Human-induced pluripotent stem cell-derived exosomes promote skin wound healing through activating FGF2-mediated p38 pathway.

The acute and large area skin healing has been an intractable problem for both clinician and patient. Exosomes derived from human-induced pluripotent stem cells (hiPSC-Exos) have been a novel promising cell-free treatment on skin damage repair. In this study, in vivo skin trauma model of full-layer skin damage on mouse back and in vitro skin-like trauma model of human keratinocytes (HaCaT) scratches were established to investigate the effects of hiPSC-Exos on the acute wound healing, and its potential regulation mechanism would be tried to explore. Our in vivo results showed that hiPSC-Exos labeled with PKH26 could be well taken up by cells in the wound area, and could effectively accelerate acute skin wound healing by inhibiting the mRNA expressions of inflammation factors and chemokines such as Il-1β, Ccl2, Cxcl5, Ccl7 as well as promoting PCNA positive cell ratio. The in vitro data showed that hiPCS-Exos could markedly increase the numbers of EdU positive keratinocytes and expedite keratinocyte migration, which could be reversed by fibroblast growth factor receptor 3 (FGFR3) antagonist AZD4547 and p38 inhibitor SB203580. In addition, fibroblast growth factor 2 (FGF-2) was existent in hiPSC-Exos, and hiPSC-Exos could upregulate the p-p38/p38 level, which could be significantly reversed by AZD4547, but not affect the p-ERK/ERK and p-JNK/JNK levels in wound model tissues and cells. In conclusion, hiPSC-Exos may have the potential to promote wound healing by inhibiting cell inflammation as well as promoting cell proliferation and migration based on inherent FGF-2 targeting to FGFR3 to activate p38 pathway, which may serve as a promising candidate for skin healing.