Clarke, Sarah Elizabeth; (2023) Basal Cell Heterogeneity in the Proximal Human Airway. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

There is emerging evidence that the basal cell population of the human airway is heterogenous, which has implications for repair and regeneration, and disease pathogenesis. This project sought to investigate whether subpopulations of basal cells could be identified on the basis of extracellular marker expression and whether these subpopulations showed different susceptibility to acquisition of tobacco smoke-induced mutations. An extracellular marker, podoplanin, was found to demarcate subsets of basal cells with differing progenitor capacity: those expressing high levels of podoplanin were found to show higher colony-forming efficiency and markers associated with the more stem-like basal cell subsets. Next, the stem cell characteristics and clonal dynamics of airway-derived basal cell clones known to have a high or low mutational burden following tobacco smoke exposure were investigated to identify features that may explain the heterogeneity in susceptibility of basal cells to acquisition of tobacco smoke-induced mutations. No differences in stem cell characteristics were identified but preliminary analysis of transcriptomic data suggests that there may be differences in metabolism of tobacco smoke and immune surveillance. Finally, the mutational burden was investigated in different regions of the airway over time and in response to treatment with an immunotherapy agent to investigate whether the immune system could be manipulated to remove high mutational burden basal cell clones, potentially reducing the risk of cancer development. Interestingly, mutational burden was actually found to increase in the airway after treatment with Nivolumab, although how this relates to risk of developing cancer remains to be established.

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