Direct Reprogramming of Human Fibroblasts to Functional and Expandable Hepatocytes
Open accessAbstract
The generation of large numbers of functional human hepatocytes for cell-based approaches to liver disease is an important and unmet goal. Direct reprogramming of fibroblasts to hepatic lineages could offer a solution to this problem but so far has only been achieved with mouse cells. Here, we generated human induced hepatocytes (hiHeps) from fibroblasts by lentiviral expression of FOXA3, HNF1A, and HNF4A. hiHeps express hepatic gene programs, can be expanded in vitro, and display functions characteristic of mature hepatocytes, including cytochrome P450 enzyme activity and biliary drug clearance. Upon transplantation into mice with concanavalin-A-induced acute liver failure and fatal metabolic liver disease due to fumarylacetoacetate dehydrolase (Fah) deficiency, hiHeps restore the liver function and prolong survival. Collectively, our results demonstrate successful lineage conversion of nonhepatic human cells into mature hepatocytes with potential for biomedical and 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 [60]
Liver transcription factor overexpression can reprogram fibroblasts into more mature hepatocytes.
“Recent progress has shown that liver transcription factor overexpression can reprogram fibroblasts into more mature hepatocytes (Huang et al., 2014; Sekiya and Suzuki, 2011; Song et al., 2016; Yu et al., 2013; Zhu et al., 2014).”
From A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells (2018) · cites this paper as Huang et al., 2014
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- Authors
- Huang, P., Zhang, L., Gao, Y., He, Z., Yao, D., Wu, Z., Cen, J., Chen, X., Liu, C., Hu, Y., Lai, D., Hu, Z., Chen, L., Zhang, Y., Cheng, X., Ma, X., Pan, G., Wang, X., & Hui, L.
- Affiliations
- Chinese Academy of Sciences (CN)
- Second Military Medical University (CN)
- Shanghai Jiao Tong University (CN)
- Dalian Institute of Chemical Physics (CN)
- University of Minnesota (US)
- Corresponding author
- Hui, Lijian
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 14
- Issue
- 3
- Pages
- 370-384
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W1986947784
- Cited by
- 560
- References
- 7
- Citations by year
- 2026: 18 · 2025: 36 · 2024: 38 · 2023: 38 · 2022: 44 · 2021: 50 · 2020: 50 · 2019: 52 · 2018: 60 · 2017: 48 · 2016: 61 · 2015: 41 · 2014: 24
- FWCI
- 23.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Dalian Institute of Chemical Physics, CAS Institutional Repository (submittedVersion)
- Funders
- National Natural Science Foundation of China (31225016, 913193023)
- Ministerio de Ciencia y Tecnología (2012CB945001)
- Chinese Academy of Sciences (XDA01030301, XDA01020308)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- direct reprogramming, human fibroblasts, hepatocyte differentiation, FOXA3, HNF1A, HNF4α, lentiviral transduction, hepatocyte expansion, cytochrome P450 activity, acute liver failure, fumarylacetoacetate hydrolase deficiency, metabolic liver disease, cell transplantation, liver disease treatment
- MeSH terms
- Adult, Animals, Antigens, Polyomavirus Transforming, Biliary Tract, Cell Differentiation, Concanavalin A, Fetus, Fibroblasts, Gene Expression Regulation, Humans, Hydrolases, Inactivation, Metabolic, Mice, Inbred C57BL, Stem Cells, Liver Failure, Cell Lineage, Hepatocytes, Cell Proliferation, Mice, Cellular Reprogramming
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