Human Amniotic Epithelial Stem Cells Activate Autophagy via the IL-6/STAT3/FOXO3a Pathway to Facilitate Liver Regeneration Following Hepatectomy

Background and Aim: Post-Hepatectomy Liver Failure (PHLF) leads to a poor prognosis in patients receiving hepatectomy treatment, and cell therapy can promote liver regeneration. In this study, we investigated the therapeutic potential of human amniotic epithelial cells (hAECs) in promoting liver regeneration after partial hepatectomy (PHx) and the underlying molecular mechanism. Methods: We established a 70% PHx liver regeneration model, after which 5x105 hAECs were injected into the tail vein of mice. The resulting liver function, weight, and immunohistochemistry data were analyzed to determine whether hAECs can promote liver regeneration. Then, we explored the possible mechanism by which hAECs promote liver regeneration after PHx through RNA sequencing. Finally, western blotting and immunofluorescence were used to confirm the discovered potential mechanism and signaling pathway involved. Results: The mice in the hAECs group displayed enhanced liver regeneration 48 hours after 70% PHx and the expression levels of cell proliferation-related proteins were significantly higher than those in the control group. RNA sequencing analysis revealed that the key signaling pathway through which hAECs promote liver regeneration is the FOXO3a pathway. Mechanistically, IL-6 activates FOXO3a through STAT3, thereby promoting liver autophagy to enhance liver regeneration after PHx. Finally, western blotting and immunofluorescence confirmed that the IL-6/STAT3/FOXO3a pathway promotes liver regeneration by activating autophagy. Conclusion: These results suggest that hAECs treatment promoted liver regeneration after PHx through the IL-6/ STAT3/FOXO3a/autophagy pathway.