MSCs-derived HGF alleviates senescence by inhibiting unopposed mitochondrial fusion-based elongation in post-acute kidney injury
Abstract Background The underlying mechanism of human umbilical-derived mesenchymal stem cells (hUC-MSCs) therapy for renal senescence in post-acute kidney injury (post-AKI) remains unclear. Unopposed mitochondrial fusion-based mitochondrial elongation is required for cellular senescence. This study...
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BMC
2024-11-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13287-024-04041-3 |
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| author | Kaiting Zhuang Wenjuan Wang Xumin Zheng Xinru Guo Cheng Xu Xuejing Ren Wanjun Shen Qiuxia Han Zhe Feng Xiangmei Chen Guangyan Cai |
| author_facet | Kaiting Zhuang Wenjuan Wang Xumin Zheng Xinru Guo Cheng Xu Xuejing Ren Wanjun Shen Qiuxia Han Zhe Feng Xiangmei Chen Guangyan Cai |
| author_sort | Kaiting Zhuang |
| collection | DOAJ |
| description | Abstract Background The underlying mechanism of human umbilical-derived mesenchymal stem cells (hUC-MSCs) therapy for renal senescence in post-acute kidney injury (post-AKI) remains unclear. Unopposed mitochondrial fusion-based mitochondrial elongation is required for cellular senescence. This study attempted to dissect the role of hUC-MSCs therapy in modulating mitochondrial elongation-related senescence by hUC-MSCs therapy in post-AKI. Methods Initially, a unilateral renal ischemia–reperfusion (uIRI) model was established in C57 mice. Subsequently, lentivirus-transfected hUC-MSCs were given by subcapsular injection. Two weeks after transplantation, histochemical staining, and transmission electron microscopy were used to assess the efficacy of hUC-MSCs in treating renal senescence, fibrosis, and mitochondrial function. To further investigate the mitochondrial regulation of hUC-MSCs secretion, hypoxic HK-2 cells were built. Finally, antibodies of HGF and its receptor were used within the hUC-MSCs supernatant. Results Unopposed mitochondrial fusion, renal senescence, and renal interstitial fibrosis were successively identified after uIRI in mice. Then, the efficacy of hUC-MSCs after uIRI was confirmed. Subsequently, inhibiting hUC-MSCs-derived HGF significantly compromises the efficacy of hUC-MSCs and leads to ineffectively curbing mitochondrial elongation, accompanying insufficient control of elevated PKA and inhibitory phosphorylation of drp1 (Drp1pSer637). As a result, the treatment efficacy of renal senescence and fibrosis alleviation was also weakened. Furthermore, similar results were obtained with antibodies blocking HGF or cMet in hypoxic HK-2 cells treated with hUC-MSCs-condition medium for further proving. Uncurbed mitochondrial elongation induced by PKA and Drp1pSer637 was inhibited by hUC-MSCs derived HGF but reversed in the activation or overexpression of PKA. Conclusions The research concluded that hUC-MSCs-derived HGF can inhibit PKA-Drp1pSer637-mitochondrial elongation via its receptor cMet to alleviate renal senescence and fibrosis in post-AKI. |
| format | Article |
| id | doaj-art-7c9b9232ffd84e44a33ea3ea44d7e73a |
| institution | Kabale University |
| issn | 1757-6512 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj-art-7c9b9232ffd84e44a33ea3ea44d7e73a2024-11-24T12:13:37ZengBMCStem Cell Research & Therapy1757-65122024-11-0115112310.1186/s13287-024-04041-3MSCs-derived HGF alleviates senescence by inhibiting unopposed mitochondrial fusion-based elongation in post-acute kidney injuryKaiting Zhuang0Wenjuan Wang1Xumin Zheng2Xinru Guo3Cheng Xu4Xuejing Ren5Wanjun Shen6Qiuxia Han7Zhe Feng8Xiangmei Chen9Guangyan Cai10Medical School of Chinese PLADepartment of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney DiseasesMedical School of Chinese PLASchool of Medicine, Nankai UniversityDepartment of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney DiseasesDepartment of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney DiseasesDepartment of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney DiseasesDepartment of