ORIGINAL RESEARCH article
Front. Immunol.
Sec. Alloimmunity and Transplantation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1586174
This article is part of the Research TopicCommunity Series in Safety, Efficacy and Mechanisms of Action of Mesenchymal Stem Cell Therapies - Volume IIView all 10 articles
Small extracellular vesicles from human umbilical cord mesenchymal stem cells delivering miR-202-5p alleviate renal ischemia-reperfusion injury by targeting GOLIM4 through the PI3K/AKT pathway
Provisionally accepted
- 1Department of Urology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- 2Chongqing Key Laboratory of Molecular Oncology and Epigenetics, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- 3Chongqing Clinical Research Center for Reproductive Medicine, Chongqing Health Center for Women and Children, Chongqing, China
- 4Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States
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Ischemia-reperfusion injury (IRI) is a leading contributor to acute kidney injury (AKI), resulting in severe renal dysfunction and increased mortality. Despite progress in medical research, effective therapies for IRI remain limited. Recently, small extracellular vesicles (sEVs) originating from human umbilical cord mesenchymal stem cells (HucMSC-sEVs) have gained attention as potential therapeutic agents for alleviating organ damage. This study aimed to investigate the protective effects of HucMSC-sEVs in renal IRI and explore the underlying mechanisms involved.HucMSC-sEVs were isolated from HucMSCs via differential ultracentrifugation. Their characteristics were analyzed via transmission electron microscopy (TEM), nanoFCM, and western blotting. The protective effects of HucMSC-sEVs on OGD/R-induced apoptosis in HK-2 cells were evaluated via western blotting and flow cytometric analysis. Additionally, to explore the molecular mechanisms, qRT-PCR, dual-luciferase reporter assays, and other techniques were employed to investigate the role of miR-202-5p in HucMSC-sEVs, with a focus on its ability to regulate the PI3K/AKT pathway through the targeting of GOLIM4. Finally, the therapeutic effects of HucMSC-sEVs were evaluated in vivo via a mouse model of IRI. The HucMSC-sEVs exhibited a characteristic biconcave circular morphology, with a particle size range of 60-100 nm and an average diameter of 79.8 nm. Western blotting confirmed the presence of sEV markers CD9 and TSG101, and HucMSC-sEVs were efficiently taken up by HK-2 cells. In the OGD/R model, HucMSC-sEVs significantly reduced apoptosis, attenuated the expression of BAX and CC3, and promoted the upregulation of BCL-2. Mechanistic studies revealed that HucMSC-sEVs deliver miR-202-5p, which targets GOLIM4 and activates the PI3K/AKT pathway, ultimately reducing renal tubular cell apoptosis. In the mouse IRI model, HucMSC-sEVs significantly alleviated kidney damage and reduced the serum creatinine and urea nitrogen levels.This study is the first to demonstrate the role of HucMSC-sEVs in attenuating renal IRI both in vitro and in vivo through the modulation of the GOLIM4/PI3K/AKT pathway via miR-202-5p. These findings identify a novel molecular target for the treatment of AKI via HucMSC-sEVs and provide a strong theoretical basis for their potential clinical application.
Keywords: Renal ischemia reperfusion injury, Acute Kidney Injury, Human umbilical cord mesenchymal stem cells, Small extracellular vesicles, miR-202-5p, GOLIM4
Received: 02 Mar 2025; Accepted: 06 May 2025.
Copyright: © 2025 Peng, Shi, Yu, Feng, Wei, He, Gou and Xie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yongpeng Xie, Department of Urology, First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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