Biology subjects

Dando, S. J.

Publications and source records attributed to Dando, S. J..

4 recordsLinked to original sources

bioRxiv2026

Linking Systemic Endotoxin Exposure to Retinal Microglia Migration Through Mathematical Modeling

Microglia are the resident immune cells of the central nervous system (CNS), including the brain, spinal cord, and retina, where they serve as the first line of defense against infection and inflammation. Dys-regulated microglia activity has been implicated in vision-threatening diseases, highlighting the need to understand how retinal microglia respond to inflammatory stimuli. Importantly, acute inflammation induces substantial redistribution of microglia across retinal layers, yet the mechanisms governing this migration remain poorly understood. Here, we develop the first mathematical model of retinal microglia migration during inflammation to determine how inflammatory exposure, administration route, and species-specific pharmacokinetics shape redistribution dynamics across the retina. The model couples lipopolysaccharide (LPS) pharmacokinetics with microglia migration between the outer plexiform layer (OPL), inner plexiform layer (IPL), and ganglion cell layer/nerve fiber layer (GCL/NFL). Model parameters are calibrated to retinal microglia density measurements from mice following LPS (bacterial endotoxin) challenge, before extending the framework to rats and rhesus macaques to investigate species-specific responses. Simulations also compare how administration route, i.e. intravenous or intraperitoneal injections, alter retinal LPS exposure and subsequent microglia redistribution. Our results suggest that redistribution patterns are driven primarily by LPS delivery route and species-specific pharmacokinetics, rather than the initial microglia distribution across retinal layers. Together, these findings provide new insight into immune cell reorganization in the inflamed retina and demonstrate how mechanistic mathematical modeling can be adapted across experimental designs, administration routes, and animal species.

immunology↗

bioRxiv2026

Regional and sub-regional microglial heterogeneity in the steady-state mouse brain and retina

CNS-resident immune cells are uniquely adapted to their microenvironment; however, the extent of their regional specialisation remains unclear. We combined morphometric and transcriptomic profiling of microglia across the healthy adult mouse CNS, including the olfactory bulbs, cortex, hippocampus, cerebellum and retina, to define their regional and sub-regional heterogeneity. Bulk RNA-sequencing revealed region-specific signatures, with retinal microglia showing the most divergent transcriptomes, and genes related to antigen presentation, phagocytosis and chemokine signalling among the top differentially expressed genes. Single-cell RNA sequencing identified predominantly homeostatic microglia across all examined regions, alongside smaller clusters of interferon-responsive, chemokine-enriched, apolipoprotein-enriched and proliferative microglia. Apolipoprotein-enriched microglia were restricted to the olfactory bulbs, whereas interferon-responsive microglia were most abundant in the retina. Single-cell profiling of human retinal microglia confirmed clusters enriched for interferon-stimulated genes. Together, this study reveals previously unrecognised microglial heterogeneity within the healthy brain and eye and provides a comparison of microglia transcriptomes across different neuroanatomical regions of the CNS.

immunology↗

bioRxiv2025

Therapeutic targeting of oligodendrocytes in an agent-based model of multiple sclerosis

Multiple sclerosis (MS) is a neurodegenerative disease in which misdirected, persistent activity of the immune system degrades the protective myelin sheaths of nerve axons. Historically, treatment of MS has relied on disease-modifying therapies that involve immunosuppression, such as targeting of the blood-brain barrier (BBB) to restrict lymphocyte movement. New therapeutic ideas in the development pipeline are instead designed to promote populations of myelin producing cells, oligodendrocytes, by exploiting their innate resilience to the stressors of MS or restoring their numbers. Given the significant advancements made in immunological disease understanding due to mathematical and computational modelling, we sought to develop a platform to (1) interrogate our understanding of the neuroimmunological mechanisms driving MS development and (2) examine the impact of different therapeutic strategies. To this end we propose a novel, open-source, agent-based model of lesion development in the CNS. Our model includes crucial populations of T cells, perivascular macrophages, and oligodendrocytes. We examine the sensitivity of the model to key parameters related to disease targets and conclude that lesion stabilisation can be achieved when targeting the integrated stress response of oligodendrocytes. Most significantly, complete prevention of lesion formation is observed when a combination of approved BBB-permeability targeting therapies and integrated-stress response targeting therapies is administered, suggesting the potential to strike a balance between a patients immune inflammation and their reparative capacity. Given that there are many open questions surrounding the etiology and treatment of MS, we hope that this malleable platform serves as a tool to test and generate further hypotheses regarding this disease. Author summaryMultiple sclerosis is a disease that is not yet fully understood and has no cure. Some patient phenotypes see little benefit from current therapeutic interventions besides symptomatic treatment. Typically, MS studies have focused on the prevention of damage to brain tissue. As such, there are unanswered questions about how to reverse the damage in the brain and spinal cord of MS patients caused by immune cells. In light of this there is an urgent need for mathematical modelling of new therapeutic strategies - some of which remain to be clinically examined - shifting the attention from the targeting of aberrant immune activity to the upregulation of resident, reparative cells called oligodendrocytes. Here, we have developed a mathematical model to probe the potential benefits of oligodendrocyte targeted therapies in silico. We focus on T cells as damaging agents and monitor oligodendrocyte function in response to their activity. We show that oligodendrocytes strongly influence the tissues ability to stabilise and even recover under persistent, harmful immune activity. In practice, these therapies could hold the potential to unlock neuroprotection by means of enhanced remyelination.

immunology↗

bioRxiv2024

Tissue-specific immune transcriptional signatures in the bordering tissues of the mouse brain and retina

BackgroundBordering the central nervous system (CNS) parenchyma are the pia mater (the innermost layer of the meninges enveloping the brain) and the choroid (underlying the retina). While near the neural parenchyma, the pia mater and choroid are external to the immune privileged environment of the brain and retina and thus are distinct immune compartments. This study aimed to characterise the transcriptomic signatures of immune cells within the pia mater and choroid bordering the healthy adult mouse CNS. MethodsBrains and eyes were obtained from 7-week-old female C57Bl/6J mice. Pia mater-enriched tissue and choroid were dissected and processed for fluorescence activated cell sorting of CD45+ immune cells and single cell RNA-sequencing. Additionally, single cell RNA-sequencing was performed on immune cells isolated from choroid obtained from human donor eye tissue. Immunostaining and confocal microscopy of wholemount tissue were used to validate selected immune cell populations in situ. ResultsA total of 3,606 cells were sequenced from mouse tissues, including 1,481 CD45+ cells from pia mater-enriched tissue and 2,125 CD45+ cells from choroid. Clustering and differential gene expression analysis revealed heterogeneous subtypes of monocytes/macrophages, dendritic cells, T cells and B cells. While some clusters were common to both pia mater and choroid, others exhibited tissue-specific gene expression profiles and potential functional specialisations. Analysis of 6,501 CD45+ cells sequenced from human choroid identified similar immune cell populations to mouse choroid. ConclusionsThis study provides a detailed characterisation of the molecular signatures of immune cells within the vascular connective tissues bordering the healthy brain and retina, and their potential roles in immune protection.

immunology↗