Novel role of substance-p as a systemic wound messenger to mobilize mesenchymal stem cell from bone marrow and be engaged in the wound healing epithelial layer

Tissue injury may bring up the systemic participation of bone marrow stem cells in the repair. In this study, we report that substance-p is a systemically acting messenger to mobilize mesenchymal stem cell (MSC) probably from the bone marrow and be engaged in the wound healing process. This was supported by the injury-inducible substance-p detection in the tissue and the peripheral blood and subsequent MSC mobilization in the alkali-burn rabbit eye model, whose kinetics were dependent on the wound size. Furthermore, i.v. injection of exogenous substance-p stimulated MSC mobilization in the uninjured rabbits and those mobilized cells showed multipotent differentiation capacity. We demonstrated that earlier substance-p elevation in the circulation by substance-p injection or transfusion of autologous PKH-labeled MSC mobilized by substance-p strongly accelerated the wound healing of the alkali-burned rabbit eye and the transfused MSCs were engrafted to the epithelial and stromal layer of the injured tissue, suggesting their epithelial transdifferentiation in the regenerating tissue. Finally, we showed that substance-p stimulated transmigration of human MSC with concomitant induction of MMPs and inhibition of their inhibitors, cell proliferation, ERK1/2 activation, and nuclear translocation of [beta]-catenin in vitro. In conclusion, substance-p plays a role as a systemic wound-messenger to promote the MSC mobilization from the marrow and their participation in the wound healing possibly through its stimulant effect on MSC repopulation as well.