Melatonin‐stimulated exosomes enhance the regenerative potential of chronic kidney disease‐derived mesenchymal stem/stromal cells via cellular prion proteins

Abstract Chronic kidney disease (CKD) is caused by dysfunctional kidneys, which result in complications like cardiovascular diseases. Chronic kidney disease‐induced pathophysiological conditions decrease efficacy of autologous mesenchymal stem/stromal cell (MSC)‐based therapy by reducing MSC functionality. To enhance therapeutic potential in patients with CKD, we isolated exosomes derived from melatonin‐treated healthy MSCs (MT exosomes) and assessed the biological functions of MT exosome–treated MSCs isolated from patients with CKD (CKD‐MSCs). Treatment with melatonin increased the expression of cellular prion protein (PrP C ) in exosomes isolated from MSCs through the upregulation of miR‐4516. Treatment with MT exosomes protected mitochondrial function, cellular senescence, and proliferative potential of CKD‐MSCs. MT exosomes significantly increased the level of angiogenesis‐associated proteins in CKD‐MSCs. In a murine hindlimb ischemia model with CKD, MT exosome–treated CKD‐MSCs improved functional recovery and vessel repair. These findings elucidate the regenerative potential of MT exosome–treated CKD‐MSCs via the miR‐4516‐PrP C signaling axis. This study suggests that the treatment of CKD‐MSCs with MT exosomes might be a powerful strategy for developing autologous MSC‐based therapeutics for patients with CKD. Furthermore, miR‐4516 and PrP C could be key molecules for enhancing the regenerative potential of MSCs in ischemic diseases.