WNT/NOTCH Pathway Is Essential for the Maintenance and Expansion of Human MGE Progenitors
WNT/NOTCH Pathway Is Essential for the Maintenance and Expansion of Human MGE Progenitors
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WNT/NOTCH 通路对于人类 MGE 祖细胞的维持和扩增至关重要
DOI：
10.1016/j.stemcr.2019.04.007
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发表时间：
2019-05-14
影响因子：
5.9
通讯作者：
Zhang, Xiaoqing
中科院分区：
文献类型：
--
作者：
Ma, Lin;Wang, Yiran;Zhang, Xiaoqing
由人多能干细胞（human pluripotent stem cells，hPSC）诱导的内侧神经节隆起（Medial ganglionic eminence，MGE）样细胞在相关神经系统疾病的细胞治疗中具有巨大的潜力。然而，协调人MGE祖细胞的维持与分化的线索，以及这些细胞的大规模扩增的方法尚未研究。在这里，我们报告说，WNT/CTNNB 1信号在维持来自hPSC的MGE样细胞中起着至关重要的作用。CTNNB 1在MGE细胞中的消融导致早熟的细胞周期退出和高级神经元分化。通过遗传或化学方法激活WNT信号传导足以通过激活内源性NOTCH信号传导以可扩展的方式维持具有真实神经元分化潜能的MGE细胞。我们的研究结果表明，WNT/NOTCH信号级联是一个关键的球员在管理的维持与终末分化的MGE祖细胞在人类。因此，用于细胞疗法的功能性MGE祖细胞的大规模扩增可以通过修饰WNT/NOTCH途径来实现。
Medial ganglionic eminence (MGE)-like cells yielded from human pluripotent stem cells (hPSCs) hold great potentials for cell therapies of related neurological disorders. However, cues that orchestrate the maintenance versus differentiation of human MGE progenitors, and ways for large-scale expansion of these cells have not been investigated. Here, we report that WNT/CTNNB1 signaling plays an essential role in maintaining MGE-like cells derived from hPSCs. Ablation of CTNNB1 in MGE cells led to precocious cell-cycle exit and advanced neuronal differentiation. Activation of WNT signaling through genetic or chemical approach was sufficient to maintain MGE cells in an expandable manner with authentic neuronal differentiation potencies through activation of endogenous NOTCH signaling. Our findings reveal that WNT/NOTCH signaling cascade is a key player in governing the maintenance versus terminal differentiation of MGE progenitors in humans. Large-scale expansion of functional MGE progenitors for cell therapies can therefore be achieved by modifying WNT/NOTCH pathway.