Anti-liver fibrotic effects of small extracellular vesicle microRNAs from human umbilical cord-derived mesenchymal stem cells and their differentiated hepatocyte-like cells.

Objective: The aim of this study is to identify therapeutic cargos within mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) for the treatment of liver fibrosis, a condition that poses significant health risks.

Results: sEVs from human umbilical cord-derived MSCs (UCMSCs) and their differentiated hepatocyte-like cells (hpUCMSCs) were found to alleviate liver fibrosis in mouse models, reduce fibrogenic gene expression in the liver, and inhibit hepatic stellate cell (HSC) activation, a central driver of liver fibrosis, in vitro. Deep sequencing identified differentially abundant microRNAs (miRNAs) (high-abundance: 57, low-abundance: 22) in both UCMSC- and hpUCMSC-derived sEVs, compared to HeLa cell-derived sEVs, which lack anti-liver fibrotic activity. Functional enrichment analysis of the high-abundance sEV miRNA targets revealed their involvement in transcriptional regulation, apoptosis, and cancer-related pathways, all of which are linked to liver fibrosis and hepatocellular carcinoma. Notably, many of the top 10 most abundant miRNAs reduced pro-fibrotic marker levels in activated HSCs in vitro.

Conclusion: The therapeutic potential of the high-abundance miRNAs shared by UCMSC- and hpUCMSC-derived sEVs in treating liver fibrosis is highlighted.