Direct conversion of human fibroblasts into hepatocyte-like cells by ATF5, PROX1, FOXA2, FOXA3, and HNF4A transduction
Open accessAbstract
Recently, it has been reported that human hepatocyte-like cells can be generated from fibroblasts by direct reprogramming technology. However, the conversion efficiency of human induced hepatocyte-like cells (hiHeps) is not high enough. In addition, comparative analysis with the existing models of hepatocytes, such as human iPS cell-derived hepatocyte-like cells and primary human hepatocytes, has not been sufficiently carried out. In this study, we screened hepatic transcription factors for efficient direct hepatic reprogramming and compared hepatic functions between hiHeps and other existing hepatocyte models. We found that human fibroblasts were efficiently converted into hiHeps by using a combination of ATF5, PROX1, FOXA2, FOXA3, and HNF4A (albumin+/alpha-1 antitrypsin+ cells = 27%, asialoglycoprotein receptor 1+ cells = 22%). The CYP expression levels and CYP activities in hiHeps were higher than those in human iPS cell-derived hepatocyte-like cells, but lower than those in short-term (4 hr) cultured primary human hepatocytes and primary human hepatocytes collected immediately after thawing. These results suggested that functional hiHeps could be efficiently generated by ATF5, PROX1, FOXA2, FOXA3, and HNF4A transduction. We believe that hiHeps generated by our method will be useful for the drug-discovery activities such as hepatotoxicity screening and drug metabolism tests.
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HNF4A is crucial for generating induced hepatocyte-like cells (iHeps), and HNF4A overexpression alone may be sufficient to generate these cells.
“These studies revealed that HNF4A is crucial for generating induced hepatocyte-like cells (iHeps) (25, 26) as HNF4A overexpression alone may be sufficient to generate these cells (27).”
From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [27]
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Thakur, A., Wong, J. C. H., Wang, E. Y., Lotto, J., Kim, D., Cheng, J., Mingay, M., Cullum, R., Moudgil, V., Ahmed, N., et al. (2019) · Hepatology · doi:10.1002/hep.30631 · Cited by 75 · see citing works
HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements
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- Authors
- Nakamori, D., Akamine, H., Takayama, K., Sakurai, F., & Mizuguchi, H.
- Affiliations
- The University of Osaka (JP)
- National Institute of Biomedical Innovation, Health and Nutrition (JP)
- Corresponding author
- Mizuguchi, Hiroyuki
- Venue
- Scientific Reports
- Published
- 2017-11-30
- Volume
- 7
- Issue
- 1
- Pages
- 16675-16675
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5709502
- OpenAlex
- W2770650361
- Cited by
- 64
- References
- 3
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 11 · 2021: 8 · 2020: 18 · 2019: 11 · 2018: 5
- FWCI
- 3.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Division of Human Resource Development
- 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
- direct reprogramming, human fibroblasts, hepatocyte-like cells, ATF5, Prox1, FOXA2, FOXA3, HNF4α, drug metabolism, hepatotoxicity screening, primary human hepatocytes, induced pluripotent stem cell-derived hepatocytes
- MeSH terms
- Cell Line, Fibroblasts, Humans, Transcription Factors, Transduction, Genetic, Biomarkers, Gene Expression Regulation, Developmental, Transgenes, Gene Expression Profiling, Hepatocytes, Hepatocyte Nuclear Factor 3-beta, Hepatocyte Nuclear Factor 3-gamma, Hepatocyte Nuclear Factor 4, Activating Transcription Factors, Cell Transdifferentiation, Transcriptome, Cellular Reprogramming
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