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

Stem Cell Reports, 2019 · DOI: https://doi.org/10.1016/j.stemcr.2019.04.007 · Published: May 2, 2019

Regenerative Medicine Neurology Genetics

Simple Explanation

The medial ganglionic eminence (MGE) is a brain structure that produces GABA-ergic interneurons, which are important for brain function and are implicated in neurological disorders. This study focuses on understanding how to maintain and expand MGE-like cells derived from human pluripotent stem cells (hPSCs), which have therapeutic potential. The researchers found that the WNT/CTNNB1 signaling pathway is crucial for keeping these MGE-like cells in an undifferentiated state, allowing them to proliferate. When this pathway is disrupted, the cells prematurely differentiate into neurons. Activating the WNT pathway, either genetically or chemically, helps maintain MGE cells and allows them to expand while retaining their ability to differentiate into specific types of neurons through activation of the NOTCH signaling pathway.

Study Duration

Not specified

Participants

Human embryonic stem cells (hESCs)

Evidence Level

Not specified

Key Findings

1
WNT/CTNNB1 signaling is essential for maintaining human MGE progenitors in an undifferentiated state.
2
Ablation of CTNNB1 leads to precocious cell-cycle exit and advanced neuronal differentiation of MGE cells.
3
Activation of WNT signaling maintains MGE cells in an expandable manner with authentic neuronal differentiation potencies through activation of endogenous NOTCH signaling.

Research Summary

The study investigates the cues that govern the maintenance versus differentiation of human medial ganglionic eminence (MGE) progenitors and explores methods for their large-scale expansion. It identifies WNT/CTNNB1 signaling as essential for maintaining MGE-like cells derived from human pluripotent stem cells (hPSCs), preventing premature differentiation and promoting proliferation. The research demonstrates that activating WNT signaling, either genetically or chemically, can sustain MGE cell expansion while preserving their capacity for neuronal differentiation through the activation of NOTCH signaling.

Practical Implications

Cell Therapies for Neurological Disorders

The findings suggest that MGE-like cells derived from hPSCs could be used for cell therapies of related neurological disorders.

Large-Scale Production of MGE Progenitors

The study provides a method for large-scale expansion of functional MGE progenitors by modulating the WNT/NOTCH pathway, which will greatly improve the accessibility and affordability of these cells.

Understanding Brain Development

The research contributes to a better understanding of the molecular mechanisms underlying human brain development, particularly the role of WNT and NOTCH signaling in MGE progenitor maintenance and differentiation.

Study Limitations

1
The study is primarily in vitro, and further in vivo studies are needed to validate the therapeutic potential of the expanded MGE progenitors.
2
The long-term effects of WNT/NOTCH pathway modulation on MGE progenitor differentiation and function require further investigation.
3
The precise mechanisms by which WNT/CTNNB1 signaling regulates NOTCH signaling in MGE progenitors need to be further elucidated.

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