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Generation of functional striatal neurons from human pluripotent stem cells

Noakes, Zoe 2016. Generation of functional striatal neurons from human pluripotent stem cells. PhD Thesis, Cardiff University.
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Abstract

The striatal neuronal populations comprise medium spiny projection neurons (MSNs) and GABAergic and cholinergic interneurons. Huntington’s disease (HD) involves massive degeneration of striatal neurons. The derivation of MSNs and interneurons from human pluripotent stem cells (hPSCs) would allow modelling of striatal function and HD in vitro, as well as provide a viable source of tissue for cell replacement therapy. Our lab has previously demonstrated that Activin A can induce MSN fate in hPSCs, and that these cells can survive and differentiate in vitro and in vivo. In this study, it was found that this effect occurs via the Activin receptor, independently of SHH signalling. Furthermore, blockade of BMP signalling accelerated MSN differentiation. Electrophysiological analysis demonstrated their potential to acquire functional membrane properties and synaptic activity in vitro. Wnt inhibition and SHH activation have been shown to pattern hPSCs into medial ganglionic eminence (MGE) progenitors and cortical interneurons. Both cortical and striatal interneurons are born in the MGE. This thesis presents the first account of generating MGE progenitors for the purpose of producing striatal interneurons in vitro. They expressed subtype markers such as parvalbumin, somatostatin, calretinin and choline acetyltransferase. When transplanted into neonatal rat striatum, hPSC-derived MGE progenitors migrated to the septum and hippocampus within 6 weeks. The majority of differentiated neurons became calretinin GABAergic interneurons, and a few in the striatum acquired cholinergic interneuron fate. Patch clamp analysis both in vitro and in vivo revealed functional neuronal characteristics and synaptic connectivity, although a more mature neuronal phenotype was achieved in vivo. In conclusion, functional striatal MSNs and interneurons can be generated using hPSCs, which will be invaluable for research into striatal function and dysfunction in HD and other striatum relevant disorders. They may also serve as a desperately needed therapy for HD, pending further preclinical studies in HD animal models.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH301 Biology
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Date of First Compliant Deposit: 13 March 2017
Last Modified: 08 May 2019 02:02
URI: http://orca.cf.ac.uk/id/eprint/98932

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