Potentiation of biological effects of mesenchymal stem cells in ischemic conditions by melatonin via upregulation of cellular prion protein expression

Mesenchymal stem cells (MSCs) are promising candidates for stem cell‐based therapy in ischemic diseases. However, ischemic injury induces pathophysiological conditions, such as oxidative stress and inflammation, which diminish therapeutic efficacy of MSC‐based therapy by reducing survival and functionality of transplanted MSCs. To overcome this problem, we explored the effects of melatonin on the proliferation, resistance to oxidative stress, and immunomodulatory properties of MSCs. Treatment with melatonin enhanced MSC proliferation and self‐renewal via upregulation of cellular prion protein (PrP^C) expression. Melatonin diminished the extent of MSC apoptosis in oxidative stress conditions by regulating the levels of apoptosis‐associated proteins, such as BCL‐2, BAX, PARP‐1, and caspase‐3, in a PrP^C‐dependent manner. In addition, melatonin regulated the immunomodulatory effects of MSCs via the PrP^C‐IDO axis. In a murine hind‐limb ischemia model, melatonin‐stimulated MSCs improved the blood flow perfusion, limb salvage, and vessel regeneration by lowering the extent of apoptosis of affected local cells and transplanted MSCs as well as by reducing infiltration of macrophages. These melatonin‐mediated therapeutic effects were inhibited by silencing of PrP^C expression. Our findings for the first time indicate that melatonin promotes MSC functionality and enhances MSC‐mediated neovascularization in ischemic tissues through the upregulation of PrP^C expression. In conclusion, melatonin‐treated MSCs could provide a therapeutic strategy for vessel regeneration in ischemic disease, and the targeting of PrP^C levels may prove instrumental for MSC‐based therapies.