤维细胞的分化，但有力地抑制了成纤维细胞的增殖和迁移。此外，体内PDGFR-β抑制伴随着微血管形态异常，这让人联想到在PDGFR-β基因敲除小鼠中观察到的情况，周细胞标志物NG2的免疫染色显著减少。伊马替尼治疗在体外也抑制了周细胞的增殖和迁移。这项研究突出了PDGFR-β信号传导在伤口愈合早期阶段对成纤维细胞和周细胞的募集、增殖及功能活动的重要性。
