Efficient and reproducible generation of human induced pluripotent stem cell-derived expandable liver organoids for disease modeling

Genetic liver disease modeling is difficult because it is challenging to access patient tissue samples and to develop practical and relevant model systems. Previously, we developed novel proliferative and functional liver organoids from pluripotent stem cells; however, the protocol requires improvem...

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Bibliographic Details
Published in:Scientific reports 2023-12, Vol.13 (1), p.22935-22935, Article 22935
Main Authors: Mun, Seon Ju, Hong, Yeon-Hwa, Shin, Yongbo, Lee, Jaeseo, Cho, Hyun-Soo, Kim, Dae-Soo, Chung, Kyung-Sook, Son, Myung Jin
Format: Article
Language:English
Subjects:
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692/699
Fibroblast growth factor receptor 4
Glycogen
Hepatocytes
Humanities and Social Sciences
Liver
Liver diseases
multidisciplinary
Organoids
Phenotypes
Pluripotency
Science
Science (multidisciplinary)
Standardization
Stem cells
Storage diseases
Transcriptomes
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Summary:Genetic liver disease modeling is difficult because it is challenging to access patient tissue samples and to develop practical and relevant model systems. Previously, we developed novel proliferative and functional liver organoids from pluripotent stem cells; however, the protocol requires improvement for standardization and reproducible mass production. Here, we improved the method such that it is suitable for scalable expansion and relatively homogenous production, resulting in an efficient and reproducible process. Moreover, three medium components critical for long-term expansion were defined. Detailed transcriptome analysis revealed that fibroblast growth factor signaling, the essential pathway for hepatocyte proliferation during liver regeneration, was mainly enriched in proliferative liver organoids. Short hairpin RNA-mediated knockdown of FGFR4 impaired the generation and proliferation of organoids. Finally, glycogen storage disease type Ia (GSD1a) patient-specific liver organoids were efficiently and reproducibly generated using the new protocol. They well maintained disease-specific phenotypes such as higher lipid and glycogen accumulation in the liver organoids and lactate secretion into the medium consistent with the main pathologic characteristics of patients with GSD1a. Therefore, our newly established liver organoid platform can provide scalable and practical personalized disease models and help to find new therapies for incurable liver diseases including genetic liver diseases.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-023-50250-w