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

Abstract

SummaryDevelopmentally, the pancreas and liver are closely related and pathological conditions -including elevated glucocorticoid levelsresult 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 -catenin, loss of -catenin nuclear localisation, and significant reductions in T-cell factor/lymphoid enhancer factor (Tcf/Lef) transcriptional activity before overt changes in phenotype into hepatocytelike (B-13/H) cells. A return to higher Tcf/Lef transcriptional activity correlated with the re-expression of WNT3a in B-13/H cells. -catenin knock down alone substituted for and enhanced glucocorticoid-dependent transdifferentiation. Overexpression of a mutant -catenin (pt-X-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-X-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.

Serine/threonine protein kinase SGK1 in glucocorticoid-dependent transdifferentiation of pancreatic acinar cells to hepatocytes

“…siRNA-mediated knockdown of SGK1 and overexpression of SGK1 inhibited and promoted (without the requirement for glucocorticoid) transdifferentiation, respectively, unequivocally demonstrating a regulatory role for SGK1 in the response. Our data also suggest that the mechanism is likely to involve crosstalk with the WNT signalling pathway, which has previously been shown to regulate B-13 cell transdifferentiation (Wallace et al, 2010c), because overexpression of SGK1 inhibited transcriptional activity of distal WNT signalling, an effect that was absent when the SGK1 kinase function was blocked. The transdifferentiation of pancreatic acinar cells to hepatocyte-like…”

“…Previous work has demonstrated that -catenin phosphorylation, which targets the protein for degradation (Hoppler and Kavanagh, 2007), and reductions in the levels of -catenin are early upstream 409 Role for SGK1 in transdifferentiation events to C/EBP- induction and B-13 transdifferentiation to B-13/H cells (Wallace et al, 2010c). It was therefore hypothesised that expression of SGK1C and SGK1F or induction of endogenous SGK1C resulted in phosphorylation of -catenin.…”

“…More recently, we have shown that a transient repression of WNT3a expression, WNT signalling and Tcf/Lef transcriptional activity in B-13 cells is an upstream event to induction of C/EBP- (Wallace et al, 2010c). Thus, siRNA knockdown of -catenin -the intracellular messenger for WNT signalling (Hoppler and Kavanagh, 2007) -substituted for glucocorticoid and led to an induction of C/EBP- expression and transdifferentiation (Wallace et al, 2010c). Overexpression of a dominant-negative -catenin protein blocked glucocorticoiddependent transdifferentiation (Wallace et al, 2010c).…”

“…Thus, siRNA knockdown of -catenin -the intracellular messenger for WNT signalling (Hoppler and Kavanagh, 2007) -substituted for glucocorticoid and led to an induction of C/EBP- expression and transdifferentiation (Wallace et al, 2010c). Overexpression of a dominant-negative -catenin protein blocked glucocorticoiddependent transdifferentiation (Wallace et al, 2010c).…”

Rejuvenating liver and pancreas through cell transdifferentiation

“…Glucocorticoid dexamethasone could efficiently induce rat pancreatic exocrine cells into hepatocytes [13]. Similarly, another report confirmed the inductive role of dexamethasone in transdifferentiation of pancreatic acinar cells into functional hepatocytes through a transient suppression of Wnt signaling [14]. These findings may suggest that adult pancreatic cells might retain epigenetic memory from their common embryonic origin with hepatocytes and thereby are flexible to convert into hepatocytes under permissive conditions.…”