title: Stepwise reprogramming of liver cells to a pancreas progenitor state by the transcriptional regulator Tgif2.
abstract: The development of a successful lineage reprogramming strategy of liver to pancreas holds promises for the treatment and potential cure of diabetes. The liver is an ideal tissue source for generating pancreatic cells, because of its close developmental origin with the pancreas and its regenerative ability. Yet, the molecular bases of hepatic and pancreatic cellular plasticity are still poorly understood. Here, we report that the TALE homeoprotein TGIF2 acts as a developmental regulator of the pancreas versus liver fate decision and is sufficient to elicit liver-to-pancreas fate conversion both ex vivo and in vivo. Hepatocytes expressing Tgif2 undergo extensive transcriptional remodelling, which represses the original hepatic identity and, over time, induces a pancreatic progenitor-like phenotype. Consistently, in vivo forced expression of Tgif2 activates pancreatic progenitor genes in adult mouse hepatocytes. This study uncovers the reprogramming activity of TGIF2 and suggests a stepwise reprogramming paradigm, whereby a 'lineage-restricted' dedifferentiation step precedes the identity switch.
authors.affiliation: Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13092, Germany.
authors.forename: Nuria
authors.initials: N
authors.lastname: Cerdá-Esteban
authors.affiliation: Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13092, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Naumann
authors.affiliation: Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13092, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ruzittu
authors.affiliation: Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin 13092, Germany.|BCRT, Charité University Medicine Berlin, Augustenburger Platz 1, Berlin 13353, Germany.
authors.forename: Nancy
authors.initials: N
authors.lastname: Mah
authors.affiliation: Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13092, Germany.
authors.forename: Igor M
authors.initials: IM
authors.lastname: Pongrac
authors.affiliation: Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13092, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Cozzitorto
authors.affiliation: DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Fetscher Straße 105, Dresden 01307, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Hommel
authors.affiliation: Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin 13092, Germany.|Faculty of Biology, Johannes Gutenberg University Mainz and Institute of Molecular Biology, Ackermannweg 4, Mainz 55128, Germany.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Andrade-Navarro
authors.affiliation: DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden, Fetscher Straße 105, Dresden 01307, Germany.
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.affiliation: Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13092, Germany.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Spagnoli
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010179:Pancreas / Q000166:cytology / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D012097:Repressor Proteins; C505201:TG-interacting factor 2, mouse