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Optimisation of transplantation methodology in mouse models of Huntington’s Disease

Harrison, David John 2018. Optimisation of transplantation methodology in mouse models of Huntington’s Disease. PhD Thesis, Cardiff University.
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The objective of the experiments described in this thesis was to optimise transplantation protocols to improve the outcome of striatal mouse-to-mouse grafts in lesion models of Huntington’s Disease. There is a need to develop the model since the results observed, both in published studies and from within the lab, show typically small and pencil-like grafts, with little integration into the host compared to the widely-used rat model. The starting point was current practice – procedures based on the efficacious rat model - with studies designed to probe the effect of altering key components of the protocol. These are grouped into three experimental chapters; • Exploring the effect of host These experiments examine potential reasons a poorer outcome is seen in mice. By comparing the mouse and rat quinolinic acid lesion models it was shown that mice maintain a greater inflammatory response. This result prompted studies into the effect of delaying grafting until beyond peak post-lesion inflammation, and if the inflammatory response was strain-specific. Whilst no differences were detected, it was concluded that group sizes were not adequate to make a definitive conclusion. • Exploring the effect of donor The first experiment focussing on donor parameters compared different methods of cell preparation and identified that E14 single-cell suspension yielded the best results. However, all groups demonstrated large variance in the graft outcome. This led to the exploration of the cell suspension and cell viability, finding that the trypan blue method may not be ideal for measuring the health of cell suspensions. • Functional outcome measures These experiments demonstrated a variety of graft outcomes; however, none could describe which were ‘best’ in terms of functional efficacy, a fundamental outcome for cell transplantation therapies. A field-wide lack of systematic behavioural testing of the mouse quinolinic acid models was identified, and the final experiments describe a comprehensive motor and cognitive characterisation of the model, culminating in recommendations for appropriate test batteries to identify functional recovery.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Date of First Compliant Deposit: 11 September 2019
Last Modified: 11 Sep 2019 16:06

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