Exosomes from adipose‐derived mesenchymal stem cells alleviate liver ischaemia reperfusion injury subsequent to hepatectomy in rats by regulating mitochondrial dynamics and biogenesis

Abstract

Hepatic ischaemia reperfusion injury (HIRI) is a major factor leading to liver dysfunction after liver resection and liver transplantation. Adipose‐derived mesenchymal stem cells (ADSCs) have potential therapeutic effects on HIRI. Exosomes derived from ADSCs (ADSCs‐exo) have been widely studied as an alternative of ADSCs therapy. Thus, the aim of this study was to evaluate the potential protective effect and related mechanism of ADSCs‐exo on HIRI subsequent to hepatectomy. Rats were randomly divided into four groups: Sham, I30R+PH, ADSCs and ADSCs‐exo group. After 24 h of reperfusion, liver and serum of the rats were immediately collected. ADSCs‐exo improved liver function, inhibited oxidative stress and reduced apoptosis of hepatocytes in HIRI subsequent to hepatectomy in rats. ADSCs‐exo significantly promoted the recovery of mitochondrial function, markedly increased the content of ATP in the liver tissue, and improved the ultrastructure of mitochondria in hepatocytes. Moreover, ADSCs‐exo significantly increased the expression of OPA‐1, MFN‐1 and MFN‐2 proteins related to mitochondrial fusion, while DRP‐1 and Fis‐1 mRNA and protein expression associated with mitochondrial fission were significantly decreased after the treatment with ADSCs‐exo. In addition, ADSCs‐exo significantly increased the expression of PGC‐1α, NRF‐1 and TFAM genes and proteins related to mitochondrial biogenesis. ADSCs‐exo improves liver function induced by HIRI subsequent to hepatectomy in rats and maintains mitochondrial homeostasis by inhibiting mitochondrial fission, promoting mitochondrial fusion and promoting mitochondrial biogenesis. Therefore, ADSCs‐exo may be considered as a potential promising alternative to ADSCs in the treatment of HIRI subsequent to hepatectomy.

Effects of Exosomes Derived from Adipose-Derived Mesenchymal Stem Cells on Pyroptosis and Regeneration of Injured Liver

“…However, ADSC-Exo administration inhibited pyroptosis. This is consistent with the results of previous studies that demonstrated the effect of ADSCs-Exo on liver injury [ 8 ]. It is well-known that pyroptosis is a kind of cell perforation and death that is caused by the accumulation and release of a large number of inflammatory factors by inflammatory cells.…”

“…The ADSCs from passages 3 to 5 were cultured in a serum-free medium for 24 h, and the exosomes were obtained via differential centrifugation. As previously described, living cells, dead cells, cell debris, and large vesicles were removed from the supernatant through centrifugation at 300× g for 15 min, 2000× g for 25 min, and 10,000× g for 50 min, respectively [ 8 ]. The supernatant before centrifugation at 10,000× g was filtered through a 0.22 μm sterile filter.…”

“…At the same time, 0.6 mL of PBS was injected into rats in the Sham or Model groups, respectively. In the Sham group, the liver lobe was slightly turned over after laparotomy, while the rats in the Model, ADSC-transplanted, and ADSC-Exo-transplanted groups underwent hepatic ischemia–reperfusion and partial hepatectomy as previously described [ 8 ].…”

“…The exosomes derived from ADSCs (ADSCs-Exo) have been shown to be effective in treating rat liver injury. They can restore liver function and structure by reducing mitochondrial damage and cell apoptosis [ 8 ]. However, the effect of ADSCs-Exo on cell pyroptosis and regeneration in rat liver ischemia–reperfusion combined with partial resection injury has not yet been reported.…”

The emerging role of exosomes in innate immunity, diagnosis and therapy

“…In contrast, they decreased DRP-1 and Fis-1 mRNA and protein expression related to mitochondrial fission. Additionally, exosomes significantly increase the expression of PGC-1α, NRF-1, and TFAM genes and proteins related to mitochondrial biogenesis ( 225 ). Another study in hindlimb ischemic animal models reported that MSC-derived extracellular vesicles activated VEGF receptors in endothelial cells, increased neovascularization at the site of ischemia, and accelerated recovery ( 226 ).…”