Glucocorticoid-dependent transdifferentiation of pancreatic progenitor cells into hepatocytes is dependent on transient suppression of WNT signalling

Abstract

Developmentally, the pancreas and liver are closely related and pathological conditions – including elevated glucocorticoid levels – result in the appearance of hepatocytes in the pancreas. The role of the WNT signalling pathway in this process has been examined in the model transdifferentiating pancreatic acinar AR42J-B-13 (B-13) cell. Glucocorticoid treatment resulted in a transient loss of constitutive WNT3a expression, phosphorylation and depletion of β-catenin, loss of β-catenin nuclear localisation, and significant reductions in T-cell factor/lymphoid enhancer factor (Tcf/Lef) transcriptional activity before overt changes in phenotype into hepatocyte-like (B-13/H) cells. A return to higher Tcf/Lef transcriptional activity correlated with the re-expression of WNT3a in B-13/H cells. β-catenin knock down alone substituted for and enhanced glucocorticoid-dependent transdifferentiation. Overexpression of a mutant β-catenin (pt-Xβ-cat) protein that blocked glucocorticoid-dependent suppression of Tcf/Lef activity resulted in inhibition of transdifferentiation. A small-molecule activator of Tcf/Lef transcription factors blocked glucocorticoid-dependent effects, as observed with pt-Xβ-cat expression. Quercetin – a Tcf/Lef inhibitor – did not promote transdifferentiation into B-13/H cells, but did potentiate glucocorticoid-mediated transdifferentiation. These data demonstrate that the transdifferentiation of B-13 cells into hepatocyte-like cells in response to glucocorticoid was dependent on the repression of constitutively active WNT signalling.