Critchley, Bethan; (2024) The role of vascular endothelium in the transmigration of haematopoietic cells to the central nervous system during haematopoietic stem cell transplantation. Doctoral thesis (Ph.D), UCL (University College London).

Text B Critchley PhD Thesis FINAL.pdf - Other Access restricted to UCL open access staff until 1 March 2025. Download (13MB)

Abstract

Haematopoietic stem and progenitor cell transplantation (HSCT) involves administering HSCs to reestablish production of blood cell lineages in patients. HSCT has been successfully applied to treat many diseases including some lysosomal storage diseases (LSDs) which are monogenic, multisystem diseases caused by deficient lysosomal function that leads to toxic macromolecule accumulation. HSCT attenuates neurological LSD symptoms, with the critical mechanism being migration of an HSC subpopulation into the central nervous system (CNS) and engraftment as microglia-like cells that secrete functional lysosomal enzyme which is taken up by neighbouring enzyme-deficient cells and restores lysosomal function. Furthermore, busulfan conditioning before HSCT is associated with increased CNS cell engraftment due to depletion of resident microglia, and through potential vascular injury via an as-yet-unknown mechanism. Treatment success depends on HSCs’ ability to cross the blood-brain barrier (BBB), which controls substance exchange between the systemic circulation and the CNS. Brain endothelium has specialised characteristics that confer enhanced BBB tightness, such as tight junctions (TJs) between neighbouring endothelial cells. I therefore investigated the impact of vascular endothelial components, specifically junction adhesion molecule A (JAM-A) which is crucial for TJ formation and function, on HSC migration in vitro and in vivo to identify mechanism(s) to improve HSC delivery to the brain. Migration of HSCs and HSC progeny in an in vitro BBB model in which JAM-A had been knocked out revealed significantly increased migration of HSC progeny compared to a wild-type BBB model. Simultaneously, in vivo examination of brain vasculature and TJs at multiple timepoints post-busulfan or irradiation conditioning revealed that claudin-5 is temporarily disrupted in busulfan-conditioned brains at 24 hours. Overall, our work suggested two vascular endothelial proteins, JAM-A and claudin-5, as targets to potentially increase HSC migration into the brain during HSCT, with a view to improving HSCT outcome for neurological LSD patients.

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