Resetting the transcription factor network reverses terminal chronic hepatic failure
Open accessAbstract
The cause of organ failure is enigmatic for many degenerative diseases, including end-stage liver disease. Here, using a CCl4-induced rat model of irreversible and fatal hepatic failure, which also exhibits terminal changes in the extracellular matrix, we demonstrated that chronic injury stably reprograms the critical balance of transcription factors and that diseased and dedifferentiated cells can be returned to normal function by re-expression of critical transcription factors, a process similar to the type of reprogramming that induces somatic cells to become pluripotent or to change their cell lineage. Forced re-expression of the transcription factor HNF4α induced expression of the other hepatocyte-expressed transcription factors; restored functionality in terminally diseased hepatocytes isolated from CCl4-treated rats; and rapidly reversed fatal liver failure in CCl4-treated animals by restoring diseased hepatocytes rather than replacing them with new hepatocytes or stem cells. Together, the results of our study indicate that disruption of the transcription factor network and cellular dedifferentiation likely mediate terminal liver failure and suggest reinstatement of this network has therapeutic potential for correcting organ failure without cell replacement.
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MPH dedifferentiation can only be partially inhibited by combined inhibition of multiple dedifferentiating signaling pathways or by forced expression of supra-physiologic amounts of HNF4A.
“previous reports indicated that MPH dedifferentiation could only be partially inhibited when using combined inhibition of multiple dedifferentiating signaling pathways (Sun et al, 2019; Xiang et al, 2019) or through forced expression of supra‐physiologic amounts of the Hep‐ID TF HNF4A (Nishikawa et al, 2015; Tafaleng et al, 2021; Yang et al, 2021).”
From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Nishikawa et al, 2015
For the HNF4A portion attributed to Nishikawa et al., the Results say forced HNF4α re-expression reversed hepatocyte dedifferentiation in vitro, and the Discussion says hepatocytes could be completely corrected. The Discussion also says forced re-expression generated only 0.01% of the endogenous HNF4α level, contrary to the claim that supra-physiologic amounts were required. (LLM, conf=0.92)
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- Authors
- Nishikawa, T., Bell, A., Brooks, J. M., Setoyama, K., Melis, M., Han, B., Fukumitsu, K., Handa, K., Tian, J., Kaestner, K. H., Vodovotz, Y., Locker, J., Soto-Gutierrez, A., & Fox, I. J.
- Affiliations
- University of Pittsburgh (US)
- University of Pennsylvania (US)
- Venue
- Journal of Clinical Investigation
- Published
- 2015-03-16
- Volume
- 125
- Issue
- 4
- Pages
- 1533-1544
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4396487
- OpenAlex
- W2051063852
- Cited by
- 124
- References
- 49
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 15 · 2023: 13 · 2022: 12 · 2021: 17 · 2020: 11 · 2019: 8 · 2018: 9 · 2017: 5 · 2016: 11 · 2015: 5 · 2014: 1
- FWCI
- 5.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (W81XWH-11-1-, W81XWH, W81XWH1110803)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099320, R01DK48794, DK099257, R01DK099257, P01DK049210, R01DK048794)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- end-stage liver disease, transcriptional regulatory networks, HNF4α, hepatocyte dedifferentiation, cellular reprogramming, carbon tetrachloride-induced liver injury, extracellular matrix
- MeSH terms
- Dependovirus, Animals, Carbon Tetrachloride Poisoning, Cells, Cultured, Gene Expression Regulation, Genetic Vectors, Liver Cirrhosis, Experimental, Male, Rats, Inbred Lew, Recombinant Fusion Proteins, Transcription Factors, Transduction, Genetic, Genetic Therapy, Down-Regulation, Liver Failure, Disease Progression, Gene Expression Profiling, CCAAT-Enhancer-Binding Protein-alpha, Hepatocytes, PPAR alpha, Rats, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 3-beta, Hepatocyte Nuclear Factor 4, Gene Regulatory Networks, Cell Dedifferentiation, Transcriptome
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