Signal requirement for cortical potential of transplantable human neuroepithelial stem cells

Balazs V. Varga (), Maryam Faiz, Helena Pivonkova, Gabriel Khelifi, Huijuan Yang, Shangbang Gao, Emma Linderoth, Mei Zhen, Ragnhildur Thora Karadottir, Samer M. Hussein and Andras Nagy ()
Additional contact information
Balazs V. Varga: Mount Sinai Hospital
Maryam Faiz: Mount Sinai Hospital
Helena Pivonkova: University of Cambridge, Puddicombe Way
Gabriel Khelifi: Université Laval
Huijuan Yang: Mount Sinai Hospital
Shangbang Gao: Mount Sinai Hospital
Emma Linderoth: Mount Sinai Hospital
Mei Zhen: Mount Sinai Hospital
Ragnhildur Thora Karadottir: University of Cambridge, Puddicombe Way
Samer M. Hussein: Mount Sinai Hospital
Andras Nagy: Mount Sinai Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract The cerebral cortex develops from dorsal forebrain neuroepithelial progenitor cells. Following the initial expansion of the progenitor cell pool, these cells generate neurons of all the cortical layers and then astrocytes and oligodendrocytes. Yet, the regulatory pathways that control the expansion and maintenance of the progenitor cell pool are currently unknown. Here we define six basic pathway components that regulate proliferation of cortically specified human neuroepithelial stem cells (cNESCs) in vitro without the loss of cerebral cortex developmental potential. We show that activation of FGF and inhibition of BMP and ACTIVIN A signalling are required for long-term cNESC proliferation. We also demonstrate that cNESCs preserve dorsal telencephalon-specific potential when GSK3, AKT and nuclear CATENIN-β1 activity are low. Remarkably, regulation of these six pathway components supports the clonal expansion of cNESCs. Moreover, cNESCs differentiate into lower- and upper-layer cortical neurons in vitro and in vivo. The identification of mechanisms that drive the neuroepithelial stem cell self-renewal and differentiation and preserve this potential in vitro is key to developing regenerative and cell-based therapeutic approaches to treat neurological conditions.

Date: 2022
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DOI: 10.1038/s41467-022-29839-8

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