The efficacy of exosomes from human chemically derived hepatic progenitors in liver damage alleviation: a preclinical experimental study

Abstract

Purpose: Over the past decade, interest in exosomes as therapeutics has surged. In particular, stem-cell-derived exosomes may be more effective as a treatment for liver disease than the stem cells themselves. We have previously developed human chemically derived hepatic progenitors (hCdHs) from human hepatocytes. hCdHs can differentiate into hepatocytes and cholangiocytes, regenerating the liver in mouse models. In this study, we evaluated the mitigating effects of hCdHs-derived exosomes (hCdHs-exo) on liver damage and compared them with those of exosomes from bone marrow mesenchymal stem cells (BMMSCs-exo). Methods: Exosomes were isolated from hCdHs and BMMSCs by culturing cells in large quantities and separating the exosomes from the culture medium using ultracentrifugation. Isolated exosomes were characterized by various methods before experimental use. In vitro, the ability of exosomes to inhibit activation of hepatic stellate cells (HSCs) by transforming growth factor beta 1 was evaluated. In vivo, exosomes were injected into mice with carbon tetrachloride (CCl4)-induced liver damage, and their effectiveness in mitigating liver damage was assessed by histological staining and biochemical analysis. Results: The analyses confirmed the successful isolation of exosomes from both cell types. In vitro, hCdHs-exo significantly reduced the levels of transcription factors and activation markers in induced HSCs. In vivo, hCdHs-exo effectively alleviated liver damage caused by CCl4. Furthermore, both in vitro and in vivo studies confirmed that hCdHs-exo had a greater effect in alleviating liver damage than did BMMSCs-exo. Conclusion: These results demonstrate that hCdHs-exo, similarly to hCdHs, have superior efficacy in alleviating liver damage compared with BMMSCs-exo.