Biology subjects

Kooij, G.

Publications and source records attributed to Kooij, G..

4 recordsLinked to original sources

bioRxiv2026

Focal and subtle myelin damage in multiple sclerosis-derived post-mortem human brain slice cultures

The mechanisms that drive myelin damage as seen in demyelinating disorders such as multiple sclerosis remain incompletely understood. Much of our current knowledge is derived from animal models, but interspecies differences limit their relevance in the context of human pathology and could explain why various promising preclinical therapies failed during clinical translation. Human post-mortem organotypic brain slice cultures provide a unique platform to study human myelin biology, as they preserve genetic, cytoarchitectural, pathological and species-specific context. Here, we evaluated myelin integrity in a human post-mortem brain organotypic slice culture model and experimentally induce focal myelin damage. Human post-mortem organotypic slices cultures retain key features throughout the culturing period, but exhibit gradual cellular and myelin loss over time. Myelin fibres within the white matter remain detectable and present preserved structural and chemical integrity up to 13 days in vitro, indicated by the conserved paranodal and nodal organization and stable myelin spectroscopic signature. Delivery of lysophosphatidylcholine using cryogel scaffolds enables focal drug administration throughout the full depth of the slice with minimal diffusion into surrounding tissue and induces localized demyelination after lysophosphatidylcholine application. Similar focal application of the selective Nav1.6 stimulator {beta}-mammal scorpion toxin Cn2 induces subtle myelin destabilization. Overall, our results demonstrate the suitability of a human post-mortem brain organotypic slice culture model as an adequate platform for studying myelin damage in a human disease context.

neuroscience↗

bioRxiv2025

PIA SSN: Parallel Image Acquisition and Spatial Similarity Network for Tandem Mass Spectrometry Imaging

Unambiguous molecular annotations are essential to discern complex local biochemical processes in spatial biology. Here we present a scalable and broadly applicable platform for tandem mass spectrometry imaging (MS2I) that overcomes current limitations in annotation with MSI by integrating Parallel Image Acquisition (PIA) with a novel open-access computational framework, Spatial Similarity Networking (SSN). The PIA employs parallelized acquisition of untargeted MSI and targeted MS2I data using multiple inclusion lists to ensure spatially consistent and structure-resolved imaging of hundreds of molecular species in a single experiment. For molecular annotation, we have developed the SSN that complements PIA by leveraging spatial correlations among product ions through a graph-based analysis framework to enable confident molecular annotation even within highly complex MS2I datasets. Using this integrated approach, we successfully resolved and annotated 134 phospholipid isomers and isobars from mouse brain tissue and suggest confidence levels for annotation for the MSI community. Furthermore, we applied our platform to interrogate cholesterol metabolism in human multiple sclerosis brain tissue, achieving annotation of six novel brain-related oxysterols and revealing spatially correlated oxidation pathways linked to lesion severity. Together, PIA and SSN establish a new framework for large-scale, structure-specific mass spectrometry imaging, with broad implications for spatial metabolomics, lipidomics, and chemical pathology beyond current capabilities.

neuroscience↗

bioRxiv2022

Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity

The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T cell (Treg) differentiation and augments autoimmunity in an animal model of MS. Guided by RNA sequencing and lipidomics analysis, we found that absence of Scd1 promotes hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders.

immunology↗

bioRxiv2021

Single-cell profiling reveals periventricular CD56bright NK cell accumulation in multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease characterised by immune cell infiltration resulting in lesions that preferentially affect periventricular areas of the brain. Despite research efforts to define the role of various immune cells in MS pathogenesis, the focus has been on a few immune cell populations while full-spectrum analysis, encompassing others such as natural killer (NK) cells, has not been performed. Here, we used single-cell mass cytometry (CyTOF) to profile the immune landscape of brain periventricular areas - septum and choroid plexus - and blood from MS donors and controls with and without other neurological diseases. Using a 37-marker panel, we revealed the infiltration of T cells and antibody-secreting cells in periventricular brain regions and identified a novel NK cell signature specific to MS. CD56bright NK cells accumulated in the septum of MS donors, displaying an activated and migratory phenotype that was similar to that of CD56bright NK cells in their circulation. We validated this signature by multiplex immunohistochemistry and found that NK cells with high expression of granzyme K, which is typical of the CD56bright subset, accumulated in both periventricular lesions and the choroid plexus. Together, our multi-tissue single-cell data suggests that CD56bright NK cells infiltrate the periventricular brain regions in MS patients via both the blood-brain and blood-CSF barriers and brings NK cells to the spotlight of MS pathology.

immunology↗