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

• Published in: Cell stem cell Vol. 18; no. 6; pp. 797 - 808
• Main Authors: Song, Guangqi, Pacher, Martin, Balakrishnan, Asha, Yuan, Qinggong, Tsay, Hsin-Chieh, Yang, Dakai, Reetz, Julia, Brandes, Sabine, Dai, Zhen, Pützer, Brigitte M., Araúzo-Bravo, Marcos J., Steinemann, Doris, Luedde, Tom, Schwabe, Robert F., Manns, Michael P., Schöler, Hans R., Schambach, Axel, Cantz, Tobias, Ott, Michael, Sharma, Amar Deep
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-06-2016
• Subjects: Adenoviridae; Adenovirus; 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
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2016.01.010

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.
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•Transcription factor induction converts hepatic myofibroblasts to iHeps in vitro•Lineage tracing documents in vivo reprogramming of myofibroblasts into iHeps•iHeps induced in vivo closely resemble hepatocytes•In vivo induction of iHeps ameliorates chemically induced liver fibrosis
Sharma, Ott, and colleagues show that expression of a key set of four transcription factors can reprogram hepatic myofibroblasts to induced hepatocyte-like cells in vivo and reduce liver fibrosis, suggesting that direct in vivo reprogramming may be an effective treatment approach for chronic liver disease.