Advances and challenges in developing expandable human hepatocytes for regenerative medicine.

Liver transplantation remains the only effective treatment for severe liver disease, but donor shortages pose a serious challenge, underscoring the need for alternative therapeutic strategies. Hepatocyte transplantation has been proposed as a promising alternative; however, the lack of expandable cell sources remains a major obstacle. Considerable efforts have been made to establish culture systems that can preserve both the proliferative capacity and functional properties of hepatocytes. Recent advances in expandable hepatocytes and organoid technologies have shown partial success in repopulating injured mouse livers. However, achieving both sufficient cell numbers and robust repopulation efficiency has remained difficult, preventing clinical translation. Furthermore, when cells are transplanted, the engraftment success and replacement efficiency significantly influence the extent of repopulation. In this review, we first revisit the history of hepatocyte transplantation, then summarize recent progress in hepatocyte expansion technologies, and finally discuss the remaining challenges toward clinical application.