Extracellular vesicle‐associated cholesterol supports the regenerative functions of macrophages in the brain

Vanherle, Sam; Guns, Jeroen; Loix, Melanie; Mingneau, Fleur; Dierckx, Tess; Wouters, Flore; Kuipers, Koen; Vangansewinkel, Tim; Wolfs, Esther; Lins, Paula Pincela; Bronckaers, Annelies; Lambrichts, Ivo; Dehairs, Jonas; Swinnen, Johannes V.; Verberk, Sanne G. S.; Haidar, Mansour; Hendriks, Jerome J. A.; Bogie, Jeroen F. J.

doi:10.1002/jev2.12394

Cited by 4 publications

(1 citation statement)

References 95 publications

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“…Lipids are essential components of the EV architecture, and the lipid bilayer could potentially offer a unique perspective into the origin, function, and possible pathological alterations of EVs in joint diseases. Furthermore, evidence is accumulating that EV-associated lipids may be actively involved in the functional modulation of target cells by EVs [82,83] . Hence, the exploration of the EV lipidome provides an exciting avenue for future research, shedding light on the complex relationship between lipids and other EV components and the role of EV-associated lipids in intercellular communication and in (patho)physiological processes.…”

Section: Lipids: Their Importance For Ev Researchmentioning

confidence: 99%

Synovial fluid extracellular vesicles as arthritis biomarkers: the added value of lipid-profiling and integrated omics

Varela,

van de Lest,

van Weeren

et al. 2024

Extracell Vesicles Circ Nucleic Acids

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Arthritis, a diverse group of inflammatory joint disorders, poses great challenges in early diagnosis and targeted treatment. Timely intervention is imperative, yet conventional diagnostic methods are not able to detect subtle early symptoms. Hence, there is an urgent need for specific biomarkers that discriminate between different arthritis forms and for early diagnosis. The pursuit of such precise diagnostic tools has prompted a growing interest in extracellular vesicles (EVs). EVs, released by cells in a regulated fashion, are detectable in body fluids, including synovial fluid (SF), which fills the joint space. They provide insights into the intricate molecular landscapes of arthritis, and this has stimulated the search for minimally invasive EV-based diagnostics. As such, the analysis of EVs in SF has become a focus for identifying EV-based biomarkers for joint disease endotyping, prognosis, and progression. EVs are composed of a lipid bilayer and a wide variety of different cargo types, of which proteins and RNAs are widely investigated. In contrast, membrane lipids of EVs, especially the abundance, presence, or absence of specific lipids and their contribution to the biological activity of EVs, are largely overlooked in EV research. Furthermore, the identification of specific combinations of different EV components acting in concert in EVs can fuel the definition of composite biomarkers. We here provide a state-of-the-art overview of the knowledge on SF-derived EVs with emphasis on lipid analysis and we give an example of the added value of integrated proteomics and lipidomics analysis in the search for composite EV-associated biomarkers.

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Section: Lipids: Their Importance For Ev Researchmentioning

confidence: 99%

Synovial fluid extracellular vesicles as arthritis biomarkers: the added value of lipid-profiling and integrated omics

Varela,

van de Lest,

van Weeren

et al. 2024

Extracell Vesicles Circ Nucleic Acids

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Microglia Morphological Response to Mesenchymal Stromal Cell Extracellular Vesicles Demonstrates EV Therapeutic Potential for Modulating Neuroinflammation

