Medical School of Chinese PLA, Beijing, 100853, China.
Department 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 Diseases, Beijing, 100853, China.
Stem Cell Res Ther. 2024 Nov 19;15(1):438. 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.
人脐带来源间充质干细胞（hUC-MSCs）治疗急性肾损伤后（post-AKI）肾脏衰老的潜在机制尚不清楚。细胞衰老需要未被拮抗的基于线粒体融合的线粒体延长。本研究试图通过 hUC-MSCs 治疗来剖析 hUC-MSCs 治疗在调节 post-AKI 中线粒体延长相关衰老中的作用。
首先，在 C57 小鼠中建立单侧肾缺血再灌注（uIRI）模型。随后，通过囊下注射给予慢病毒转染的 hUC-MSCs。移植后 2 周，通过组织化学染色和透射电子显微镜评估 hUC-MSCs 治疗肾衰老、纤维化和线粒体功能的效果。为了进一步研究 hUC-MSCs 分泌的线粒体调节作用，构建了缺氧 HK-2 细胞。最后，在 hUC-MSCs 上清液中使用 HGF 及其受体的抗体。
在小鼠 uIRI 后，相继鉴定出未被拮抗的线粒体融合、肾衰老和肾间质纤维化。然后，确认了 uIRI 后 hUC-MSCs 的疗效。随后，抑制 hUC-MSCs 衍生的 HGF 显著降低了 hUC-MSCs 的疗效，并导致线粒体延长无法有效抑制，同时未能充分控制升高的 PKA 和 drp1（Drp1pSer637）的抑制性磷酸化。因此，肾衰老和纤维化缓解的治疗效果也减弱了。此外，用阻断 HGF 或 cMet 的抗体处理用 hUC-MSCs 条件培养基处理的缺氧 HK-2 细胞，进一步证明了这一点。PKA 和 Drp1pSer637 诱导的未被抑制的线粒体延长被 hUC-MSCs 衍生的 HGF 抑制，但在 PKA 的激活或过表达时被逆转。
该研究得出结论，hUC-MSCs 衍生的 HGF 可以通过其受体 cMet 抑制 PKA-Drp1pSer637-线粒体延长，从而缓解 post-AKI 中的肾衰老和纤维化。
