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Mesenchymal Stem Cell-Derived Extracellular Vesicles Attenuate Mitochondrial Damage and Inflammation by Stabilizing Mitochondrial DNA. Zhao Meng,Liu Shuyun,Wang Chengshi,Wang Yizhuo,Wan Meihua,Liu Fang,Gong Meng,Yuan Yujia,Chen Younan,Cheng Jingqiu,Lu Yanrong,Liu Jingping ACS nano Mitochondrial dysfunction is a key feature of injury to numerous tissues and stem cell aging. Although the tissue regenerative role of mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) is well known, their specific role in regulating mitochondrial function in target cells remains elusive. Here, we report that MSC-EVs attenuated mtDNA damage and inflammation after acute kidney injury (AKI) and that this effect was at least partially dependent on the mitochondrial transcription factor A (TFAM) pathway. In detail, TFAM and mtDNA were depleted by oxidative stress in MSCs from aged or diabetic donors. Higher levels of TFAM mRNA and mtDNA were detected in normal control (NC) MSC-EVs than in TFAM-knockdown (TFAM-KD) and aged EVs. EV-mediated TFAM mRNA transfer in recipient cells was unaffected by transcriptional inhibition. Accordingly, the application of MSC-EVs restored TFAM protein and TFAM-mtDNA complex (nucleoid) stability, thereby reversing mtDNA deletion and mitochondrial oxidative phosphorylation (OXPHOS) defects in injured renal tubular cells. Loss of TFAM also led to downregulation of multiple anti-inflammatory miRNAs and proteins in MSC-EVs. , intravenously injected EVs primarily accumulated in the liver, kidney, spleen, and lung. MSC-EVs attenuated renal lesion formation, mitochondrial damage, and inflammation in mice with AKI, whereas EVs from TFAM-KD or aged MSCs resulted in poor therapeutic outcomes. Moreover, TFAM overexpression (TFAM-OE) improved the rescue effect of MSC-EVs on mitochondrial damage and inflammation to some extent. This study suggests that MSC-EVs are promising nanotherapeutics for diseases characterized by mitochondrial damage, and TFAM signaling is essential for maintaining their regenerative capacity. 10.1021/acsnano.0c08947
Renal Endothelial Cell-Targeted Extracellular Vesicles Protect the Kidney from Ischemic Injury. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Endothelial cell injury plays a critical part in ischemic acute kidney injury (AKI) and participates in the progression of AKI. Targeting renal endothelial cell therapy may ameliorate vascular injury and further improve the prognosis of ischemic AKI. Here, P-selectin as a biomarker of ischemic AKI in endothelial cells is identified and P-selectin binding peptide (PBP)-engineered extracellular vesicles (PBP-EVs) with imaging and therapeutic functions are developed. The results show that PBP-EVs exhibit a selective targeting tendency to injured kidneys, while providing spatiotemporal information for the early diagnosis of AKI by quantifying the expression of P-selectin in the kidneys by molecular imaging. Meanwhile, PBP-EVs reveal superior nephroprotective functions in the promotion of renal repair and inhibition of fibrosis by alleviating inflammatory infiltration, improving reparative angiogenesis, and ameliorating maladaptive repair of the renal parenchyma. In conclusion, PBP-EVs, as an ischemic AKI theranostic system that is designed in this study, provide a spatiotemporal diagnosis in the early stages of AKI to help guide personalized therapy and exhibit superior nephroprotective effects, offering proof-of-concept data to design EV-based theranostic strategies to promote renal recovery and further improve long-term outcomes following AKI. 10.1002/advs.202204626
The role of extracellular vesicles in renal fibrosis. Jing H,Tang S,Lin S,Liao M,Chen H,Zhou J Cell death & disease As a particularly important mediator of intercellular communication, extracellular vesicles (EVs) have been proved to be extensively involved in various system diseases over the past two decades, including in renal diseases. As is well-known, renal fibrosis is the common pathological process of any ongoing renal disease or adaptive repair of kidney injury based on current knowledge. Although much work has been performed focusing on EVs in various renal diseases, the role of EVs in renal fibrosis has not been described in detail and summarized. In this review, we provide a brief overview of the definition, classification and biological process of EVs. Then, the potential mechanisms of EVs in renal fibrosis are illustrated. Lastly, recent advances in EVs and the implications of EVs for diagnosis and therapy in renal fibrosis disease are introduced. We look forward to a more comprehensive understanding of EVs in renal fibrosis, which could be a boon to patients with renal fibrosis disease. 10.1038/s41419-019-1605-2