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

• Published in: Nature communications Vol. 8; no. 1; p. 14127
• Main Authors: Cerdá-Esteban, Nuria, Naumann, Heike, Ruzittu, Silvia, Mah, Nancy, Pongrac, Igor M., Cozzitorto, Corinna, Hommel, Angela, Andrade-Navarro, Miguel A., Bonifacio, Ezio, Spagnoli, Francesca M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-02-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 14; 14/1; 14/19; 38; 38/61; 631/136/2060; 631/136/2128; 631/136/532/2435; 64; 64/60; Animals; Biology; Cell Differentiation - genetics; Cell Lineage - genetics; Cells, Cultured; Cellular Reprogramming - genetics; Diabetes; Embryos; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Developmental; Hepatocytes - cytology; Hepatocytes - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humanities and Social Sciences; Liver; Liver - cytology; Liver - metabolism; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; multidisciplinary; Pancreas; Pancreas - cytology; Pancreas - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Science; Science (multidisciplinary); Stem Cells - metabolism; Germany
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14127

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.
Liver and pancreas cells arise from a common endoderm progenitor in the embryo, but what regulates their cell fate is unclear. Here, the authors show that expression of the Three-Amino-acid-Loop-Extension (TALE) homeobox TG-interacting factor 2 (TGIF2) in hepatocytes reprogrammes the cells to a pancreatic fate.