Glucocorticoid-dependent transdifferentiation of pancreatic progenitor cells into hepatocytes is dependent on transient suppression of WNT signalling
Glucocorticoid-dependent transdifferentiation of pancreatic progenitor cells into hepatocytes is dependent on transient suppression of WNT signalling
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DOI：
10.1242/jcs.070722
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发表时间：
2010-06
影响因子：
4
通讯作者：
K. Wallace;Carylyn J. Marek;S. Hoppler;M. Wright
中科院分区：
文献类型：
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作者：
K. Wallace;Carylyn J. Marek;S. Hoppler;M. Wright
从发育角度来看，胰腺和肝脏密切相关，病理状况（包括糖皮质激素水平升高）会导致胰腺中出现肝细胞。 WNT 信号通路在此过程中的作用已在胰腺腺泡 AR42J-B-13 (B-13) 细胞转分化模型中得到检验。糖皮质激素治疗导致组成性 WNT3a 表达短暂丧失、β-连环蛋白磷酸化和耗竭、β-连环蛋白核定位丧失以及 T 细胞因子/淋巴增强因子 (Tcf/Lef) 转录活性显着降低，然后表型明显改变为肝细胞样 (B-13/H) 细胞。 Tcf/Lef 转录活性的恢复与 B-13/H 细胞中 WNT3a 的重新表达相关。单独敲除β-连环蛋白可替代并增强糖皮质激素依赖性转分化。突变型 β-连环蛋白 (pt-Xβ-cat) 蛋白的过度表达可阻断糖皮质激素依赖性 Tcf/Lef 活性抑制，从而抑制转分化。正如在 pt-Xβ-cat 表达中观察到的，Tcf/Lef 转录因子的小分子激活剂可阻断糖皮质激素依赖性效应。槲皮素（一种 Tcf/Lef 抑制剂）不会促进 B-13/H 细胞的转分化，但会增强糖皮质激素介导的转分化。这些数据表明，B-13 细胞响应糖皮质激素而转分化为肝细胞样细胞取决于对组成型活性 WNT 信号传导的抑制。
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.