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Title: Directed differentiation of human pluripotent stem cells to telencephalic lateral ganglionic eminence progenitors using small molecules
Author: Joy, Shona
ISNI:       0000 0004 6349 3359
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2016
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This thesis focused on directing the differentiation of pluripotent stem cells towards telencephalic lateral ganglionic eminence-like fate. The study aimed at developing chemically defined conditions for optimized production of cell types for application in Huntington's disease. The signalling pathways known to be involved in in vivo telencephalon development and regional specification were addressed. The temporal integration of pathways was achieved in vitro by utilizing small molecule pathway agonists or antagonists. In chapter 3, BMP antagonism by Dorsomorphin, LDN193189 and DMH1 was found to promote PAX6+ neuroectoderm fate specification of hPSCs by day 8 of differentiation. In chapter 4, concomitant inhibition of BMP and WNT signalling by IWR1 and KY02111 was found to enhance FOXG1+ telencephalic fate and regional specification towards LGE-like fate by day 16 of differentiation. In chapter 5 SHH pathway activation by Purmorphamine from day 8 to day 16 led to telencephalic fate specification towards MGE fate whereas Activin exposure in the same temporal window specifically enhanced LGE-like specification. In chapter 6, the day16 neural progenitors were terminally differentiated and analysed for DARPP32/CTIP2 expression indicative of LGE derived striatal MSN-like fate. BMP inhibitor+ WNT inhibitor patterned progenitors generated ~60% CTIP2+ and ~16% DARPP32+ neurons and addition of Activin nearly doubled the number of DARPP32+ neurons. Activation of SHH signalling downregulated these markers. Thus, the study using hPSC as model system identified distinct cell responses to different signalling pathways involved in telencephalon specification.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available