BACKGROUND: Mesenchymal stem cells (MSCs) can improve cutaneous wound healing via the secretion of growth factors. However, the therapeutic efficacy of MSCs varies depending upon their source. Induced pluripotent stem cells are emerging as a promising source of MSCs with the potential to overcome several limitations of adult MSCs. This study compared the effectiveness of conditioned medium of MSCs derived from induced pluripotent stem cells (iMSC-CdM) with that derived from umbilical cord MSCs (uMSC-CdM) in a mouse cutaneous wound healing model. We also investigated the mechanisms of protection. METHODS: The iMSC-CdM or uMSC-CdM were topically applied to mice cutaneous wound model. The recovery rate, scar formation, inflammation and angiogenesis were measured. We compared angiogenesis cytokine expression between iMSC-CdM and uMSC-CdM and their protective effects on human umbilical vein endothelial cells (HUVECs) under HO-induced injury. The effects of iMSC-CdM on energy metabolism, mitochondria fragmentation and apoptosis were measured. RESULTS: Topical application of iMSC-CdM was superior to the uMSC-CdM in accelerating wound closure and enhancing angiogenesis. Expression levels of angiogenetic cytokines were higher in iMSC-CdM than they were in uMSC-CdM. The iMSC-CdM protected HUVECs from HO induced injury more effectively than uMSC-CdM did. Administration of iMSC-CdM stimulated HUVEC proliferation, tube formation and energy metabolism via the ERK pathway. Mechanistically, iMSC-CdM inhibited HO-induced mitochondrial fragmentation and apoptosis of HUVECs. CONCLUSION: Collectively, these findings indicate that iMSC-CdM is more effective than uMSC-CdM in treating cutaneous wounds, and in this way, iMSC-CdM may serve as a more constant and sustainable source for cell-free therapeutic approach.