Arsenic inhibits stem cell differentiation by altering the interplay between the Wnt3a and Notch signaling pathways.
Arsenic inhibits stem cell differentiation by altering the interplay between the Wnt3a and Notch signaling pathways.
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DOI：
10.1016/j.toxrep.2016.03.011
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发表时间：
2016
影响因子：
--
通讯作者：
League RE
中科院分区：
文献类型：
--
作者：
Bain LJ;Liu JT;League RE
数以百万计的人通过饮用水和食物接触到砷，但它影响胚胎发育的机制尚不清楚。胚胎发育过程中的砷暴露与神经发育的影响，体重增加减少，改变自发活动，体外数据表明，砷暴露抑制干细胞分化。本研究调查了砷是否破坏了Wnt 3a信号通路，在肌管和神经元的形成中至关重要，在P19小鼠胚胎干细胞的分化过程中。将细胞暴露于0、0.1或0.5 μM亚砷酸盐（含或不含外源性Wnt 3a），分化时间长达9天。单独的砷暴露抑制干细胞向神经元和骨骼肌管的分化，并将β-连环蛋白和GSK 3 β mRNA的表达降低至对照水平的约55%。砷暴露的细胞与外源性Wnt 3a的共培养挽救了形态学表型，但不改变GSK 3 β或β-连环蛋白的转录物、蛋白质或磷酸化状态。然而，砷暴露维持高水平的Hes 5和降低MASH 1的表达2.2倍，这是抗和促肌源性和神经源性基因，分别在Notch信号通路。虽然用外源性Wnt 3a进行拯救降低了Hes 5水平，但MASH 1水平仍然受到抑制。因此，虽然Wnt 3a可以部分挽救砷对分化的抑制，但它也通过调节Notch靶基因而不仅仅是通过经典的Wnt信号传导途径发挥作用。这些结果表明，砷改变了多种信号通路之间的相互作用，导致干细胞分化减少。
Millions of people are exposed to arsenic through their drinking water and food, but the mechanisms by which it impacts embryonic development are not well understood. Arsenic exposure during embryogenesis is associated with neurodevelopmental effects, reduced weight gain, and altered locomotor activity, and in vitro data indicates that arsenic exposure inhibits stem cell differentiation. This study investigated whether arsenic disrupted the Wnt3a signaling pathway, critical in the formation of myotubes and neurons, during the differentiation in P19 mouse embryonic stem cells. Cells were exposed to 0, 0.1, or 0.5 μM arsenite, with or without exogenous Wnt3a, for up to 9 days of differentiation. Arsenic exposure alone inhibits the differentiation of stem cells into neurons and skeletal myotubes, and reduces the expression of both β-catenin and GSK3β mRNA to ∼55% of control levels. Co-culture of the arsenic-exposed cells with exogenous Wnt3a rescues the morphological phenotype, but does not alter transcript, protein, or phosphorylation status of GSK3β or β-catenin. However, arsenic exposure maintains high levels of Hes5 and decreases the expression of MASH1 by 2.2-fold, which are anti- and pro-myogenic and neurogenic genes, respectively, in the Notch signaling pathway. While rescue with exogenous Wnt3a reduced Hes5 levels, MASH1 levels stay repressed. Thus, while Wnt3a can partially rescue the inhibition of differentiation from arsenic, it does so by also modulating Notch target genes rather than only working through the canonical Wnt signaling pathway. These results indicate that arsenic alters the interplay between multiple signaling pathways, leading to reduced stem cell differentiation.