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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Resetting the transcription factor network reverses terminal chronic hepatic failure

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 6

Improvement in liver function after treatment with HNF4α re-expression is not mediated by expansion of new cells.

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Improvement in liver function after treatment with HNF4α re-expression i...
(A) Fluorescence staining for Ki-67, a proliferation marker in AAV-HNF4α-GFP–treated decompensated cirrhotic hepatocytes; original magnification, ×200. Images are representative of four images per biologic group. (B) qPCR analyses of hepatic progenitor marker genes (Afp, Cd44, and Epcam) and mature hepatic-specific genes (Alb, Asgpr1, and Ck18) from animals with liver disease. (C) HNF4α-treated end-stage hepatocytes were transplanted into the livers of Nagase analbuminemic rats, which were treated with retrorsine and underwent partial hepatectomy. (D) qPCR analysis for Tert expression and telomere length by genomic DNA analysis. qPCR and other studies were performed using three technical replicates from hepatocytes isolated from one animal representing each biological group. Each transplant group represents five animals infused with hepatocytes isolated from one animal that underwent each of the various interventions. Each value represents the mean ± SD (A–D). Statistical analyses were performed using the Tukey-Kramer multiple comparisons procedure among isolated hepatocytes from normal livers, compensated and decompensated cirrhotic livers, and decompensated cirrhotic livers 14 weeks after AAV-HNF4α/GFP treatment. Statistical results are shown among three groups (normal hepatocytes and functionally compensated and decompensated hepatocytes from cirrhotic livers) and between untreated decompensated cirrhotic hepatocytes and decompensated cirrhotic hepatocytes 14 weeks after in vivo HNF4α re-expression (A and B, *P < 0.05, **P < 0.01); and among isolated hepatocytes from normal livers, compensated and decompensated cirrhotic livers, and decompensated cirrhotic livers 14 weeks after AAV-HNF4α/GFP treatment (D, *P < 0.05, **P < 0.01).