Abstract
Delayed wound healing is a serious clinical problem in patients after surgery. A recent study has demonstrated that bone marrow-derived c-kit-positive (c-kit+) cells play important roles in repairing and regenerating various tissues and organs. To examine the hypothesis that surgical injury induces the mobilization and recruitment of c-kit+ cells to accelerate wound healing. Mice were subjected to a left pneumonectomy. The mobilization of c-kit+ cells was monitored after surgery. Using green fluorescent protein (GFP+) bone marrow-transplanted chimera mice, we investigated further whether the mobilized c-kit+ cells were recruited to effect wound healing in a skin puncture model. The group with left pneumonectomies increased the c-kit+ and CD34+ stem cells in peripheral blood 24 h after surgery. At 3 days after surgery, the skin wound size was observed to be significantly smaller, and the number of bone marrow-derived GFP+ cells and GFP+/c-kit+ cells in the wound tissue was significantly greater in mice that had received pneumonectomies, as compared with those that had received a sham operation. Furthermore, some of these GFP+ cells were positively expressed specific markers of macrophages (F4/80), endothelial cells (CD31), and myofibroblasts (αSMA). The administration of AMD3100, an antagonist of a stromal-cell derived factor (SDF)-1/CXCR4 signaling pathway, reduced the number of GFP+ cells in wound tissue and completely negated the accelerated wound healing. Surgical injury induces the mobilization and recruitment of c-kit+ cells to contribute to wound healing. Regulating c-kit+ cells may provide a new approach that accelerates wound healing after surgery.
Highlights
Delayed wound healing continues to be a serious clinical problem after surgery because it increases the risk of surgical site infections [1,2], extends postoperative hospitalizations [3], and increases medical expenses [4,5,6,7]
Because c-kit-positive (c-kit+) cells in bone marrow can be mobilized into peripheral blood in response to ischemia, inflammation, and injuries including surgical injury [15,16], we investigated whether surgical injuries affect wound healing through the mobilization and recruitment of c-kit+ cells in order to understand the relative mechanisms in detail
It is well known that hypoxia and ischemia can stimulate the release of various factors, such as HIF-1, vascular endothelial growth factor (VEGF), and stromal-cell derived factor (SDF)-1a, to induce the mobilization and recruitment of stem/progenitor cells [29,30,31]
Summary
Delayed wound healing continues to be a serious clinical problem after surgery because it increases the risk of surgical site infections [1,2], extends postoperative hospitalizations [3], and increases medical expenses [4,5,6,7]. Wound healing involves complex processes, and many factors may contribute to delay these processes. Wound healing of the skin is a dynamic process involving fibroplasia, angiogenesis and reepithelialization. [9] Recent studies have demonstrated that stem/progenitor cells play important roles in promoting the development of new vessels [10,11,12,13], one of the critical processes during early wound healing, through direct (endothelial differentiation) and indirect (release of various angiogenic factors) mechanisms. Stem/progenitor cells can produce many other factors (e.g., EGF and KGF) that increase the proliferation of keratinocytes, epithelial cells, and myofibroblasts, which are known to be involved in wound healing [14]. The implantation of stem/progenitor cells has been demonstrated to improve wound healing in an animal model
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