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Engineering of midbrain organoids containing long-lived dopaminergic neurons

Tieng Caulet, Vannary
Published in Stem cells and development. 2014, vol. 23, no. 13, p. 1535-47
Abstract The possibility to generate dopaminergic (DA) neurons from pluripotent stem cells represents an unlimited source of material for tissue engineering and cell therapy for neurodegenerative disease. We set up a protocol based on the generation of size-calibrated neurospheres for a rapid production (3 weeks) of a high amount of DA neurons (>60%) oriented toward a midbrain-like phenotype, characterized by the expression of FOXA2, LMX1A, tyrosine hydroxylase (TH), NURR1, and EN1. By using γ-secretase inhibitors and varying culture time of neurospheres, we controlled maturation and cellular composition of a three-dimensional (3D) engineered nervous tissue (ENT). ENT contained neurons and glial cells expressing various markers of maturity, such as synaptophysin, neuronal nuclei-specific protein (NeuN), and glial fibrillary acidic protein (GFAP), and were electrophysiologically active. We found that 3-week-old neurospheres were optimal to generate 3D tissue containing DA neurons with typical A9 morphology. ENT generated from 4-week-old neurospheres launched glial cell type since astrocytes and myelin could be detected massively at the expense of TH-immunoreactive neurons. All γ-secretase inhibitors were not equivalent; compound E was more efficient than DAPT in generating DA neurons. This DA tissue provides a tool for drug screening, and toxicology. It should also become a useful biomaterial for studies on Parkinson's disease.
Keywords Cells, CulturedDopaminergic Neurons/physiologyEmbryonic Stem CellsHumansInduced Pluripotent Stem CellsMesencephalon/cytologyOrganoids/cytologyReceptors, Notch/metabolismSpheroids, Cellular/cytologyTissue Engineering
PMID: 24576173
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Research group Radicaux libres et cellules souches embryonnaires (60)
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TIENG CAULET, Vannary et al. Engineering of midbrain organoids containing long-lived dopaminergic neurons. In: Stem cells and development, 2014, vol. 23, n° 13, p. 1535-47. doi: 10.1089/scd.2013.0442 https://archive-ouverte.unige.ch/unige:82443

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Deposited on : 2016-04-07

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