Ameliorative effects of HGF-overexpressed exosomes derived from ADMSCs on oxidative stress in hepatic fibrosis.

[BACKGROUND] Hepatic fibrosis, ultimately causing hepatic sclerosis, remains significant health concerns. Adipose-derived mesenchymal stem cell (ADMSC)-derived exosomes (Exo) exhibit amelioration of liver injury. Hepatocyte growth factor (HGF) regulates hepatocyte growthn. However, its involvement during hepatic fibrosis remains unclear.

[METHODS] Isolation of ADMSCs and Exo, transfection of HGF overexpression, and activation of hepatic stellate cells (HSCs) by Angiotensin II (AngII) were conducted. Cells were randomized into HSC, AngII-HSC, ADMSCs-Exo, ADMSCs-Exo, and ADMSCs-Exo, DPI, LY294002, and SB203580 groups. MTT for cell viability, cell migration, and flow cytometry for ROS were performed. BALB/c mice were treated with CCL4 for hepatic fibrosis models. The mice were randomized into Control, PBS, ADMSCs-Exo, ADMSCs-Exo, and ADMSCs-Exo groups (n=6). HE, Sirius red, and Oil Red O staining, liver function indicators, and ELISA for oxidative stress were performed. ROS generation-related and PI3K/Akt/P38MAPK-related factors were detected by immunofluorescence, immunohistochemistry, and western blot.

[RESULTS] After identification of ADMSC-Exo and transfection, AngII increased cell viability, migration, Collagen I (CoLI), α-smooth muscle actin (α-SMA), ROS, NADPH oxidase 4 (NOX4), PI3K, p-Akt, p-P38MAPK, ras-related C3 botulinum toxin substrate 1 (RAC1), p47, and p22 expression. However, ADMSCs-Exo, DPI, LY294002, and SB203580 reversed the above effects. Moreover, ADMSCs-Exo inhibited pathological damage, fibrosis, lipid accumulation, ALT, AST, TBIL, CoLI, α-SMA, NOX4, MDA, PI3K, P-Akt, and P-P38MAPK expression, and increased ALB, SOD, GPx, CAT, GSH, Mn-SOD, Na-K-ATPase, and Ca-Mg-ATPase levels in hepatic fibrosis mice.

[CONCLUSION] ADMSCs-Exo attenuated hepatic fibrosis by inhibiting oxidative stress through activating the PI3K/Akt/P38MAPK pathway, providing valuable insights for potential treatment of liver fibrosis.