Laboratory of Molecular and Cellular Basis of Embryonic Development, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13092, Germany.
Computational Biology and Data Mining, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin 13092, Germany.
Nat Commun. 2017 Feb 13;8:14127. 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.
成功地将肝谱系重编程为胰腺的策略有望为糖尿病的治疗和潜在治愈提供可能。肝脏是生成胰腺细胞的理想组织来源，因为它与胰腺具有密切的发育起源和再生能力。然而，肝和胰腺细胞可塑性的分子基础仍知之甚少。在这里，我们报告称，TALE 同源蛋白 TGIF2 作为胰腺与肝脏命运决定的发育调节剂，足以在体外和体内引发肝向胰腺的命运转换。表达 Tgif2 的肝细胞经历广泛的转录重编程，抑制原始的肝特性，并随着时间的推移诱导出胰腺祖细胞样表型。一致地，在体内强制表达 Tgif2 可激活成年小鼠肝细胞中的胰腺祖细胞基因。这项研究揭示了 TGIF2 的重编程活性，并提出了一个逐步重编程范例，其中“谱系受限”的去分化步骤先于身份转换。
