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Transdifferentiation of liver to pancreas by ectopic expression of Pdx1
- The molecular basis of transdifferentiation

Several labs have recently shown that it is possible to induce some degree of pancreatic gene expression in liver cells using unmodified Pdx1 [35–37]. Results from our own lab showed that unmodified Pdx1 has very low activity in converting liver to pancreas, but that the activity can be greatly increased by incorporation of a transcriptional activation domain from the Herpes simplex protein VP16 [38]. In Xenopus transgenics, Pdx1-VP16 is able to reprogram macroscopic areas of the liver to pancreas (Fig. 2). We have shown that the endogenous Pdx1 gene is activated in the ectopic pancreas and that the transthyretin (TTR) promoter, which drives the transgene, is not active in the pancreas. This suggests that the requirement for the presence of the transgene is only temporary and that once the cells have transdifferentiated to pancreas, transgene expression is shut off and the tissue is as stable as the endogenous pancreas. Li et al. [39] further confirmed the transdifferentiation of human hepatoma HepG2 cells into functional pancreaticlike cells using the same transgene (Fig. 1B). The pancreatic-like cells induced in liver using Pdx1 as a transgene show similar results from different groups and most of them also demonstrate rescue from hyperglycaemia in diabetic animals [40].

Endocrine differentiation

Ngn3, a bHLH transcription factor, is expressed in all endocrine precursor cells. The knockout lacks endocrine cells, and overexpression drives the formation of additional endocrine cells [41, 42]. Ngn3 is also expressed in the developing central nervous system [43]. More recently, Ngn3 was shown to be crucial for differentiation of endocrine cell types in pancreas, intestine and stomach [42, 44]. It is expressed from embryonic day 9.5 (E9.5), peaks at E15.5 and diminishes thereafter to undetectable levels in the neonatal mouse pancreas [41]. It is thought that Ngn3 is probably responsible for the commitment of endocrine cells rather than all pancreatic cell lineages. Ngn3 is also able to drive pancreatic duct cells to a neuroendocrine phenotype with the formation of insulin-positive cells [45]. This mirrors its role in the later stages of pancreas development and suggests that Ngn3 may require another 'central regulator' to change cell fate. More recently, it has been demonstrated that Ngn3 might be a mediator for converting intestinal epithelial cells to insulin-positive cells following treatment with glucagon-like peptide 1 in vitro and in vivo [46]. The bHLH transcription factor PTF1-p48 was first described in exocrine-specific pancreas development and gene expression [47]. Recent results have revised the role of PTF1-p48, with involvement in both exocrine and endocrine cell lineages in murine and zebrafish models [48, 49]. Kawaguchi et al. [50] demonstrated conversion of pancreatic progenitors into duodenal epithelium through the inactivation of PTF1-p48, thereby suggesting a close developmental relationship between intestine and pancreas (similar to that between liver and pancreas). Also, it provides a possible route for creating new pancreatic cells following the overexpression of PTF1-p48 in other cell types such as intestine.

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