Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrPC‐dependent enhancement of the mitochondrial function

Although mesenchymal stem cell (MSC)‐based therapy is a treatment strategy for ischemic diseases associated with chronic kidney disease (CKD), MSCs of CKD patients undergo accelerated senescence, with decreased viability and proliferation upon uremic toxin exposure, inhibiting their utility as a potent stem cell source for transplantation therapy. We investigated the effects of melatonin administration in protecting against cell senescence and decreased viability induced by pathophysiological conditions near the engraftment site. MSCs harvested from CKD mouse models were treated with H₂O₂ to induce oxidative stress. CKD‐derived MSCs exhibited greater oxidative stress‐induced senescence than normal‐mMSCs, while melatonin protected CKD‐mMSCs from H₂O₂ and associated excessive senescence. The latter was mediated by PrP^C‐dependent mitochondrial functional enhancement; melatonin upregulated PrP^C, which bound PINK1, thus promoting mitochondrial dynamics and metabolism. In vivo, melatonin‐treated CKD‐mMSCs survived longer, with increased secretion of angiogenic cytokines in ischemic disease engraftment sites. CKD‐mMSCs are more susceptible to H₂O₂‐induced senescence than normal‐mMSCs, and melatonin administration protects CKD‐mMSCs from excessive senescence by upregulating PrP^C and enhancing mitochondrial function. Melatonin showed favorable therapeutic effects by successfully protecting CKD‐mMSCs from related ischemic conditions, thereby enhancing angiogenesis and survival. These results elucidate the mechanism underlying senescence inhibition by melatonin in stem cell‐based therapies using mouse‐derived CKD‐mMSCs.