Cited by 124Liver physiology and pathologyDrug-Induced Hepatotoxicity and ProtectionTissue Engineering and Regenerative Medicine

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Resetting the transcription factor network reverses terminal chronic hepatic failure

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Nishikawa, Taichiro, Bell, Aaron, Brooks, Jenna M., Setoyama, Kentaro, Melis, Marta, Han, Bing, Fukumitsu, Ken, Handa, Kan, Tian, Jianmin, Kaestner, Klaus H., Vodovotz, Yoram, Locker, Joseph, Soto-Gutierrez, Alejandro, Fox, Ira J.·2015·Journal of Clinical Investigation

DOI 10.1172/jci73137PMC PMC4396487

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Abstract

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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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)
ORCID: Bell, Aaron
Brooks, Jenna M.
Han, Bing
Fukumitsu, Ken
Kaestner, Klaus H.
Locker, Joseph
Fox, Ira J.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2015-03-16
Volume: 125
Issue: 4
Pages: 1533-1544
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci73137
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
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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Resetting the transcription factor network reverses terminal chronic hepatic failure

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