title: 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.forename: Taichiro
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Aaron
authors.initials: A
authors.lastname: Bell
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Brooks
authors.forename: Kentaro
authors.initials: K
authors.lastname: Setoyama
authors.forename: Marta
authors.initials: M
authors.lastname: Melis
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.forename: Ken
authors.initials: K
authors.lastname: Fukumitsu
authors.forename: Kan
authors.initials: K
authors.lastname: Handa
authors.forename: Jianmin
authors.initials: J
authors.lastname: Tian
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
authors.forename: Joseph
authors.initials: J
authors.lastname: Locker
authors.forename: Alejandro
authors.initials: A
authors.lastname: Soto-Gutierrez
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Fox
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000096:biosynthesis / Q000235:genetics; D002252:Carbon Tetrachloride Poisoning / Q000235:genetics / Q000628:therapy; D054337:Cell Dedifferentiation / Q000235:genetics; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics; D018450:Disease Progression; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000096:biosynthesis / Q000235:genetics; D051542:Hepatocyte Nuclear Factor 3-beta / Q000096:biosynthesis / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D017093:Liver Failure / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008297:Male; D047493:PPAR alpha / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D059467:Transcriptome; D014161:Transduction, Genetic
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; C496504:Foxa2 protein, rat; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C496489:Hnf1a protein, rat; C496594:Hnf4a protein, rat; D047493:PPAR alpha; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta