ArticleNeurobiology of disease2021
Neonatal stroke enhances interaction of microglia-derived extracellular vesicles with microglial cells.
Article in Neurobiology of disease, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 8 citations in OpenAlex.
- Lipid metabolism, microglia, and stroke.Neural regeneration research · 2026Article
- Deep chemical structure graph learning deciphers the lipotoxicity code of hypertriglyceridemic pancreatitis.NPJ digital medicine · 2026Article
- Extracellular vesicles derived from different brain tissue cells: A potential therapeutic measure for hypoxic-ischemic brain injury in immature brains.Histology and histopathology · 2025Review
- Hepatic sphingomyelin phosphodiesterase 3 promotes steatohepatitis by disrupting membrane sphingolipid metabolism.Cell metabolism · 2025Article
- Hypoxic Human Microglia Promote Angiogenesis Through Extracellular Vesicle Release.International journal of molecular sciences · 2024Article
- Immune-Neurovascular Interactions in Experimental Perinatal and Childhood Arterial Ischemic Stroke.Stroke · 2024Review
- The Extracellular Vesicle Citrullinome and Signature in a Piglet Model of Neonatal Seizures.International journal of molecular sciences · 2023Article
- Vascular Smooth Muscle Cell Neutral Sphingomyelinase 2 in the Release of Exosomes and Vascular Calcification.International journal of molecular sciences · 2022Review
- Switching Roles: Beneficial Effects of Adipose Tissue-Derived Mesenchymal Stem Cells on Microglia and Their Implication in Neurodegenerative Diseases.Biomolecules · 2022Review
- The multiple faces of extracellular vesicles released by microglia: Where are we 10 years after?Frontiers in cellular neuroscience · 2022Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Microglial cells support brain homeostasis under physiological conditions and modulate brain injury in a context-dependent and brain maturation-dependent manner. Microglial cells protect neonatal brain from acute stroke. While microglial signaling via direct cell-cell interaction and release of variety of molecules is intensely studied, less is known about microglial signaling via release and uptake of extracellular vesicles (EVs). We asked whether neonatal stroke alters release of microglial EVs (MEV) and MEV communication with activated microglia. We pulled down and plated microglia from ischemic-reperfused and contralateral cortex 24 h after transient middle cerebral artery occlusion (tMCAO) in postnatal day 9 mice, isolated and characterized microglia-derived microvesicles (P3-MEV) and exosomes (P4-MEV), and determined uptake of fluorescently labeled P3-MEV and P4-MEV by plated microglia derived from ischemic-reperfused and contralateral cortex. We then examined how reducing EVs release in neonatal brain-by intra-cortical injection of CRISPR-Cas9-Smpd3/KO (Smpd3/KD) to downregulate Smpd3 gene to disrupt neutral sphingomyelinase-2 (N-SMase2)-impacts P3-MEV and P4-MEV release and stroke injury. Both size and protein composition differed between P3-MEV and P4-MEV. tMCAO further altered protein composition of P3-MEV and P4-MEV and significantly, up to 5-fold, increased uptake of both vesicle subtypes by microglia from ischemic-reperfused regions. Under physiological conditions neurons were the predominant cell type expressing N-SMase-2, an enzyme involved in lipid signaling and EVs release. After tMCAO N-SMase-2 expression was diminished in injured neurons but increased in activated microglia/macrophages, leading to overall reduced N-SMase-2 activity. Compared to intracerebral injection of control plasmid, CRISPR-Cas9-Smpd3/Ct, Smpd3/KD injection further reduced N-SMase-2 activity and significantly reduced injury. Smpd3 downregulation decreased MEV release from injured regions, reduced Smpd3/KD-P3-MEV uptake and abolished Smpd3/KD-P4-MEV uptake by microglia from ischemic-reperfused region. Cumulatively, these data demonstrate that microglial cells release both microvesicles and exosomes in naïve neonatal brain, that the state of microglial activation determines both properties of released EVs and their recognition/uptake by microglia in ischemic-reperfused and control regions, suggesting a modulatory role of MEV in neonatal stroke, and that sphingosine/N-SMase-2 signaling contributes both to EVs release and uptake (predominantly P4-MEV) after neonatal stroke.
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Registered trials
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