Generation of expandable human pluripotent stem cell-derived hepatocyte-like liver organoids

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Title
Generation of expandable human pluripotent stem cell-derived hepatocyte-like liver organoids
Author(s)
Seon Ju Mun; Jae Sung Ryu; Mi Ok Lee; Ye Seul Son; S J Oh; Hyun Soo ChoMi Young SonDae Soo Kim; S J Kim; H J Yoo; Ho-Joon Lee; Janghwan KimCho Rok JungKyung-Sook ChungMyung Jin Son
Bibliographic Citation
Journal of Hepatology, vol. 71, no. 5, pp. 970-985
Publication Year
2019
Abstract
BACKGROUND & AIMS: The development of hepatic models capable of long-term expansion with competent liver functionality is technically challenging in a personalized setting. Stem cell-based organoid technologies can provide an alternative source of patient-derived primary hepatocytes. However, self-renewing and functionally competent human pluripotent stem cell (PSC)-derived hepatic organoids have not been developed. METHODS: We developed a novel method to efficiently and reproducibly generate functionally mature human hepatic organoids derived from PSCs, including human embryonic stem cells and induced PSCs. The maturity of the organoids was validated by a detailed transcriptome analysis and functional performance assays. The organoids were applied to screening platforms for the prediction of toxicity and the evaluation of drugs that target hepatic steatosis through real-time monitoring of cellular bioenergetics and high-content analyses. RESULTS: Our organoids were morphologically indistinguishable from adult liver tissue-derived epithelial organoids and exhibited self-renewal. With further maturation, their molecular features approximated those of liver tissue, although these features were lacking in 2D differentiated hepatocytes. Our organoids preserved mature liver properties, including serum protein production, drug metabolism and detoxifying functions, active mitochondrial bioenergetics, and regenerative and inflammatory responses. The organoids exhibited significant toxic responses to clinically relevant concentrations of drugs that had been withdrawn from the market due to hepatotoxicity and recapitulated human disease phenotypes such as hepatic steatosis. CONCLUSIONS: Our organoids exhibit self-renewal (expandable and further able to differentiate) while maintaining their mature hepatic characteristics over long-term culture. These organoids may provide a versatile and valuable platform for physiologically and pathologically relevant hepatic models in the context of personalized medicine. LAY SUMMARY: A functionally mature, human cell-based liver model exhibiting human responses in toxicity prediction and drug evaluation is urgently needed for pre-clinical drug development. Here, we develop a novel human pluripotent stem cell-derived hepatocyte-like liver organoid that is critically advanced in terms of its generation method, functional performance, and application technologies. Our organoids can contribute to the better understanding of liver development and regeneration, and provide insights for metabolic studies and disease modeling, as well as toxicity assessments and drug screening for personalized medicine.
Keyword
Disease modelingDrug toxicityHepatocytesLiverOrganoidsPluripotent stem cells
ISSN
0168-8278
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.jhep.2019.06.030
Type
Article
Appears in Collections:
Division of Research on National Challenges > Stem Cell Convergenece Research Center > 1. Journal Articles
Division of Research on National Challenges > Environmental diseases research center > 1. Journal Articles
Division of Research on National Challenges > 1. Journal Articles
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