Investigation of the functional integration of hESC-derived grafts in models of Huntington’s disease

Garcia Jareno, Patricia 2023. Investigation of the functional integration of hESC-derived grafts in models of Huntington’s disease. PhD Thesis, Cardiff University. Item availability restricted.

Preview	PDF - Accepted Post-Print Version Download (34MB) | Preview
	PDF (Cardiff University Electronic Publication Form) - Supplemental Material Restricted to Repository staff only Download (376kB)

Abstract

Huntington’s disease (HD) is an autosomal dominant genetic disorder associated with progressive deterioration of movement, cognition and behaviour. Currently, there are no approved disease-modifying therapies and symptomatic treatments are limited, but cell replacement therapy (CRT), in which striatal medium spiny neurons (MSN) progenitors are transplanted directly into the adult striatum, is in development as a potential therapeutic intervention. Preclinical data and proof-of-concept clinical studies, using foetal-derived donor cells, suggest that striatal grafts containing mature MSNs can alleviate motor and cognitive deficits. It is hypothesized that functional recovery relies largely on reconstruction of the basal ganglia circuitry that is disrupted in the HD brain. The overall aim of this thesis was to investigate if hESC-derived MSNs can reconstruct the damaged basal ganglia circuit principally using the monosynaptic tracing based on the modified rabies virus (ΔG-rabies) technology. Firstly, a hESC line expressing the TVA receptor and rabies glycoprotein for the ΔGrabies was made for all host-to-graft experiments in this thesis. In Chapter 3 hESCderived MSNs were transplanted into the striatal quinolinic acid (QA) lesion model and host-to-graft (Experiment 1) and graft-to-host (Experiment 2) connectivity were investigated. Experiment 1 demonstrated that from 5 weeks post grafting, various efferent striatal areas in the host brain, such as the cortex, thalamus or substantia nigra (SN), made synaptic contacts with the graft, and these contacts were maintained overtime. Interpretation of Experiment 2 exploring graft-to-host connectivity were unfortunately limited because the grafts were very large and ventrally located. Chapter 4 explored host-to-graft connectivity in the F344tgHD transgenic rat model in young and aged rats. These studies revealed that both wild-type (WT) and F344tgHD rat host brain were able to make synaptic contacts with transplanted hESC-derived MSNs at both ages, although graft volumes were smaller in F344tgHD rats compared to WT rats. Chapter 5 set out to investigate the expression of immediate early genes (IEG) as possible biomarkers for neural network repair after cell transplantation. Surprisingly, these experiments showed an unexpected cell loss in the globus pallidus (GP) in the QA model. The mechanism underlying this cell loss was explored, with a view to making adjustments to the QA lesion in the striatum so as to make it more suitable for exploring circuit reconstruction. iii This work outlines the potential of hESC-derived MSNs for CRT, establishes the proof of concept that this Activin-A-based cell product can form early synaptic contacts with the host brain, and emphasizes the importance of reviewing animal models and selecting the most appropriate to address the research question.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	14 May 2024
Last Modified:	14 May 2024 13:54
URI:	https://orca.cardiff.ac.uk/id/eprint/168902

Actions (repository staff only)

Edit Item