한빛사 논문
Seon Ju Mun1,2, Jae-Sung Ryu1, Mi-Ok Lee1, Ye Seul Son1,2, Soo Jin Oh3, Hyun-Soo Cho1,2, Mi-Young Son1,2, Dae-Soo Kim2,4, Su Jung Kim3, Hyun Ju Yoo3, Ho-Joon Lee1, Janghwan Kim1,2, Cho-Rok Jung1,2, Kyung-Sook Chung1,2,5,*, Myung Jin Son1,2,*
1 Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
2 Department of Functional Genomics, Korea University of Science & Technology (UST), 217 Gajungro, Yuseong-gu, Daejeon 34113, Republic of Korea
3 Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
4 Environmental Diseases Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
5 Biomedical Translational Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
*Corresponding author : Kyung-Sook Chung, Myung Jin Son
Abstract
Background & Aims
The development of hepatic models capable of long-term expansion with competent liver functionality in a personalized setting is technically challenging. 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 are still lacking.
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 predicting toxicity and evaluating 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 two-dimensionally differentiated hepatocytes. Our organoids preserved mature liver properties, including serum proteins 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, and they 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 provide 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 better understanding liver development and regeneration and provide insights for metabolic studies and disease modeling as well as toxicity assessments and drug screening for personalized medicine.
Keywords : Liver; Organoids; PSCs; Drug toxicity; Disease modeling
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