Stepwise reprogramming of liver cells to a pancreas progenitor state by the transcriptional regulator Tgif2

Nuria Cerdá-Esteban, Heike Naumann, Silvia Ruzittu, Nancy Mah, Igor M. Pongrac, Corinna Cozzitorto, Angela Hommel, Miguel A. Andrade-Navarro, Ezio Bonifacio and Francesca M. Spagnoli ()
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Nuria Cerdá-Esteban: Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine
Heike Naumann: Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine
Silvia Ruzittu: Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine
Nancy Mah: Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine
Igor M. Pongrac: Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine
Corinna Cozzitorto: Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine
Angela Hommel: DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden
Miguel A. Andrade-Navarro: Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine
Ezio Bonifacio: DFG-Center for Regenerative Therapies Dresden, Technische Universität Dresden
Francesca M. Spagnoli: Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14127

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