Microglia care for neurons through tunneling nanotubes [Dataset 2 Microglia mRNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE209971 | GEO | 2023/12/01
REPOSITORIES: GEO
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Project description:Microglia care for neurons through tunneling nanotubes [Dataset 2 Microglia mRNA-seq]
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Project description:We report the exchange of alpha-synuclein aggregates from one cell to another and examined transcriptomic changes following protein exchange. By obtaining 12,461 genes from isolated RNA samples, we performed differential expression analysis and generated gene ontology enrichment and network analysis. Differential expression (DE) analysis comparing alpha-synuclein-treated with untreated microglia identified 687 upregulated and 1502 downregulated genes. Upregulated genes were linked to inflammation, apoptosis, ER stress and intracellular protein targeting, while downregulated genes included categories related to mitosis, cytoskeleton and vesicle mediated transport. Co-culturing alpha-synuclein treated with untreated microglia largely suppressed the inflammatory and apoptotic phenotype of microglia thereby rescuing cells from cell death.
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Project description:Tunneling nanotubes (TNTs) are thin F-actin based membranous structures that form continuous cytoplasmic bridges between cells over distances ranging from several hundred nm up to 100 µm. They allow cell-to-cell communication by facilitating the transfer of different cargoes directly from cytoplasma to cytoplasma of the connected cells, including organelles (lysosomes, mitochondria), micro or mRNAs, pathogens, and misfolded proteins (for example prion proteins, tau or α-synuclein aggregates). TNTs could play major roles in various diseases, including neurodegenerative diseases or cancers of different types. TNT formation is highly dynamic and depends on cellular stresses and actin regulators. However, the mechanisms of TNT formation and TNT molecular components and regulators are still poorly understood. Because of their size, of some common components, of the ability to transfer cellular material to remote cells and because TNTs are fragile and easily broken and released in cell culture supernatants (where EVs are also found), TNTs were difficult to distinguish from EVs for their composition and function. With the goal of identifying structural components of TNTs, beside actin filaments, and possibly markers and regulators of these structures, we established a protocol of purification from U2OS cultured cells, allowing to separate TNTs from extracellular vesicles (EVs) and from cell bodies. We obtained the full composition of TNTs, compared to EVs.
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Project description:Background: Cell-to-cell propagation of α-synuclein (α-syn) aggregates is thought to contribute to the pathogenesis of Parkinson’s disease (PD) and underlie the spread of α-syn neuropathology. Increased pro-inflammatory cytokine levels and activated microglia are present in PD and activated microglia can promote α-syn aggregation. However, it is unclear how microglia influence α-syn cell-to-cell transfer. Methods: We developed a clinically relevant mouse model to monitor α-syn prion-like propagation between cells; we transplanted wild-type mouse embryonic midbrain neurons into a mouse striatum overexpressing human α-syn (huα-syn) following adeno-associated viral injection into the substantia nigra. In this system, we depleted or activated microglial cells and determined the effects on the transfer of huα-syn from host nigrostriatal neurons into the implanted dopaminergic neurons, using the presence of huα-syn within the grafted cells as a readout. Results: First, we compared α-syn cell-to-cell transfer between host mice with a normal number of microglia to mice in which we had pharmacologically ablated 80% of the microglia from the grafted striatum. With fewer host microglia, we observed increased accumulation of huα-syn in grafted dopaminergic neurons. Second, we assessed the transfer of α-syn into grafted neurons in the context of microglia activated by one of two stimuli, lipopolysaccharide (LPS) or interleukin-4 (IL-4). LPS exposure led to a strong activation of microglial cells (as determined by microglia morphology and cytokine production) and significantly higher amounts of huα-syn in grafted neurons. In contrast, injection of IL-4 did not change the proportion of grafted dopamine neurons that contained huα-syn relative to controls. RNA sequencing analysis revealed differential gene expression between LPS and IL-4 injected mice; many genes were upregulated in LPS including those involved with the inflammatory response. Conclusions: The absence or the hyperstimulation of microglia affected α-syn transfer in the brain. Our results suggest that under resting, non-inflammatory conditions, microglia modulate the transfer of α-syn. Pharmacological regulation of neuroinflammation could represent a future avenue for limiting the spread of PD neuropathology.
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Project description:Intercellular communication within the bone marrow niche significantly influences leukemogenesis and the sensitivity of leukemic cells to therapy. However, the landscape of possible cell-cell interactions is still incomplete. Tunneling nanotubes (TNTs) are a novel mode of intercellular cross-talk. They are long, thin membranous conduits that enable the direct transfer of various cargo between cells. The present study found that TNTs are formed between leukemic and bone marrow stromal cells. Confocal three-dimensional reconstructions, correlative light-electron microscopy, and electron tomography provided evidence that TNTs transfer cellular vesicles between cells. The quantitative analysis demonstrated the stimulation of TNT-mediated vesicle transfer from stromal cells to leukemic cells by the stromal component. The vesicular cargo that was received from stroma cells conferred resistance to anti-leukemic treatment. Moreover, specific sets of proteins with a potential role in survival and the drug response were transferred within these vesicles. Altogether, we found that TNTs are involved in a novel and potent mechanism that participates in leukemia-stroma cross-talk and the stroma-mediated cytoprotection of leukemic cells. Our findings implicate TNT connections as a possible target for therapeutic interventions within the leukemia microenvironment to attenuate stroma-conferred protection.
2022-02-16 | PXD011013 | Pride
Project description:Intercellular communication within the bone marrow niche significantly influences leukemogenesis and the sensitivity of leukemic cells to therapy. However, the landscape of possible cell-cell interactions is still incomplete. Tunneling nanotubes (TNTs) are a novel mode of intercellular cross-talk. They are long, thin membranous conduits that enable the direct transfer of various cargo between cells. The present study found that TNTs are formed between leukemic and bone marrow stromal cells. Confocal three-dimensional reconstructions, correlative light-electron microscopy, and electron tomography provided evidence that TNTs transfer cellular vesicles between cells. The quantitative analysis demonstrated the stimulation of TNT-mediated vesicle transfer from stromal cells to leukemic cells by the stromal component. The vesicular cargo that was received from stroma cells conferred resistance to anti-leukemic treatment. Moreover, specific sets of proteins with a potential role in survival and the drug response were transferred within these vesicles. Altogether, we found that TNTs are involved in a novel and potent mechanism that participates in leukemia-stroma cross-talk and the stroma-mediated cytoprotection of leukemic cells. Our findings implicate TNT connections as a possible target for therapeutic interventions within the leukemia microenvironment to attenuate stroma-conferred protection.
2019-11-11 | PXD013504 | Pride