Exploring mast cell-mediated brain microvascular endothelial cell dysfunction in autism spectrum disorder and inflammation
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Authors
Ebbert, Katherine, Anne
Issue Date
2025-05
Type
Electronic thesis
Thesis
Thesis
Language
en_US
Keywords
Biomedical engineering
Alternative Title
Abstract
Autism Spectrum Disorder (ASD) represents a diverse collection of neurodevelopmental disorders characterized by persistent deficits in social communication and restricted or repetitive patterns of behavior. Despite diagnoses being based on these behavioral manifestations, ASD has detrimental implications for overall health, particularly in profound ASD. The development of effective treatment remains a challenge as the etiology of this heterogenous disorder remains poorly understood. Nevertheless, pathological features such as immune dysfunction, neuroanatomical abnormalities, and neuroinflammation are consistently observed. Under neuroinflammatory conditions, alterations in blood-brain barrier (BBB) integrity are commonly noted. Compromise of the BBB – which is designed to protect the brain from the periphery and maintain a homeostatic environment – leads to increased infiltration of neurotoxins, immune cells, and inflammatory mediators. This establishes a positive feedback loop of inflammation between the central and peripheral immune systems. BBB disruption has been suggested in ASD, yet impaired BBB function and stability and its implication in the pathogenesis of ASD remains largely obscure. Here, we explore this dysfunction along with potential therapeutics in the context of immune-BBB crosstalk between brain microvascular endothelial cells (BMECs), which are the primary constituents of the BBB, and mast cells (MCs), immune cells that have implications in ASD pathogenesis. Toward exploring BMEC-MC interactions under inflammatory conditions, we first established co-cultures of primary BMECs and immortalized MCs following inflammatory stimuli, investigating their individual and combined responses and exploring potential beneficial effects of two therapeutics: rapamycin and suramin. We then developed an ASD BMEC/neural cell co-culture system using induced pluripotent stem cells (iPSCs) to investigate combined dysregulation and response to MC secretory products. Finally, we explored the therapeutic potential of quercetin and the differential response of ASD BMECs following stimulation with minor or severe MC inflammatory stimuli. Together, we observed dysregulation of neural cells and BMECs from FXS donor iPSCs. These cells exhibited greater reactivity in response to medium conditioned by activated MCs – increasing production of inflammatory cytokines and adhesion molecules. Treatment by rapamycin and suramin showed slight beneficial effects by reducing extracellular chemokines and oxidative stress in BMEC/MC co-cultures. However, quercetin treatment exhibited potent inhibition of MC activation and mitigated MC-mediated BMEC production of adhesion molecules and inflammatory cytokines/chemokines in FXS and TD. These findings provide preliminary evidence of barrier and endothelial dysfunction in FXS. Further, we report the therapeutic potential of quercetin in the context of BMEC-MC dysfunction, which may prove promising in clinical manifestations of neuroinflammation and BBB impairment.
Description
May2025
School of Engineering
School of Engineering
Full Citation
Publisher
Rensselaer Polytechnic Institute, Troy, NY