Acute kidney injury (AKI) is characterized by rapid failure of renal function and has no curative therapies. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) are known to carry therapeutic factors, which have shown promise in regenerative medicine applications, including AKI. However, there remains an unmet need to optimize their therapeutic effect. One potential avenue of optimization lies in pulsed focused ultrasound (pFUS), where tissues-of-interest are treated with sound waves. pFUS has been shown to enhance MSC therapy via increased cell homing, but its effects on cell-free EV therapy remain largely unexplored. We combine pFUS pretreatment of the kidney with MSC-derived EV therapy in a mouse model of cisplatin-induced AKI. EVs significantly improved kidney function, reduced injury markers, mediated increased proliferation, and reduced inflammation and apoptosis. While pFUS did not enhance EV homing to the kidney, the combined treatment resulted in a superior therapeutic effect compared to either treatment alone. We identified several molecular mechanisms underlying this synergistic therapeutic effect, including upregulation of proliferative signaling (MAPK/ERK, PI3K/Akt) and regenerative pathways (eNOS, SIRT3), as well as suppression of inflammation. Taken together, pFUS may be a strategy for enhancing the therapeutic efficacy of MSC-derived EV treatment for the treatment of AKI.

中文翻译：

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脉冲聚焦超声增强间充质基质细胞来源的细胞外囊泡在急性肾损伤中的治疗效果。

急性肾损伤 (AKI) 的特点是肾功能迅速衰竭，并且没有治愈性疗法。间充质基质细胞 (MSC) 衍生的细胞外囊泡 (EV) 已知携带治疗因子，这些因子在包括 AKI 在内的再生医学应用中显示出前景。然而，优化其治疗效果的需求仍未得到满足。一种潜在的优化途径在于脉冲聚焦超声 (pFUS)，其中用声波处理感兴趣的组织。pFUS 已被证明可通过增加细胞归巢来增强 MSC 治疗，但其对无细胞 EV 治疗的影响在很大程度上仍未得到探索。我们在顺铂诱导的 AKI 小鼠模型中将肾脏的 pFUS 预处理与 MSC 衍生的 EV 治疗相结合。EVs 显着改善肾功能，减少损伤标志物，介导增殖增加，并减少炎症和细胞凋亡。虽然 pFUS 不会增强 EV 向肾脏的归巢，但与单独的任一治疗相比，联合治疗产生了更好的治疗效果。我们确定了这种协同治疗作用背后的几种分子机制，包括增殖信号（MAPK/ERK、PI3K/Akt）和再生途径（eNOS、SIRT3）的上调，以及炎症的抑制。总之，pFUS 可能是一种提高 MSC 衍生的 EV 治疗 AKI 治疗效果的策略。包括增殖信号（MAPK/ERK、PI3K/Akt）和再生途径（eNOS、SIRT3）的上调，以及炎症的抑制。总之，pFUS 可能是一种提高 MSC 衍生的 EV 治疗 AKI 治疗效果的策略。包括增殖信号（MAPK/ERK、PI3K/Akt）和再生途径（eNOS、SIRT3）的上调，以及炎症的抑制。总之，pFUS 可能是一种提高 MSC 衍生的 EV 治疗 AKI 治疗效果的策略。