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J Hepatol. 2019 Jan 7. pii: S0168-8278(19)30002-9. doi: 10.1016/j.jhep.2018.12.028. [Epub ahead of print]

Generation of hepato-biliary organoids from human induced pluripotent stem cells.

Author information

1
State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, College of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China.
2
State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, College of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China; School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China. Electronic address: lssxal@mail.sysu.edu.cn.

Abstract

BACKGROUND & AIMS:

Human induced pluripotent stem cells (iPSC)-derived liver modeling systems have the potential to overcome the shortage of donors for clinical application and become a model for drug development. Although several strategies available to generate hepatic micro-tissues, few have succeeded in generating a liver organoid with hepato-biliary structure from hiPSCs.

METHODS:

At differentiation stages I and II (day 1-15), 25% of mTeSR culture medium was added to hepatic differentiation medium to induce endodermal and mesodermal commitment and thereafter hepatic and biliary co-differentiation. At Stage III (day 15-45), 10% cholesterol+ MIX were added into the maturation medium to promote the formation and maturation of the hepato-biliary organoids (HBO). Phenotypes and functions of organoids were determined by specific markers and multiple functional assays both in vitro and in vivo.

RESULTS:

In this system, hiPSC was induced to 3D hepato-biliary organoids and to some extent recapitulated key aspects of early hepatogenesis in a parallel fashion. The organoids displayed a series of functional attributes. Specifically, the induced hepatocyte-like cells could uptake ICG, accumulate lipid and glycogen, and displayed appropriate secretion ability (ALB and urea) and drug metabolic ability (CYP3A4 activity and inducibility); the biliary structures in the system showed GGT activity and the ability to efflux rhodamine and store bile acid. Furthermore, after transplantation into the immune-deficient mice, the organoids survived for more than 8 weeks.

CONCLUSION:

This is the first time that functional hepato-biliary organoids have been generated from hiPSCs. The organoid model will be useful for in vitro studies of the molecular mechanisms of liver development and has important potential in the therapy of liver diseases.

LAY SUMMARY:

Herein, we established a system to in vitro generate hiPSC-derived functional hepato-biliary organoids without any exogenous cells or DNA transfections. This model to some extent recapitulated several key aspects of hepato-biliary organogenesis in a parallel fashion, holding great promise for drug developmental research and liver transplantation.

KEYWORDS:

Differentiation; Hepato-biliary organoids; HiPSC; Organogenesis

PMID:
30630011
DOI:
10.1016/j.jhep.2018.12.028
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