Wound healing can be improved by transplanting mesenchymal stem cells (MSCs). In this study, we have demonstrated the benefits of the conditioned medium derived from human MSCs (CM-MSC) in wound healing using an excisional wound model. CM-MSC accelerated wound closure with increased reepithelialization, cell infiltration, granulation formation, and angiogenesis. Notably, CM-MSC enhanced epithelial and endothelial cell migration, suggesting the contribution of increased cell migration to wound healing enhanced by CM-MSC. Cytokine array, ELISA analysis, and quantitative RT-PCR revealed high levels of IL-6 in CM-MSC. Moreover, IL-6 added to the preconditioned medium enhanced both cell migration and wound healing, and antibodies against IL-6 blocked the increase in cell motility and wound closure by CM-MSC. The IL-6 secretory pathway of MSCs was inhibited by SB203580, an inhibitor of p38 MAPK or siRNA against p38 MAPK, suggesting IL-6 secretion by MSCs is mediated through the activation of p38 MAPK. Inactivation of p38 MAPK also reduced the expression and production of IL-8 and CXCL1 by MSCs, both of which were also demonstrated to enhance cell migration and wound closure. Thus, our data suggest MSCs promote wound healing through releasing a repertoire of paracrine factors via activation of p38 MAPK, and the CM-MSC may be applied to enhance wound healing.
These results strongly suggest that hypoxic MSCs are intrinsically immunoprivileged and can serve as a 'universal donor cell' for treating cardiovascular diseases.
To realize the therapeutic potential of mesenchymal stem cells (MSCs), a large number of high-quality MSCs isolated from different species, such as mouse, were acquired for preclinical animal studies. Surprisingly, isolation and purification of mouse MSCs (mMSCs) is arduous because of the low frequency of MSCs and contamination of haematopoietic cells in culture. We have developed a method based on low density and hypoxic culture to isolate and expand mMSCs from different strains, including BALB/c, C57BL/6J, FVB/N and DBA/2. The cells from all of the strains expanded more rapidly when plated at low density in hypoxic culture compared with normoxic culture. These cells expressed CD44, CD105, CD29 and Sca-1 markers but not CD11b, CD34, CD45 and CD31 markers. Moreover, they were able to differentiate along osteoblastic, adipocytic and chondrocytic lineages. In conclusion, we have developed a robust method for isolation and expansion of mMSCs by combining low-density culture with hypoxic culture.
Our results indicate that PTH-GAM with a collagen matrix promotes local PTH production for at least 8 weeks and bone regeneration in craniofacial bone defect. Moreover, our results indicate that replacement of the collagen matrix with the D/C matrix improves the osteogenic effects of PTH-GAM.
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