2. Academic Validation
  3. Extracellular vesicle-associated cholesterol supports the regenerative functions of macrophages in the brain

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

  • J Extracell Vesicles. 2023 Dec;12(12):e12394. doi: 10.1002/jev2.12394.
Sam Vanherle 1 2,  Jeroen Guns 1 2,  Melanie Loix 1 2,  Fleur Mingneau 1 2,  Tess Dierckx 1 2,  Flore Wouters 1 2,  Koen Kuipers 1 2,  Tim Vangansewinkel 3 4,  Esther Wolfs 3,  Paula Pincela Lins 3 5,  Annelies Bronckaers 3,  Ivo Lambrichts 3,  Jonas Dehairs 6,  Johannes V Swinnen 6,  Sanne G S Verberk 1 2,  Mansour Haidar 1 2,  Jerome J A Hendriks 1 2,  Jeroen F J Bogie 1 2
Affiliations

Affiliations

  • 1 Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
  • 2 University MS Center Hasselt, Pelt, Belgium.
  • 3 Department of Cardio and Organs Systems, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.
  • 4 VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, University of Leuven, Leuven, Belgium.
  • 5 Health Department, Flemish Institute for Technological Research, Mol, Belgium.
  • 6 Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven Cancer Institute, University of Leuven, Leuven, Belgium.
PMID: 38124258 DOI: 10.1002/jev2.12394
Abstract

Macrophages play major roles in the pathophysiology of various neurological disorders, being involved in seemingly opposing processes such as lesion progression and resolution. Yet, the molecular mechanisms that drive their harmful and benign effector functions remain poorly understood. Here, we demonstrate that extracellular vesicles (EVs) secreted by repair-associated macrophages (RAMs) enhance remyelination ex vivo and in vivo by promoting the differentiation of oligodendrocyte precursor cells (OPCs). Guided by lipidomic analysis and applying Cholesterol depletion and enrichment strategies, we find that EVs released by RAMs show markedly elevated Cholesterol levels and that Cholesterol abundance controls their reparative impact on OPC maturation and remyelination. Mechanistically, EV-associated Cholesterol was found to promote OPC differentiation predominantly through direct membrane fusion. Collectively, our findings highlight that EVs are essential for Cholesterol trafficking in the brain and that changes in Cholesterol abundance support the reparative impact of EVs released by macrophages in the brain, potentially having broad implications for therapeutic strategies aimed at promoting repair in neurodegenerative disorders.

Keywords

cholesterol; extracellular vesicle; oligodendrocyte precursor cell differentiation; remyelination; repair-associated macrophage.

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