MSCs-derived HGF alleviates senescence by inhibiting unopposed mitochondrial fusion-based elongation in post-acute kidney injury

• Published in: Stem cell research & therapy 2024-11, Vol.15 (1), p.438-23, Article 438
• Main Authors: Zhuang, Kaiting, Wang, Wenjuan, Zheng, Xumin, Guo, Xinru, Xu, Cheng, Ren, Xuejing, Shen, Wanjun, Han, Qiuxia, Feng, Zhe, Chen, Xiangmei, Cai, Guangyan
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Acute Kidney Injury - therapy; Analysis; Animals; Antibodies; Cellular Senescence; Disease Models, Animal; Fibrosis - therapy; Hepatocyte growth factor (HGF); Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - metabolism; Humans; Ischemia; Kidney - metabolism; Kidney - pathology; Male; Mesenchymal Stem Cell Transplantation - methods; Mesenchymal stem cells (MSCs); Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; Mitochondria - metabolism; Mitochondrial Dynamics; Mitochondrial elongation; Renal premature senescence; Reperfusion Injury - metabolism; Reperfusion Injury - therapy; Stem cells; Transplantation; Viral antibodies
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-024-04041-3

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. 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. 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. 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.