Enhanced therapeutic effects of hypoxia-preconditioned mesenchymal stromal cell-derived extracellular vesicles in renal ischemic injury
Abstract Background Extracellular vesicles (EVs) secreted by mesenchymal stromal cells (MSCs) have been shown to provide significant protection against renal ischemia–reperfusion injury (IRI). Hypoxia has emerged as a promising strategy to enhance the tissue repair capabilities of MSCs. However, the...
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2025-02-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-025-04166-z |
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| author | Fei Yuan Jie Liu Liang Zhong Pengtao Liu Ting Li Kexin Yang Wei Gao Guangyuan Zhang Jie Sun Xiangyu Zou |
| author_facet | Fei Yuan Jie Liu Liang Zhong Pengtao Liu Ting Li Kexin Yang Wei Gao Guangyuan Zhang Jie Sun Xiangyu Zou |
| author_sort | Fei Yuan |
| collection | DOAJ |
| description | Abstract Background Extracellular vesicles (EVs) secreted by mesenchymal stromal cells (MSCs) have been shown to provide significant protection against renal ischemia–reperfusion injury (IRI). Hypoxia has emerged as a promising strategy to enhance the tissue repair capabilities of MSCs. However, the specific effects of hypoxia on MSCs and MSC-EVs, as well as their therapeutic potential in renal IRI, remain unclear. In this study, we investigated the alterations occurring in MSCs and the production of MSC-EVs following hypoxia pre-treatment, and further explored the key intrinsic mechanisms underlying the therapeutic effects of hypoxic MSC-EVs in the treatment of renal IRI. Methods Human umbilical cord MSCs were cultured under normoxic and hypoxic conditions. Proliferation and related pathways were measured, and RNA sequencing was used to detect changes in the transcriptional profile. MSC-EVs from both normoxic and hypoxic conditions were isolated and characterized. In vivo, the localization and therapeutic effects of MSC-EVs were assessed in a rat renal IRI model. Histological examinations were conducted to evaluate the structure, proliferation, and apoptosis of IRI kidney tissue respectively. Renal function was assessed by measuring serum creatinine and blood urea nitrogen levels. In vitro, the therapeutic potential of MSC-EVs were measured in renal tubular epithelial cells injured by antimycin A. Protein sequencing analysis of hypoxic MSC-EVs was performed, and the depletion of Glutathione S-Transferase Omega 1 (GSTO1) in hypoxic MSC-EVs was carried out to verify its key role in alleviating renal injury. Results Hypoxia alters MSCs transcriptional profile, promotes their proliferation, and increases the production of EVs. Hypoxia-pretreated MSC-EVs demonstrated a superior ability to mitigate renal IRI, enhancing proliferation and reducing apoptosis of renal tubular epithelial cells both in vivo and in vitro. Protein profiling of the EVs revealed an accumulation of numerous anti-oxidative stress proteins, with GSTO1 being particularly prominent. Knockdown of GSTO1 significantly reduced the antioxidant and therapeutic effects on renal IRI of hypoxic MSC-EVs. Conclusions Hypoxia significantly promotes the generation of MSC-EVs and enhances their therapeutic effects on renal IRI. The antioxidant stress effect induced by GSTO1 is identified as one of the most critical underlying mechanisms. Our findings highlight that hypoxia-pretreated MSC-EVs represent a novel and promising therapeutic strategy for renal IRI. Graphical Abstract |
| format | Article |
| id | doaj-art-e9e08174f0ef4332bd76bf30a18ac0cc |
| institution | Kabale University |
| issn | 1757-6512 |
| language | English |
| publishDate | 2025-02-01 |
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| series | Stem Cell Research & Therapy |
| spelling | doaj-art-e9e08174f0ef4332bd76bf30a18ac0cc2025-02-09T12:15:42ZengBMCStem Cell Research & Therapy1757-65122025-02-0116111810.1186/s13287-025-04166-zEnhanced therapeutic effects of hypoxia-preconditioned mesenchymal stromal cell-derived extracellular vesicles in renal ischemic injuryFei Yuan0Jie Liu1Liang Zhong2Pengtao Liu3Ting Li4Kexin Yang5Wei Gao6Guangyuan Zhang7Jie Sun8Xiangyu Zou9Department of Urology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineDepartment of Urology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineDepartment of Urology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineSchool of Basic Medical Sciences, Shandong Second Medical UniversitySchool of Basic Medical Sciences, Shandong Second Medical UniversitySchool of Basic Medical Sciences, Shandong