Glucocorticoid-dependent transdifferentiation of pancreatic progenitor cells into hepatocytes is dependent on transient suppression of WNT signalling.
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 beta-catenin, loss of beta-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. beta-catenin knock down alone substituted for and enhanced glucocorticoid-dependent transdifferentiation. Overexpression of a mutant beta-catenin (pt-Xbeta-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-Xbeta-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.
Wallace
Karen
K
Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle Upon Tyne, UK.
Marek
Carylyn J
CJ
Hoppler
Stefan
S
Wright
Matthew C
MC
D000818:Animals; D002460:Cell Line; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D015536:Down-Regulation; D005938:Glucocorticoids / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology* / Q000378:metabolism; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D005938:Glucocorticoids; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin