Activin A directs striatal projection neuron differentiation of human pluripotent stem cells

Arber, C., Precious, Sophie Victoria, Cambray, S., Risner-Janiczek, J. R., Kelly, Claire, Noakes, Zoe ORCID: https://orcid.org/0000-0002-1302-906X, Fjodorova, Marija, Heuer, Andreas, Ungless, M. A., Rodriguez, T. A., Rosser, Anne Elizabeth ORCID: https://orcid.org/0000-0002-4716-4753, Dunnett, Stephen Bruce ORCID: https://orcid.org/0000-0003-1826-1578 and Li, Meng ORCID: https://orcid.org/0000-0002-4803-4643 2015. Activin A directs striatal projection neuron differentiation of human pluripotent stem cells. Development 142 (7) , pp. 1375-1386. 10.1242/dev.117093

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Abstract

The efficient generation of striatal neurons from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) is fundamental for realising their promise in disease modelling, pharmaceutical drug screening and cell therapy for Huntington's disease. GABAergic medium-sized spiny neurons (MSNs) are the principal projection neurons of the striatum and specifically degenerate in the early phase of Huntington's disease. Here we report that activin A induces lateral ganglionic eminence (LGE) characteristics in nascent neural progenitors derived from hESCs and hiPSCs in a sonic hedgehog-independent manner. Correct specification of striatal phenotype was further demonstrated by the induction of the striatal transcription factors CTIP2, GSX2 and FOXP2. Crucially, these human LGE progenitors readily differentiate into postmitotic neurons expressing the striatal projection neuron signature marker DARPP32, both in culture and following transplantation in the adult striatum in a rat model of Huntington's disease. Activin-induced neurons also exhibit appropriate striatal-like electrophysiology in vitro. Together, our findings demonstrate a novel route for efficient differentiation of GABAergic striatal MSNs from human pluripotent stem cells.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Biosciences Neuroscience and Mental Health Research Institute (NMHRI) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects:	Q Science > QH Natural history > QH426 Genetics Q Science > QR Microbiology R Medicine > R Medicine (General)
Publisher:	The Company of Biologists Ltd
ISSN:	0950-1991
Date of Acceptance:	6 February 2015
Last Modified:	15 Nov 2022 11:59
URI:	https://orca.cardiff.ac.uk/id/eprint/73022

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