title: Direct Reprogramming of Hepatic Myofibroblasts into Hepatocytes In Vivo Attenuates Liver Fibrosis.
abstract: 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.
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover 30625, Germany; Junior Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover 30625, Germany; Translational Hepatology and Stem Cell Biology, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Guangqi
authors.initials: G
authors.lastname: Song
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover 30625, Germany; Twincore Centre for Experimental and Clinical Infection Research, Hannover 30625, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Pacher
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover 30625, Germany; Twincore Centre for Experimental and Clinical Infection Research, Hannover 30625, Germany.
authors.forename: Asha
authors.initials: A
authors.lastname: Balakrishnan
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover 30625, Germany; Twincore Centre for Experimental and Clinical Infection Research, Hannover 30625, Germany.
authors.forename: Qinggong
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover 30625, Germany; Junior Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover 30625, Germany; Twincore Centre for Experimental and Clinical Infection Research, Hannover 30625, Germany.
authors.forename: Hsin-Chieh
authors.initials: HC
authors.lastname: Tsay
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover 30625, Germany; Junior Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Dakai
authors.initials: D
authors.lastname: Yang
authors.affiliation: Institute for Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock 18057, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Reetz
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover 30625, Germany; Twincore Centre for Experimental and Clinical Infection Research, Hannover 30625, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Brandes
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover 30625, Germany; Junior Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Institute for Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock 18057, Germany.
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Pützer
authors.affiliation: Group of Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, San Sebastián 20014, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao 48013, Spain.
authors.forename: Marcos J
authors.initials: MJ
authors.lastname: Araúzo-Bravo
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Steinemann
authors.affiliation: Division of Hepatobiliary Oncology, Department of Medicine III, University Hospital RWTH, Aachen 52074, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
authors.affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Schwabe
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.affiliation: Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster 48149, Germany.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Schöler
authors.affiliation: Institute for Experimental Hematology, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Schambach
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover 30625, Germany; Translational Hepatology and Stem Cell Biology, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover 30625, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Cantz
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover 30625, Germany; Twincore Centre for Experimental and Clinical Infection Research, Hannover 30625, Germany. Electronic address: ott.michael@mh-hannover.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Ott
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover 30625, Germany; Junior Research Group MicroRNA in Liver Regeneration, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover 30625, Germany. Electronic address: sharma.amar@mh-hannover.de.
authors.forename: Amar Deep
authors.initials: AD
authors.lastname: Sharma
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019070:Cell Lineage; D065150:Cellular Reprogramming; D002779:Cholestasis / Q000150:complications; D000229:Dependovirus / Q000378:metabolism; D003997:Dicarbethoxydihydrocollidine; D022781:Hepatocytes / Q000166:cytology*; D019426:Integrases / Q000378:metabolism; D008099:Liver / Q000166:cytology*; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008954:Models, Biological; D058628:Myofibroblasts / Q000166:cytology*; D020411:Oligonucleotide Array Sequence Analysis; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D015415:Biomarkers; D014157:Transcription Factors; D003997:Dicarbethoxydihydrocollidine; C045073:Cre recombinase; D019426:Integrases