Casal, Giulia; (2025) Structure and regulation of the blood nerve barrier in homeostasis and following injury. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Blood barriers act as critical regulators between the bloodstream and the specialised environment of the nervous system. In the CNS, barrier properties are induced by the surrounding microenvironment, leading to the characterisation of the vascular unit of the blood brain barrier (BBB), which consists of endothelial cells (ECs) surrounded by pericytes and completely covered by astrocyte end-feet and microglia. To maintain barrier integrity, ECs exhibit restricted transcytosis and form specialised tight junctions. Similarly, peripheral nerves require a protected environment, maintained by the Blood Nerve Barrier (BNB), whose disruption is linked to conditions such as diabetes and neuropathies. However, its structural and functional properties remain poorly characterised. This thesis characterises the conserved multicellular structure of the vascular unit that comprises the BNB, in which ECs are partially covered by pericytes, fibroblast-like cells (tactocytes) and macrophages. Like the BBB, the BNB relies on low levels of transcytosis and specialised tight junctions. To investigate cell-cell communication within this vascular unit, three-dimensional electron microscopy was used to map the nanoscale surfaces of pericytes and ECs, revealing complex interwoven contacts. Building on the structural characterisation of the BNB, this thesis shows that the BNB can be reversibly opened by signals from Schwann cells. Using an inducible mouse model, we demonstrate that Schwann cells increase transcytosis in ECs while tight junction integrity remain intact, thereby enabling enhanced therapeutic delivery to the peripheral nervous system. Finally, single-cell RNA sequencing identified molecular pathways governing reversible BNB modulation. These data reveal potential regulators of barrier function and offer mechanistic insight into Schwann cell-vascular signalling. Collectively, this work defines the multicellular structure and nanoscale organisation of the BNB, and uncovers mechanisms by which it may be modulated. These findings open avenues for targeted therapeutic delivery across neural blood barriers.

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