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Stem Cell Reports. 2019 May 14;12(5):934-949. doi: 10.1016/j.stemcr.2019.04.007. Epub 2019 May 2.

WNT/NOTCH Pathway Is Essential for the Maintenance and Expansion of Human MGE Progenitors.

Author information

1
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.
2
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.
3
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; Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Room 508, Shanghai 200092, China.
4
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; Key Laboratory of Neuroregeneration of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Room 508, Shanghai 200092, China; Tsingtao Advanced Research Institute, Tongji University, Shanghai 200092, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China; Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China. Electronic address: xqzhang@tongji.edu.cn.

Abstract

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.

KEYWORDS:

NOTCH; WNT/CTNNB1; cell therapy; human pluripotent stem cells; maintenance; medial ganglionic eminence; neural progenitor; neuronal differentiation

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