Nephrology, Beijing Chao-Yang Hospital, Capital Medical UniversityDepartment of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney DiseasesDepartment of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney DiseasesDepartment of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney DiseasesAbstract Background The underlying mechanism of human umbilical-derived mesenchymal stem cells (hUC-MSCs) therapy for renal senescence in post-acute kidney injury (post-AKI) remains unclear. Unopposed mitochondrial fusion-based mitochondrial elongation is required for cellular senescence. This study attempted to dissect the role of hUC-MSCs therapy in modulating mitochondrial elongation-related senescence by hUC-MSCs therapy in post-AKI. Methods Initially, a unilateral renal ischemia–reperfusion (uIRI) model was established in C57 mice. Subsequently, lentivirus-transfected hUC-MSCs were given by subcapsular injection. Two weeks after transplantation, histochemical staining, and transmission electron microscopy were used to assess the efficacy of hUC-MSCs in treating renal senescence, fibrosis, and mitochondrial function. To further investigate the mitochondrial regulation of hUC-MSCs secretion, hypoxic HK-2 cells were built. Finally, antibodies of HGF and its receptor were used within the hUC-MSCs supernatant. Results Unopposed mitochondrial fusion, renal senescence, and renal interstitial fibrosis were successively identified after uIRI in mice. Then, the efficacy of hUC-MSCs after uIRI was confirmed. Subsequently, inhibiting hUC-MSCs-derived HGF significantly compromises the efficacy of hUC-MSCs and leads to ineffectively curbing mitochondrial elongation, accompanying insufficient control of elevated PKA and inhibitory phosphorylation of drp1 (Drp1pSer637). As a result, the treatment efficacy of renal senescence and fibrosis alleviation was also weakened. Furthermore, similar results were obtained with antibodies blocking HGF or cMet in hypoxic HK-2 cells treated with hUC-MSCs-condition medium for further proving. Uncurbed mitochondrial elongation induced by PKA and Drp1pSer637 was inhibited by hUC-MSCs derived HGF but reversed in the activation or overexpression of PKA. Conclusions The research concluded that hUC-MSCs-derived HGF can inhibit PKA-Drp1pSer637-mitochondrial elongation via its receptor cMet to alleviate renal senescence and fibrosis in post-AKI.https://doi.org/10.1186/s13287-024-04041-3Renal premature senescenceMesenchymal stem cells (MSCs)Hepatocyte growth factor (HGF)Mitochondrial elongation |
| spellingShingle | Kaiting Zhuang Wenjuan Wang Xumin Zheng Xinru Guo Cheng Xu Xuejing Ren Wanjun Shen Qiuxia Han Zhe Feng Xiangmei Chen Guangyan Cai MSCs-derived HGF alleviates senescence by inhibiting unopposed mitochondrial fusion-based elongation in post-acute kidney injury Stem Cell Research & Therapy Renal premature senescence Mesenchymal stem cells (MSCs) Hepatocyte growth factor (HGF) Mitochondrial elongation |
| title | MSCs-derived HGF alleviates senescence by inhibiting unopposed mitochondrial fusion-based elongation in post-acute kidney injury |
| title_full | MSCs-derived HGF alleviates senescence by inhibiting unopposed mitochondrial fusion-based elongation in post-acute kidney injury |
| title_fullStr | MSCs-derived HGF alleviates senescence by inhibiting unopposed mitochondrial fusion-based elongation in post-acute kidney injury |
| title_full_unstemmed | MSCs-derived HGF alleviates senescence by inhibiting unopposed mitochondrial fusion-based elongation in post-acute kidney injury |
| title_short | MSCs-derived HGF alleviates senescence by inhibiting unopposed mitochondrial fusion-based elongation in post-acute kidney injury |
| title_sort | mscs derived hgf alleviates senescence by inhibiting unopposed mitochondrial fusion based elongation in post acute kidney injury |
| topic | Renal premature senescence Mesenchymal stem cells (MSCs) Hepatocyte growth factor (HGF) Mitochondrial elongation |
| url | https://doi.org/10.1186/s13287-024-04041-3 |
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