Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing.
Bone marrow derived mesenchymal stem cells (BM-MSCs) have been shown to enhance wound healing; however, the mechanisms involved are barely understood. In this study, we examined paracrine factors released by BM-MSCs and their effects on the cells participating in wound healing compared to those released by dermal fibroblasts. Analyses of BM-MSCs with Real-Time PCR and of BM-MSC-conditioned medium by antibody-based protein array and ELISA indicated that BM-MSCs secreted distinctively different cytokines and chemokines, such as greater amounts of VEGF-alpha, IGF-1, EGF, keratinocyte growth factor, angiopoietin-1, stromal derived factor-1, macrophage inflammatory protein-1alpha and beta and erythropoietin, compared to dermal fibroblasts. These molecules are known to be important in normal wound healing. BM-MSC-conditioned medium significantly enhanced migration of macrophages, keratinocytes and endothelial cells and proliferation of keratinocytes and endothelial cells compared to fibroblast-conditioned medium. Moreover, in a mouse model of excisional wound healing, where concentrated BM-MSC-conditioned medium was applied, accelerated wound healing occurred compared to administration of pre-conditioned or fibroblast-conditioned medium. Analysis of cell suspensions derived from the wound by FACS showed that wounds treated with BM-MSC-conditioned medium had increased proportions of CD4/80-positive macrophages and Flk-1-, CD34- or c-kit-positive endothelial (progenitor) cells compared to wounds treated with pre-conditioned medium or fibroblast-conditioned medium. Consistent with the above findings, immunohistochemical analysis of wound sections showed that wounds treated with BM-MSC-conditioned medium had increased abundance of macrophages. Our results suggest that factors released by BM-MSCs recruit macrophages and endothelial lineage cells into the wound thus enhancing wound healing.
Chen
Liwen
L
Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Tredget
Edward E
EE
Wu
Philip Y G
PY
Wu
Yaojiong
Y
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D019070:Cell Lineage; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology*; D004730:Endothelium, Vascular / Q000166:cytology*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012867:Skin / Q000166:cytology; D014945:Wound Healing
D017077:Culture Media, Conditioned