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

Stem Cell Res Ther. 2024 Nov 19;15(1):438. doi: 10.1186/s13287-024-04041-3.

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.

Keywords: Hepatocyte growth factor (HGF); Mesenchymal stem cells (MSCs); Mitochondrial elongation; Renal premature senescence.

MeSH terms

  • Acute Kidney Injury* / metabolism
  • Acute Kidney Injury* / pathology
  • Acute Kidney Injury* / therapy
  • Animals
  • Cellular Senescence*
  • Disease Models, Animal
  • Fibrosis / therapy
  • Hepatocyte Growth Factor* / genetics
  • Hepatocyte Growth Factor* / metabolism
  • Humans
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Mesenchymal Stem Cell Transplantation* / methods
  • Mesenchymal Stem Cells* / cytology
  • Mesenchymal Stem Cells* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Mitochondrial Dynamics*
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / therapy

Substances

  • Hepatocyte Growth Factor