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

作者：Kaiting Zhuang, Wenjuan Wang, Xumin Zheng, Xinru Guo, Cheng Xu, Xuejing Ren, Wanjun Shen, Qiuxia Han, Zhe Feng, X. Chen, Guangyan Cai · 发表于：Stem Cell Research & Therapy · 年份：2024 · DOI：10.1186/s13287-024-04041-3 · 被引用次数：7 · 研究领域：Renal and related cancers、Chronic Kidney Disease and Diabetes、Telomeres, Telomerase, and Senescence

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 treat...