Substance P promotes diabetic wound healing by modulating inflammation and restoring cellular activity of mesenchymal stem cells

Diabetic ulceration is one of the most debilitating complications of diabetes and is the main cause of amputation. The diabetic environment is characterized by prolonged inflammation and abnormal angiogenesis, leading to delayed wound healing. Thus, regulation of inflammation and neovascularization is considered a desirable target for diabetes. The critical purpose of this study was to determine whether systemically administered Substance P (SP) could promote wound healing in diabetic environments via suppression of inflammation, induction of angiogenesis, and mobilization of stem cells. The effect of SP was assessed by analyzing epidermal and dermal recovery, vessel formation, cytokine secretion profile, and the stem cell pool in the circulation and bone marrow. Compared with the vehicle-treated group, the SP-treated group exhibited more rapid wound coverage, reduced infiltration of leukocytes, suppression of injury-mediated enlargement of the spleen and mesenteric lymph nodes, reduced tumor necrosis factor-alpha levels, increased interleukin-10, elevated pool of M2 monocytes and vascular endothelial growth factor levels in the blood. Moreover, the stem cell pool in the bone marrow, which is very low in diabetes, was markedly restored by SP to normal levels, which could provide a favorable environment to facilitate wound healing in diabetes. This result demonstrates, for the first time, a possible application of SP for the treatment of diabetic complications, including diabetic ulcers.