Brain and Spinal Cord Innovative Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Room 508, Shanghai 200092, China.
Brain and Spinal Cord Innovative Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Key Laboratory of Reconstruction and Regeneration of Spine and Spinal Cord Injury, Ministry of Education, Shanghai 200065, China.
Stem Cell Reports. 2019 May 14;12(5):934-949. doi: 10.1016/j.stemcr.2019.04.007. Epub 2019 May 2.
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.
从中胚层神经节隆起（MGE）分化而来的人多能干细胞（hPSC）在治疗相关神经疾病的细胞疗法中有很大的应用潜力。然而，目前还没有研究清楚调控人 MGE 祖细胞维持与分化的信号，以及实现这些细胞大规模扩增的方法。在此，我们发现 WNT/CTNNB1 信号在维持 hPSC 来源的 MGE 样细胞中发挥着重要作用。MGE 细胞中 CTNNB1 的缺失会导致细胞过早退出细胞周期，并提前向神经元分化。通过遗传或化学方法激活 WNT 信号足以通过激活内源性 NOTCH 信号以可扩展的方式维持 MGE 细胞，并保持其原始的神经元分化能力。我们的研究结果表明，WNT/NOTCH 信号级联是调控人类 MGE 祖细胞维持与终末分化的关键因素。通过修饰 WNT/NOTCH 通路，可以实现功能性 MGE 祖细胞的大规模扩增，从而为细胞治疗提供更多选择。
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