Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave, Boston, MA 02115, USA.
Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
J Cell Sci. 2024 May 15;137(10). doi: 10.1242/jcs.261961. Epub 2024 May 28.
Hepatocyte organoids (HOs) generated in vitro are powerful tools for liver regeneration. However, previously reported HOs have mostly been fetal in nature with low expression levels of metabolic genes characteristic of adult liver functions, hampering their application in studies of metabolic regulation and therapeutic testing for liver disorders. Here, we report development of novel culture conditions that combine optimized levels of triiodothyronine (T3) with the removal of growth factors to enable successful generation of mature hepatocyte organoids (MHOs) of both mouse and human origin with metabolic functions characteristic of adult livers. We show that the MHOs can be used to study various metabolic functions including bile and urea production, zonal metabolic gene expression, and metabolic alterations in both alcoholic liver disease and non-alcoholic fatty liver disease, as well as hepatocyte proliferation, injury and cell fate changes. Notably, MHOs derived from human fetal hepatocytes also show improved hepatitis B virus infection. Therefore, these MHOs provide a powerful in vitro model for studies of human liver physiology and diseases. The human MHOs are potentially also a robust research tool for therapeutic development.
肝细胞类器官（HOs）在体外生成，是肝脏再生的有力工具。然而，以前报道的 HOs 主要是胎儿来源的，其代谢基因的表达水平较低，与成人肝脏功能的特征不符，这限制了它们在代谢调控研究和肝脏疾病治疗测试中的应用。在这里，我们报告了一种新的培养条件的发展，该条件将三碘甲状腺原氨酸（T3）的优化水平与生长因子的去除相结合，从而成功地生成了具有成人肝脏代谢功能特征的来自小鼠和人类来源的成熟肝细胞类器官（MHOs）。我们表明，MHOs 可用于研究各种代谢功能，包括胆汁和尿素的产生、区域代谢基因表达以及酒精性肝病和非酒精性脂肪性肝病中的代谢改变，以及肝细胞增殖、损伤和细胞命运变化。值得注意的是，源自人胎肝细胞的 MHOs 也显示出对乙型肝炎病毒感染的改善。因此，这些 MHOs 为研究人类肝脏生理学和疾病提供了强大的体外模型。人类 MHOs 也可能是治疗开发的强大研究工具。
