The roles of Hmgb1-signalling in injury and repair of human brain tissue and white matter after traumatic brain injury

Ved, Ronak 2025. The roles of Hmgb1-signalling in injury and repair of human brain tissue and white matter after traumatic brain injury. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide. Widespread recognition of a neuroinflammatory response following acute TBI raised the possibility of a new option for therapeutic intervention. However, pharmacological strategies have largely failed to translate to the clinical setting, potentially due to: (i) suboptimal understanding of the relationships between neuroinflammation and brain injury/repair; and (ii) differences between animal models and human central nervous system (CNS) injury. Whilst animal-tissue evidence implicates High Mobility Group Box protein 1 (HMGB1) signalling as a promising mediator of cell damage after brain injury, studies of this signalling pathway in human tissue are sparse. This thesis begins to assess the utility of a novel, living human tissue culture paradigm, (The HiSpot©) to model TBI, and assess the role of HMGB1-signalling after human neurotrauma. It was found that neurotrauma can be modelled using HiSpots© and a standardised weight drop injury. This model of injury induces cell death, neuronal loss, and glial proliferation. HMGB1-signalling pathways were found to be upregulated in traumatised cultures when compared to equivalent-aged control HiSpots©. HMGB1-signalling antagonists consistently reduced cell death for injured HiSpots©, whilst also reducing the degree of neuroinflammation in these cultures compared to controls. HMGB1-signalling modulation did not influence the proliferation of glial or white matter progenitors after injury. This model could therefore be used to help improve the understanding of acute human TBI; it could be adapted to further probe mechanisms behind early tissue damage after neurotrauma, and to rapidly screen proposed pharmacological agents for their potential efficacy in human brain cell neuroprotection in the early stages after TBI. Furthermore, data from this thesis also highlights HMGB1-signalling modulation as a promising therapeutic target for addressing the injurious consequences of acute neuroinflammation after TBI in humans.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Subjects:	R Medicine > R Medicine (General)
Date of First Compliant Deposit:	14 May 2026
Last Modified:	14 May 2026 15:24
URI:	https://orca.cardiff.ac.uk/id/eprint/186805

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