Li, Yao-Feng; (2019) The role of cellular diversity in developmental cortical lesions. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Introduction Interactions between cells of different types are likely to be critical in developmental cortical lesions. However, methods to dissect these interactions in human tissue are limited. I have explored cell-cell interactions in Focal Cortical Dysplasia (FCD) and Tuberous Sclerosis (TS), two of the most common cortical malformations leading to multidrug-resistant paediatric epilepsy. I hypothesised that cellular diversity including heterogeneity of balloon cells in FCD2b/TS plays an important role, and that understanding this will enable a better understanding of the disease pathogenesis, leading to novel therapeutic avenues. Materials and Methods Using gene expression data, I identified the major secretory signalling molecules in the FCDIIb/TS group. Then, I characterised the cell types expressing these signalling molecules using immunohistochemistry. Finally, to explore the functional relevance, I developed an organotypic slice culture model of FCD using tissue resected from children undergoing epilepsy surgery and visualised them in 3D using the tissue-clearing technique CLARITY. Results Gene expression analysis identified 55 up-regulated secretory molecules in FCD IIb/TS. After immunohistochemical validation of selected highly differentially expressed genes, I found two interesting cell populations, that were either CHI3L1-positive or CCL2-positive, potentially involved in the pathogenesis of FCD IIb/TS. By using the 3D technique CLARITY, I demonstrated heterogeneity of the small glial cells within the 3D architecture of malformations, as well as the variability of balloon cells structure. Finally, to develop a function model for cell-cell interactions, I successfully maintained organotypic cultures for up to 2 weeks from patients undergoing neurosurgery for epilepsy. Hyperactivation of the mTOR pathway is well known in these developmental lesions. After pharmacological mTOR inhibition, I showed that these two cell populations (CHI3L1, CCL2 cells) decreased in FCD IIb and TS cases. Conclusion Heterogeneity of the cells and their interactions may play a significant role in the pathogenesis of FCDIIb/TS. I have identified diversity in small glial cells in FCDIIb/TS (namely CHI3L1 positive and CCL2 positive cells) and used CLARITY to visualise their anatomical relationships in three dimensions. I have developed a model to determine the functional roles of these interactions with the mTOR pathway. The current project provides a generalisable approach to understanding cellular heterogeneity in developmental neuropathology.

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