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人脐带间充质干细胞来源的细胞外囊泡通过抑制衰老的肾小管上皮细胞改善肾脏缺血再灌注损伤：实验研究

Human umbilical cord mesenchymal stem cells-derived extracellular vesicles ameliorate kidney ischemia-reperfusion injury by suppression of senescent tubular epithelial cells: experimental study.

作者信息

Ma Ming, Zeng Jun, Zhu Mengli, Li Hui, Lin Tao, Yang Hao, Wei Xin, Song Turun

机构信息

Department of Urology, West China Hospital, Sichuan University.

Organ Transplantation Center, West China Hospital, Sichuan University.

出版信息

Int J Surg. 2025 Jan 1;111(1):394-410. doi: 10.1097/JS9.0000000000002074.

DOI:10.1097/JS9.0000000000002074
PMID:39236098
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11745712/
Abstract

BACKGROUND

Human umbilical cord mesenchymal stem cells-derived extracellular vesicles (HUMSC-EVs) have drawn much interest in kidney transplantation, mainly because of their renoprotection by alleviating cell injury and stimulating tissue repair. Cellular senescence has been proven to play a dual regulatory role in kidney ischemia-reperfusion injury (IRI), and the regulation of HUMSC-EVs on tubular epithelial cell senescence may be a potential therapeutic target.

MATERIALS AND METHODS

In vitro , the hypoxia-reoxygenation of human kidney-2 cells was used to simulate kidney IRI, and the regulation of HUMSC-EVs on human kidney-2 cells was detected. Transcriptome sequencing of human kidney-2 cells was used to explore the potential regulatory mechanism. In vivo , adult male mice were divided into five groups: control group, IRI group, HUMSC-EVs treatment group, senolytics treatment group (dasatinib + quercetin), and combined treatments group (HUMSC-EVs and senolytics). Kidney function, senescent features of tubular epithelial cells, acute kidney injury, and chronic interstitial fibrosis in mice were detected to explore the renoprotection effects of HUMSC-EVs.

RESULTS

Kidney IRI significantly up-regulated expressions of LaminB1, p53, p21, p16, senescence-associated beta-galactosidase, and apoptosis of tubular epithelial cells. In the mouse kidney IRI model, kidney subcapsular injection of HUMSC-EVs significantly improved kidney function, reducing the senescent features of tubular epithelial cells and alleviating acute kidney injury and chronic interstitial fibrosis. HUMSC-EVs mainly achieved renoprotection by regulating Bax/Bcl-2-dependent apoptosis during acute kidney injury and mostly reduced tubular atrophy and kidney interstitial fibrosis by regulating Ras-pERK-Ets1-p53 pathway-dependent cell senescence. Oral administration of senolytics also alleviated kidney injury induced by IRI, while the combined treatments of HUMSC-EVs and senolytics had better renoprotection effects.

CONCLUSIONS

The combination of HUMSC-EVs and senolytics alleviated acute kidney injury and chronic interstitial fibrosis by dynamic regulation of cell senescence and apoptosis, which provides a therapeutic potential strategy for organ preservation and tissue repair in kidney transplantation.

摘要

背景

人脐带间充质干细胞衍生的细胞外囊泡（HUMSC-EVs）在肾移植中引起了广泛关注，主要是因为它们通过减轻细胞损伤和刺激组织修复来发挥肾脏保护作用。细胞衰老已被证明在肾脏缺血再灌注损伤（IRI）中起双重调节作用，而HUMSC-EVs对肾小管上皮细胞衰老的调节可能是一个潜在的治疗靶点。

材料与方法

在体外，利用人肾-2细胞的缺氧复氧来模拟肾脏IRI，并检测HUMSC-EVs对人肾-2细胞的调节作用。通过对人肾-2细胞进行转录组测序来探索潜在的调节机制。在体内，将成年雄性小鼠分为五组：对照组、IRI组、HUMSC-EVs治疗组、衰老细胞溶解剂治疗组（达沙替尼+槲皮素）和联合治疗组（HUMSC-EVs与衰老细胞溶解剂）。检测小鼠的肾功能、肾小管上皮细胞的衰老特征、急性肾损伤和慢性间质纤维化，以探索HUMSC-EVs的肾脏保护作用。

结果

肾脏IRI显著上调了LaminB1、p53、p21、p16、衰老相关β-半乳糖苷酶的表达以及肾小管上皮细胞的凋亡。在小鼠肾脏IRI模型中，肾包膜下注射HUMSC-EVs可显著改善肾功能，减少肾小管上皮细胞的衰老特征，减轻急性肾损伤和慢性间质纤维化。HUMSC-EVs主要通过在急性肾损伤期间调节Bax/Bcl-2依赖性凋亡来实现肾脏保护作用，并且大多通过调节Ras-pERK-Ets1-p53通路依赖性细胞衰老来减少肾小管萎缩和肾间质纤维化。口服衰老细胞溶解剂也可减轻IRI诱导的肾损伤，而HUMSC-EVs与衰老细胞溶解剂的联合治疗具有更好的肾脏保护作用。

结论

HUMSC-EVs与衰老细胞溶解剂的联合通过动态调节细胞衰老和凋亡减轻了急性肾损伤和慢性间质纤维化，这为肾移植中的器官保存和组织修复提供了一种潜在的治疗策略。

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