通过抑制衰老的肾小管上皮细胞改善肾缺血再灌注损伤--实验研究。

IF 12.5 2区 医学 Q1 SURGERY International journal of surgery Pub Date : 2024-09-05 DOI:10.1097/JS9.0000000000002074
Ming Ma, Jun Zeng, Mengli Zhu, Hui Li, Tao Lin, Hao Yang, Xin Wei, Turun Song
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引用次数: 0

摘要

背景:人脐带间充质干细胞衍生的细胞外囊泡(HUMSC-EVs)在肾移植中备受关注,这主要是因为HUMSC-EVs具有减轻细胞损伤和促进组织修复的肾脏保护作用。细胞衰老已被证实在肾脏缺血再灌注损伤(IRI)中起着双重调控作用,HUMSC-EVs对肾小管上皮细胞衰老的调控可能是一个潜在的治疗靶点:体外模拟肾脏缺血缺氧损伤(IRI),检测HUMSC-EVs对肾小管上皮细胞衰老的调控。通过对人肾-2细胞的转录组测序来探索潜在的调控机制。在体内,成年雄性小鼠被分为五组:对照组、IRI组、HUMSC-EVs治疗组、衰老素治疗组(达沙替尼+槲皮素)和联合治疗组(HUMSC-EVs和衰老素)。通过检测小鼠肾功能、肾小管上皮细胞衰老特征、急性肾损伤和慢性肾间质纤维化,探讨HUMSC-EVs的肾保护作用:结果:肾脏IRI能明显上调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,肾脏囊下注射HUMSC-EVs能显著改善肾功能,减少肾小管上皮细胞的衰老特征,缓解急性肾损伤和慢性肾间质纤维化。HUMSC-EVs主要通过调节急性肾损伤时Bax/Bcl-2依赖性细胞凋亡实现肾保护,并通过调节Ras-pERK-Ets1-p53通路依赖性细胞衰老减少肾小管萎缩和肾间质纤维化。口服解毒剂也能缓解IRI引起的肾损伤,而HUMSC-EVs和解毒剂联合治疗具有更好的肾保护效果:结论:HUMSC-EVs和抗衰老药物联合使用可通过动态调节细胞衰老和凋亡缓解急性肾损伤和慢性肾间质纤维化,为肾移植中的器官保护和组织修复提供了一种潜在的治疗策略。
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Human umbilical cord mesenchymal stem cells derived extracellular vesicles ameliorate kidney ischemia-reperfusion injury by suppression of senescent tubular epithelial cells - Experimental Study.

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.

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来源期刊
CiteScore
17.70
自引率
3.30%
发文量
0
审稿时长
6-12 weeks
期刊介绍: The International Journal of Surgery (IJS) has a broad scope, encompassing all surgical specialties. Its primary objective is to facilitate the exchange of crucial ideas and lines of thought between and across these specialties.By doing so, the journal aims to counter the growing trend of increasing sub-specialization, which can result in "tunnel-vision" and the isolation of significant surgical advancements within specific specialties.
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