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.
Highlights
The development of a successful lineage reprogramming strategy of liver to pancreas holds promises for the treatment and potential cure of diabetes
Given the fact that adult hepatocytes are differentiated and arrested in quiescence (G0 phase), the change in cell identity triggered by Tgif[2] occurs in the absence of cell division (Supplementary Fig. 8), possibly implying a direct fate transitioning through discrete steps
These studies mostly focused on the acquisition of insulin expression and some other markers of pancreatic identity, but they did not assess the degree of loss of hepatic fate and did not follow the fate transition temporally
Summary
The development of a successful lineage reprogramming strategy of liver to pancreas holds promises for the treatment and potential cure of diabetes. Additional limitations might be the lack of appropriate interaction partners or the presence of antagonistic factors in liver cells that lock cell identity, hampering cell plasticity and conversion To overcome these lineage restrictions, we investigated whether developmental regulator(s) of the pancreas versus liver fate decision might be effective reprogramming determinants for achieving conversion of liver cells into pancreas fate. In a RNASeq gene expression profile of liver and pancreas progenitor cells isolated from the mouse embryo, we identified the Three-Amino-acid-Loop-Extension (TALE) homeobox TG-interacting factor 2 (TGIF2) at the cell-fate branchpoint, being in the common endoderm progenitor pool and whose expression changes in opposite directions as cells commit to pancreatic or hepatic lineages[25,28]. In the mouse embryo, overlapping functions between Tgif[2] and its close family member, Tgif[1], have been previously reported during different embryological processes, such as gastrulation and neural development[32,33]
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