Molecular mechanisms, maturity criteria, and translational perspectives on the hepatic differentiation from human adipose stromal/stem cells

Chronic liver diseases represent a major global health burden, with orthotopic liver transplantation limited by severe organ shortages. Hepatocyte transplantation is constrained by the scarcity, limited expandability, and donor variability of primary human hepatocytes (PHHs). Human adipose stromal/stem cells (hASCs) are a readily accessible autologous source for generating functional hepatocyte-like cells (HLCs). However, current hASC-HLC preparations may remain functionally immature compared with their in vivo counterparts, and the donor’s status may influence the hepatic differentiation potential of hASCs. This review proposes operational criteria for defining HLC identity and maturity, compares representative differentiation strategies across studies, and summarizes advances in extracellular-matrix, three-dimensional, signalling, epigenetic, and mitochondrial regulation. We further discuss how cellular heterogeneity, donor ageing and obesity differentially affect differentiation efficiency, alongside strategies to alleviate age- and obesity-induced hASC dysfunction. By defining application-specific requirements for each context, we highlight how standardization, quantitative PHH benchmarking, and the targeted use of advanced technologies may advance the clinical translation of hASC-HLCs.