Daga,

Larey,

Morfin

et al. 2024

Preprint

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BackgroundMesenchymal stromal cell derived extracellular vesicles (MSC-EVs) are a promising therapeutic for neuroinflammation. MSC-EVs can interact with microglia, the resident immune cells of the brain, to exert their immunomodulatory effects. In response to inflammatory cues, such as cytokines, microglia undergo phenotypic changes indicative of their function e.g. morphology and secretion. However, these changes in response to MSC-EVs are not well understood. Additionally, no disease-relevant screening tools to assess MSC-EV bioactivity exist, which has further impeded clinical translation. Here, we developed a quantitative, high throughput morphological profiling approach to assess the response of microglia to neuroinflammation-relevant signals and whether this morphological response can be used to indicate the bioactivity of MSC-EVs.ResultsUsing an immortalized human microglia cell-line, we observed increased size (perimeter, major axis length) and complexity (form factor) upon stimulation with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α). Upon treatment with MSC-EVs, the overall morphological score (determined using principal component analysis) shifted towards the unstimulated morphology, indicating that MSC-EVs are bioactive and modulate microglia. The morphological effects of MSC-EVs in TNF-γ/IFN-α stimulated cells were concomitant with reduced secretion of 14 chemokines/cytokines (e.g. CXCL6, CXCL9) and increased secretion of 12 chemokines/cytokines (e.g. CXCL8, CXCL10). Proteomic analysis of cell lysates revealed significant increases in 192 proteins (e.g. HIBADH, MEAK7, LAMC1) and decreases in 257 proteins (e.g. PTEN, TOM1, MFF) with MSC-EV treatment. Of note, many of these proteins are involved in regulation of cell morphology and migration. Gene Set Variation Analysis revealed upregulation of pathways associated with immune response, such as regulation of cytokine production, immune cell infiltration (e.g. T cells, NK cells) and morphological changes (e.g. Semaphorin, RHO/Rac signaling). Additionally, changes in microglia mitochondrial morphology were measured suggesting that MSC-EV modulate mitochondrial metabolism.ConclusionThis study comprehensively demonstrates the effects of MSC-EVs on human microglial morphology, cytokine secretion, cellular proteome, and mitochondrial content. Our high-throughput, rapid, low-cost morphological approach enables screening of MSC-EV batches and manufacturing conditions to enhance EV function and mitigate EV functional heterogeneity in a disease relevant manner. This approach is highly generalizable and can be further adapted and refined based on selection of the disease-relevant signal, target cell, and therapeutic product.

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The interplay of inflammation and remyelination: rethinking MS treatment with a focus on oligodendrocyte progenitor cells

Zveik,

Rechtman,

Ganz

et al. 2024

Mol Neurodegeneration

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Background Multiple sclerosis (MS) therapeutic goals have traditionally been dichotomized into two distinct avenues: immune-modulatory-centric interventions and pro-regenerative strategies. Oligodendrocyte progenitor cells (OPCs) were regarded for many years solely in concern to their potential to generate oligodendrocytes and myelin in the central nervous system (CNS). However, accumulating data elucidate the multifaceted roles of OPCs, including their immunomodulatory functions, positioning them as cardinal constituents of the CNS’s immune landscape. Main body In this review, we will discuss how the two therapeutic approaches converge. We present a model by which (1) an inflammation is required for the appropriate pro-myelinating immune function of OPCs in the chronically inflamed CNS, and (2) the immune function of OPCs is crucial for their ability to differentiate and promote remyelination. This model highlights the reciprocal interactions between OPCs’ pro-myelinating and immune-modulating functions. Additionally, we review the specific effects of anti- and pro-inflammatory interventions on OPCs, suggesting that immunosuppression adversely affects OPCs’ differentiation and immune functions. Conclusion We suggest a multi-systemic therapeutic approach, which necessitates not a unidimensional focus but a harmonious balance between OPCs’ pro-myelinating and immune-modulatory functions.

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Extracellular vesicle‐associated cholesterol supports the regenerative functions of macrophages in the brain

Cited by 4 publications

References 95 publications

Synovial fluid extracellular vesicles as arthritis biomarkers: the added value of lipid-profiling and integrated omics

Synovial fluid extracellular vesicles as arthritis biomarkers: the added value of lipid-profiling and integrated omics

Microglia Morphological Response to Mesenchymal Stromal Cell Extracellular Vesicles Demonstrates EV Therapeutic Potential for Modulating Neuroinflammation

The interplay of inflammation and remyelination: rethinking MS treatment with a focus on oligodendrocyte progenitor cells

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