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Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32\(^+\) medium-sized spiny neurons

Carri, A.D., Onorati, M., Lelos, M.J., Castiglioni, V., Faedo, A., Menon, R., Camnasio, S., Vuono, Romina, Spaiardi, P., Talpo, F., and others. (2013) Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32\(^+\) medium-sized spiny neurons. Development, 140 (2). pp. 301-312. ISSN 0950-1991. (doi:10.1242/dev.084608) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:79839)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)
Official URL
http://dx.doi.org/10.1242/dev.084608

Abstract

Medium-sized spiny neurons (MSNs) are the only neostriatum projection neurons, and their degeneration underlies some of the clinical features of Huntington's disease. Using knowledge of human developmental biology and exposure to key neurodevelopmental molecules, human pluripotent stem (hPS) cells were induced to differentiate into MSNs. In a feeder-free adherent culture, ventral telencephalic specification is induced by BMP/TGFβ inhibition and subsequent SHH/DKK1 treatment. The emerging FOXG1\(^+\)/GSX2\(^+\) telencephalic progenitors are then terminally differentiated, resulting in the systematic line-independent generation of FOXP1\(^+\)/FOXP2\(^+\)/CTIP2\(^+\)/calbindin\(^+\)/DARPP-32\(^+\) MSNs. Similar to mature MSNs, these neurons carry dopamine and A2a receptors, elicit a typical firing pattern and show inhibitory postsynaptic currents, as well as dopamine neuromodulation and synaptic integration ability in vivo. When transplanted into the striatum of quinolinic acid-lesioned rats, hPS-derived neurons survive and differentiate into DARPP-32\(^+\) neurons, leading to a restoration of apomorphine-induced rotation behavior. In summary, hPS cells can be efficiently driven to acquire a functional striatal fate using an ontogeny-recapitulating stepwise method that represents a platform for in vitro human developmental neurobiology studies and drug screening approaches.

Item Type: Article
DOI/Identification number: 10.1242/dev.084608
Uncontrolled keywords: adenosine A2a receptor; calbindin; dopamine; phosphoprotein DARPP 32; quinolinic acid, animal experiment; animal model; article; cell differentiation; cell survival; controlled study; electrophysiology; female; fetus; flow cytometry; human; human cell; human tissue; Huntington chorea; immunodetection; in vivo study; nerve cell; neuromodulation; nonhuman; pluripotent stem cell; postsynaptic membrane; priority journal; rat; reverse transcription polymerase chain reaction; RNA isolation; telencephalon, Animals; Cell Adhesion; Cell Differentiation; Cell Lineage; Cell Survival; Cell Transplantation; Dopamine and cAMP-Regulated Phosphoprotein 32; Embryonic Stem Cells; Female; Fibroblasts; Flow Cytometry; GABAergic Neurons; Humans; Huntington Disease; Mice; Neurons; Oligonucleotide Array Sequence Analysis; Patch-Clamp Techniques; Pluripotent Stem Cells; Quinolinic Acid; Rats; RNA; Stem Cells; Time Factors, Rattus
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Romina Vuono
Date Deposited: 29 Jan 2020 10:53 UTC
Last Modified: 20 Feb 2020 09:57 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/79839 (The current URI for this page, for reference purposes)
Vuono, Romina: https://orcid.org/0000-0002-5162-3422
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