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

Abstract

Summary: 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. : In this article, Zhang and colleagues show that WNT/CTNNB1 signaling regulates the maintenance versus neurogenesis of human MGE progenitors through transcriptional activation of NOTCH signaling pathway. The regulation of WNT/NOTCH signaling cascade may thus contribute to large-scale expansion of functional MGE progenitors for cell therapies of related neurological disorders. Keywords: human pluripotent stem cells, medial ganglionic eminence, neural progenitor, WNT/CTNNB1, NOTCH, maintenance, neuronal differentiation, cell therapy