Human Hepatocytes with Drug Metabolic Function Induced from Fibroblasts by Lineage Reprogramming
Open accessAbstract
Obtaining fully functional cell types is a major challenge for drug discovery and regenerative medicine. Currently, a fundamental solution to this key problem is still lacking. Here, we show that functional human induced hepatocytes (hiHeps) can be generated from fibroblasts by overexpressing the hepatic fate conversion factors HNF1A, HNF4A, and HNF6 along with the maturation factors ATF5, PROX1, and CEBPA. hiHeps express a spectrum of phase I and II drug-metabolizing enzymes and phase III drug transporters. Importantly, the metabolic activities of CYP3A4, CYP1A2, CYP2B6, CYP2C9, and CYP2C19 are comparable between hiHeps and freshly isolated primary human hepatocytes. Transplanted hiHeps repopulate up to 30% of the livers of Tet-uPA/Rag2(-/-)/γc(-/-) mice and secrete more than 300 μg/ml human ALBUMIN in vivo. Our data demonstrate that human hepatocytes with drug metabolic function can be generated by lineage reprogramming, thus providing a cell resource for pharmaceutical applications.
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PROX1 is essential for hepatocyte commitment.
“PROX1, essential for hepatocyte commitment59–61, meets our safeguard repressor criteria.”
From Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis (2025) · cites this paper as [59]
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References 22 · Cited by 320
- Authors
- Du, Y., Wang, J., Jia, J., Song, N., Xiang, C., Xu, J., Hou, Z., Su, X., Liu, B., Jiang, T., Zhao, D., Sun, Y., Shu, J., Guo, Q., Yin, M., Sun, D., Lu, S., Shi, Y., & Deng, H.
- Affiliations
- Peking University (CN)
- Chinese PLA General Hospital (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Lu, Shichun
- Shi, Yan
- Deng, Hongkui
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 14
- Issue
- 3
- Pages
- 394-403
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W1968832732
- Cited by
- 320
- References
- 22
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 12 · 2023: 18 · 2022: 23 · 2021: 19 · 2020: 29 · 2019: 26 · 2018: 34 · 2017: 29 · 2016: 53 · 2015: 37 · 2014: 20
- FWCI
- 18.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Key Research and Development Program of China (2012CB966401)
- National Key New Drug Creation and Manufacturing Program, Ministry of Science and Technology (2011ZX09102-010-03)
- Bill and Melinda Gates Foundation (1023963, 37871)
- Ministry of Science and Technology (2011AA020107, 2013DFG30680)
- Ministry of Education of the People's Republic of China
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- hepatocyte differentiation, fibroblast reprogramming, lineage reprogramming, drug metabolism, drug-metabolizing enzymes, drug transporters, CYP3A4, CYP2C19, CYP2C9, CYP2B6, CYP1A2, HNF1A, HNF4α, HNF6, Prox1, CEBPA, ATF5, xenotransplantation, liver regeneration, regenerative medicine
- MeSH terms
- Animals, Cell Differentiation, Cell Separation, Cells, Cultured, DNA-Binding Proteins, Fibroblasts, Gene Expression Regulation, Humans, Inactivation, Metabolic, Mice, Inbred BALB C, Tetracycline, Transcription Factors, Urokinase-Type Plasminogen Activator, Cell Lineage, Hepatocytes, Mice, Cellular Reprogramming
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