Direct Reprogramming of Hepatic Myofibroblasts into Hepatocytes In Vivo Attenuates Liver Fibrosis

Cell Stem Cell. 2016 Jun 2;18(6):797-808. doi: 10.1016/j.stem.2016.01.010. Epub 2016 Feb 25.


Direct induction of induced hepatocytes (iHeps) from fibroblasts holds potential as a strategy for regenerative medicine but until now has only been shown in culture settings. Here, we describe in vivo iHep formation using transcription factor induction and genetic fate tracing in mouse models of chronic liver disease. We show that ectopic expression of the transcription factors FOXA3, GATA4, HNF1A, and HNF4A from a polycistronic lentiviral vector converts mouse myofibroblasts into cells with a hepatocyte phenotype. In vivo expression of the same set of transcription factors from a p75 neurotrophin receptor peptide (p75NTRp)-tagged adenovirus enabled the generation of hepatocyte-like cells from myofibroblasts in fibrotic mouse livers and reduced liver fibrosis. We have therefore been able to convert pro-fibrogenic myofibroblasts in the liver into hepatocyte-like cells with positive functional benefits. This direct in vivo reprogramming approach may open new avenues for the treatment of chronic liver disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Lineage
  • Cellular Reprogramming*
  • Cholestasis / complications
  • Dependovirus / metabolism
  • Dicarbethoxydihydrocollidine
  • Hepatocytes / cytology*
  • Integrases / metabolism
  • Liver / cytology*
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology*
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Models, Biological
  • Myofibroblasts / cytology*
  • Oligonucleotide Array Sequence Analysis
  • Transcription Factors / metabolism


  • Biomarkers
  • Transcription Factors
  • Dicarbethoxydihydrocollidine
  • Cre recombinase
  • Integrases