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Resetting the transcription factor network reverses terminal chronic hepatic failure
Taichiro Nishikawa, … , Alejandro Soto-Gutierrez, Ira J. Fox
Taichiro Nishikawa, … , Alejandro Soto-Gutierrez, Ira J. Fox
Published March 16, 2015
Citation Information: J Clin Invest. 2015;125(4):1533-1544. https://doi.org/10.1172/JCI73137.
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Research Article Hepatology Article has an altmetric score of 35

Resetting the transcription factor network reverses terminal chronic hepatic failure

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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.

Authors

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

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Figure 4

HNF4α re-expression in the hepatocytes of rats with terminal decompensated liver function and cirrhosis immediately reverses hepatic failure.

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HNF4α re-expression in the hepatocytes of rats with terminal decompensat...
Cirrhotic rats with severe terminal liver failure, 4 weeks after the last dose of CCl4, were given a recombinant AAV vector expressing either HNF4α and GFP or GFP only. (A) Fluorescence staining for GFP and costaining for hepatocyte (albumin) or non-parenchymal liver cell (α-SMA and EPCAM) markers; original magnification, ×200. (B) Fluorescence staining for GFP, HNF4α, and albumin at each time point, demonstrating the level of transduction and gene expression following intervention; original magnification, ×100. Nuclear DAPI staining is shown in blue. (C) Survival and clinical parameters of liver failure in control and AAV-GFP– and AAV-HNF4α-GFP–treated animals with decompensated cirrhosis. Immunofluorescence was performed on specimens from one animal per group and is representative of four images per biologic group. Five cirrhotic animals were untreated, four animals were treated with an AAV vector encoding the gene for GFP, and five animals were treated with an AAV vector encoding the genes for both HNF4α and GFP. Each value represents the mean ± SD, and survival was statistically evaluated by log-rank test between groups without treatment versus with treatment with the AAV vector encoding the genes for both HNF4α and GFP (C, *P < 0.01).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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