Hepatocyte-like cell therapy for end-stage liver disease: From basic science to clinical application

End-stage liver disease (ESLD) covers the end-stage of acute and chronic liver diseases, mainly involving decompensated cirrhosis, various types of liver failure, and advanced liver cancer. Hepatocyte transplantation has shown promise in treating ESLD, but its clinical application is hampered by the shortage of donor hepatocytes. Cell therapy, an emerging effective treatment for ESLD, faces the same limitation due to scarce hepatocyte availability. Hepatocyte-like cells (HLCs), which are terminally differentiated cells, can be induced from both stem cells and somatic cells. As HLCs exhibit the morphology and function of primary hepatocytes, they offer a promising supplementary source of hepatocytes for cell therapy. First, we provide a background for the differentiation and maturation of primary hepatocytes. Subsequently, based on the current insights into the molecular pathways that regulate hepatocyte differentiation in vivo , we describe a strategy for establishing HLC derived from either stem cells or somatic cells. The key characteristics of these HLCs are also detailed. Furthermore, HLC offers therapeutic potential for liver failure, and HLC-based liver organoids and bioartificial liver systems have demonstrated the ability to provide liver functions, offering an innovative approach to treating various types of ESLD. Despite their promise, challenges such as efficiency in differentiation and functional maturation need to be addressed to improve the clinical application of HLCs. This review discusses these advancements and outlines the therapeutic potential and current challenges of HLC therapy for ESLD. • End-stage liver disease (ESLD) involves decompensated cirrhosis, liver failure, and advanced liver cancer; hepatocyte transplantation therapy is limited by the scarcity of donor hepatocytes. • Hepatocyte-like cells (HLCs), derived from stem cells or somatic cells, exhibit primary hepatocyte function and morphology, making them a promising alternative for ESLD treatment. • Key molecular pathways involved in hepatocyte differentiation are leveraged to generate HLC. • HLC transplantation, HLC-based liver organoids, and bioartificial liver systems offer therapeutic potential for various ESLD types.