Aim: Non-alcoholic steatohepatitis (NASH) is liver disease caused by a chronic inflammatory response following prolonged fat accumulation. We aimed to examine the effects of immortalized human amniotic epithelial cell derived extracellular vesicles (ihAEC-EVs) on fibrosis, inflammation and the liver progenitor cell response in a pre-clinical model of NASH.
Methods: NASH was induced in 6-week-old male mice using a high-fat, high-fructose and high-cholesterol diet and weekly administration of intraperitoneal carbon tetrachloride for 12 weeks (injury, n=8). Mice were randomized to receive 10μg of ihAEC EVs via oral gavage either twice (ihAEC-2, n=8) or thrice weekly (ihAEC-3, n=8) from week 6 until week 12. Obeticholic acid (10mg/kg) via oral gavage thrice weekly acted as a comparison (OCA, n=8). Control mice were fed normal diets and received saline (control, n=8). At week 12 mice were euthanized. Serum was collected for measurement of metabolic parameters (ALT, AST, insulin and cholesterol) and livers collected for histological and molecular analysis.
Results: Injury mice demonstrated a NASH-like phenotype: hepatic fibrosis, inflammation, and steatosis. Importantly, ihAEC-3 treatment reduced the fibrotic area (p<0.05) and smooth muscle actin a-SMA (p<0.0001). Additionally, ihAEC-3 treatment reduced macrophage marker F4/80 (p<0.001) and indices of steatosis compared to the injury mice.
Conclusion: Treatment with ihAEC-EVs may be superior to OCA and when given orally thrice weekly, reduced hepatic fibrosis and steatosis. Our findings suggest repeated administration prevents the progression of NASH, supporting clinical translation. Future studies will aim to investigate the optimal route and dosage for ihAEC-EV administration for NASH.