| Summary: | 碩士 === 國立陽明大學 === 臨床醫學研究所 === 97 === Although treatment of chronic wounds remains limited and often ineffective, it can be improved through bone marrow-derived mesenchymal stem cell (MSC) transplantation. We hypothesized that MSC-enhanced wound healing was partly due to paracrine effects. Thus, we examined the effects of conditioned medium derived from a human MSC culture (CM-MSC) in wound healing. Using an excisional wound splinting model, we observed that CM-MSC significantly enhanced wound healing in mice as compared with the control preconditioned medium after direct application to the wound and wound bed. CM-MSC-treated wounds displayed significantly accelerated wound closure, with increased reepithelialization, cell infiltration, granulation formation, and angiogenesis. Notably, CM-MSC but not preconditioned medium enhanced epithelial and endothelial cell migration, highlighting the contribution of increased cell migration enhanced by CM-MSC during wound healing. Previous reports have demonstrated that interleukin- 6 (IL-6) stimulates endothelial cell proliferation, migration, and matrigel tube formation in a dose-dependent manner; application of anti-IL-6 blocking antibodies or IL-6 receptor abolished these effects. Because MSCs promote wound healing through secretion of a paracrine factor, IL-6 expression and secretion were analyzed. Cytokine array and enzyme-linked immunosorbent assay (ELISA) analysis of CM-MSC revealed high levels of IL-6. In addition, quantitative RT-PCR revealed expression of IL-6 in MSCs. Moreover, addition of IL-6 to the preconditioned medium enhanced both cell migration and wound healing, and antibodies against IL-6 blocked the enhanced cell motility and wound closure induced by CM-MSC. Inhibition of IL-6 secretion was observed using SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK), or p38 MAPK siRNA, suggesting that IL-6 secretion by MSCs is mediated through the constitutive activation of p38 MAPK. Thus, our data suggest that MSCs promote wound healing through IL-6 secretion, and application of CM-MSC may be useful for enhancing wound healing.
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