Engineered Extracellular Vesicles from LncEEF1G Overexpressing Mesenchymal Stem Cells Promote Fibrotic Liver Regeneration by Upregulating HGF Release of Hepatic Stellate Cells

Abstract Fibrosis is a critical cause for negatively affecting liver regeneration resulting in severe complications after liver surgery. However, there is still no effective treatment for promoting fibrotic liver regeneration adapting to clinical translation due to the ambiguous mechanism. Through miRNA microarray combined with the application of AAV6, we found the high expression of miR-181a-5p in the activated hepatic stellate cells (HSCs) to suppress the expression of hepatic growth factor (HGF) partially contributed to impaired the potential of regeneration in mice with hepatic fibrosis receiving a two-thirds partial hepatectomy (PHx). As a nanotherapeutic, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have been verified as an effective treatment for liver regeneration. We revealed that MSC-EVs could also promote fibrotic liver regeneration via enriched lncEEF1G that acted as a competing endogenous RNA (ceRNA) to directly sponge miR-181a-5p leading to the upregulated expression of HGF of HSCs. Finally, the engineered MSC-EVs with high expression of lncEEF1G (lncEEF1GOE-EVs) were constructed exhibiting more potential for this model. In summary, our findings present that lncEEF1GOE-EVs exert nanotherapeutic capacity in promoting regeneration of fibrotic liver by modulating miR-181a-5p/HGF pathway of HSCs, which also highlights the available of EV-engineering technology for the population of hepatic fibrosis receiving hepatic surgery.