Second Medical UniversityDepartment of Urology, Zhongda Hospital, Southeast UniversityDepartment of Urology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineDepartment of Urology, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of MedicineAbstract Background Extracellular vesicles (EVs) secreted by mesenchymal stromal cells (MSCs) have been shown to provide significant protection against renal ischemia–reperfusion injury (IRI). Hypoxia has emerged as a promising strategy to enhance the tissue repair capabilities of MSCs. However, the specific effects of hypoxia on MSCs and MSC-EVs, as well as their therapeutic potential in renal IRI, remain unclear. In this study, we investigated the alterations occurring in MSCs and the production of MSC-EVs following hypoxia pre-treatment, and further explored the key intrinsic mechanisms underlying the therapeutic effects of hypoxic MSC-EVs in the treatment of renal IRI. Methods Human umbilical cord MSCs were cultured under normoxic and hypoxic conditions. Proliferation and related pathways were measured, and RNA sequencing was used to detect changes in the transcriptional profile. MSC-EVs from both normoxic and hypoxic conditions were isolated and characterized. In vivo, the localization and therapeutic effects of MSC-EVs were assessed in a rat renal IRI model. Histological examinations were conducted to evaluate the structure, proliferation, and apoptosis of IRI kidney tissue respectively. Renal function was assessed by measuring serum creatinine and blood urea nitrogen levels. In vitro, the therapeutic potential of MSC-EVs were measured in renal tubular epithelial cells injured by antimycin A. Protein sequencing analysis of hypoxic MSC-EVs was performed, and the depletion of Glutathione S-Transferase Omega 1 (GSTO1) in hypoxic MSC-EVs was carried out to verify its key role in alleviating renal injury. Results Hypoxia alters MSCs transcriptional profile, promotes their proliferation, and increases the production of EVs. Hypoxia-pretreated MSC-EVs demonstrated a superior ability to mitigate renal IRI, enhancing proliferation and reducing apoptosis of renal tubular epithelial cells both in vivo and in vitro. Protein profiling of the EVs revealed an accumulation of numerous anti-oxidative stress proteins, with GSTO1 being particularly prominent. Knockdown of GSTO1 significantly reduced the antioxidant and therapeutic effects on renal IRI of hypoxic MSC-EVs. Conclusions Hypoxia significantly promotes the generation of MSC-EVs and enhances their therapeutic effects on renal IRI. The antioxidant stress effect induced by GSTO1 is identified as one of the most critical underlying mechanisms. Our findings highlight that hypoxia-pretreated MSC-EVs represent a novel and promising therapeutic strategy for renal IRI. Graphical Abstracthttps://doi.org/10.1186/s13287-025-04166-zHypoxia pretreatedMesenchymal stromal cellsExtracellular vesiclesRenal ischemia reperfusion injuryAnti-oxidative stress |
| spellingShingle | Fei Yuan Jie Liu Liang Zhong Pengtao Liu Ting Li Kexin Yang Wei Gao Guangyuan Zhang Jie Sun Xiangyu Zou Enhanced therapeutic effects of hypoxia-preconditioned mesenchymal stromal cell-derived extracellular vesicles in renal ischemic injury Stem Cell Research & Therapy Hypoxia pretreated Mesenchymal stromal cells Extracellular vesicles Renal ischemia reperfusion injury Anti-oxidative stress |
| title | Enhanced therapeutic effects of hypoxia-preconditioned mesenchymal stromal cell-derived extracellular vesicles in renal ischemic injury |
| title_full | Enhanced therapeutic effects of hypoxia-preconditioned mesenchymal stromal cell-derived extracellular vesicles in renal ischemic injury |
| title_fullStr | Enhanced therapeutic effects of hypoxia-preconditioned mesenchymal stromal cell-derived extracellular vesicles in renal ischemic injury |
| title_full_unstemmed | Enhanced therapeutic effects of hypoxia-preconditioned mesenchymal stromal cell-derived extracellular vesicles in renal ischemic injury |
| title_short | Enhanced therapeutic effects of hypoxia-preconditioned mesenchymal stromal cell-derived extracellular vesicles in renal ischemic injury |
| title_sort | enhanced therapeutic effects of hypoxia preconditioned mesenchymal stromal cell derived extracellular vesicles in renal ischemic injury |
| topic | Hypoxia pretreated Mesenchymal stromal cells Extracellular vesicles Renal ischemia reperfusion injury Anti-oxidative stress |
| url | https://doi.org/10.1186/s13287-025-04166-z |
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