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 (PrPC ) 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-PrPC 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 PrPC could be key molecules for enhancing the regenerative potential of MSCs in ischemic diseases.

中文翻译：

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褪黑素刺激的外来体通过细胞病毒蛋白增强了慢性肾脏疾病来源的间充质干/基质细胞的再生潜力。

慢性肾脏疾病（CKD）是由功能失调的肾脏引起的，其导致诸如心血管疾病的并发症。慢性肾脏疾病引起的病理生理状况通过降低MSC的功能性而降低了自体间充质干细胞/基质细胞（MSC）疗法的疗效。为了增强CKD患者的治疗潜力，我们分离了褪黑素治疗的健康MSC（MT外泌体）衍生的外泌体，并评估了从CKD患者（CKD-MSC）中分离出的MT外泌体治疗的MSC的生物学功能。褪黑素处理通过上调miR-4516，增加了从MSCs分离的外泌体中细胞病毒蛋白（PrPC）的表达。MT外泌体的治疗可保护线粒体功能，细胞衰老和CKD-MSC的增殖潜力。MT外泌体显着增加了CKD-MSC中血管生成相关蛋白的水平。在具有CKD的小鼠后肢缺血模型中，MT外来体处理的CKD-MSC改善了功能恢复和血管修复。这些发现阐明了通过miR-4516-PrPC信号轴对MT外来体处理的CKD-MSC的再生潜力。这项研究表明，MT外泌体对CKD-MSC的治疗可能是开发针对CKD患者自体基于MSC的疗法的有效策略。此外，miR-4516和PrPC可能是增强MSC在缺血性疾病中再生潜力的关键分子。这些发现阐明了通过miR-4516-PrPC信号轴对MT外来体处理的CKD-MSC的再生潜力。这项研究表明，MT外泌体对CKD-MSC的治疗可能是开发针对CKD患者自体基于MSC的疗法的有效策略。此外，miR-4516和PrPC可能是增强MSC在缺血性疾病中再生潜力的关键分子。这些发现阐明了通过miR-4516-PrPC信号轴对MT外来体处理的CKD-MSC的再生潜力。这项研究表明，MT外泌体对CKD-MSC的治疗可能是开发针对CKD患者自体基于MSC的疗法的有效策略。此外，miR-4516和PrPC可能是增强MSC在缺血性疾病中再生潜力的关键分子。