The incidence of liver disease is increasing globally. The only curative therapy for severe end-stage liver disease, liver transplantation, is limited by the shortage of organ donors. In vitro models of liver physiology have been developed and new technologies and approaches are progressing rapidly. Stem cells might be used as a source of liver tissue for development of models, therapies, and tissue-engineering applications. However, we have been unable to generate and maintain stable and mature adult liver cells ex vivo. We review factors that promote hepatocyte differentiation and maturation, including growth factors, transcription factors, microRNAs, small molecules, and the microenvironment. We discuss how the hepatic circulation, microbiome, and nutrition affect liver function, and the criteria for considering cells derived from stem cells to be fully mature hepatocytes. We explain the challenges to cell transplantation and consider future technologies for use in hepatic stem cell maturation, including 3-dimensional biofabrication and genome modification.

全球范围内肝病的发病率正在增加。严重终末期肝病的唯一治疗方法——肝移植，由于器官捐献者短缺而受到限制。肝脏生理学的体外模型已经开发出来，新技术和方法正在迅速发展。干细胞可用作肝组织的来源，用于开发模型、疗法和组织工程应用。然而，我们无法在体外产生并维持稳定且成熟的成年肝细胞。我们回顾了促进肝细胞分化和成熟的因素，包括生长因子、转录因子、microRNA、小分子和微环境。我们讨论肝循环、微生物组和营养如何影响肝功能，以及将干细胞衍生的细胞视为完全成熟肝细胞的标准。我们解释了细胞移植面临的挑战，并考虑了用于肝干细胞成熟的未来技术，包括 3 维生物制造和基因组修饰。