Ferroptosis in oligodendrocyte progenitor cells mediates white matter injury after hemorrhagic stroke
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ABSTRACT:
PROVIDER: PRJNA808986 | ENA |
REPOSITORIES: ENA
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Project description:Oligodendrocyte progenitor cells (OPCs) differentiate to myelin-producing mature oligodendrocytes and enwrap growing or demyelinated axons during development and post central nervous diseases. Failure of remyelination due to cell death or undifferentiation of OPC contributes to severe neurologic deficits and motor dysfunction. However, how to prevent the cell death of OPCs is still poorly understood, especially in hemorrhagic diseases. In this current study, we injected autologous blood into the mouse lateral ventricular to study the hemorrhage induced OPC cell death in vivo. The integrity of the myelin sheath of the corpus callosum was disrupted post intraventricular hemorrhage (IVH) assessed by using magnetic resonance imaging, immunostaining, and transmission electron microscopy. Consistent with the severe demethylation, we observed massive cell death of oligodendrocyte lineages in the periventricular area. In addition, we found that ferroptosis is the major cell death form in Hemin-induced OPC death by using RNA-seq analysis, and the mechanism was glutathione peroxidase 4 (GPx4) expression and activity reduction-resulted lipid peroxide accumulation. Furthermore, inhibition of ferroptosis rescued OPC cell death in vitro, and in vivo attenuated IVH-induced white matter injury and promoted recovery of neurological function. These data demonstrate that ferroptosis is an essential form of OPC cell death in hemorrhagic stroke, and rescuing ferroptotic OPCs could serve as a therapeutic target for stroke and related diseases.
2022-02-24 | GSE197104 | GEO
Project description:Tissue progenitors maintain the integrity of organ systems through aging and stress. The brain’s white matter regions experience ischemic lesions and age-dependent degeneration. Brain white matter contains progenitors, oligodendrocyte precursor cells (OPCs), which can repair some insults. The response of OPCs to white matter ischemia and aging is not known. We characterized the response of OPCs to white matter stroke using OPC reporter mice, cell migration tracking, OPC specific RNA sequencing, and mechanistic studies in candidate biochemical pathways in the aged brain. White matter stroke induces initial proliferation of local OPCs but blocks differentiation, shunting a portion into astrocytes. Candidate signaling pathways for this differentiation block including novel interactions of inhibin and matrilin-2 and new roles of NgR1 ligands following white matter stroke. Stroke induces inhibin expression in astrocytes and downregulates OPC matrilin-2 that contributes into OPC differentiation block. Antagonism of NgR1 ligands promotes OPC differentiation by attenuating the OPC astrocytic transformation and enhances functional recovery from stroke in aged animals.
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Project description:The repair of white matter damage is of paramount importance for functional recovery after brain injuries.We report that interleukin-4 (IL-4) promotes oligodendrocyte regeneration and remyelination. IL-4 receptor expression was detected in a variety of glial cells after ischemic brain injury, including oligodendrocyte lineage cells. IL-4 deficiency in knockout mice resulted in greater deterioration of white matter over 14 days after stroke. Consistent with these findings, intranasal delivery of IL-4 nanoparticles after stroke improved white matter integrity and attenuated long-term sensorimotor and cognitive deficits in wild-type mice, as revealed by histological immunostaining, electron microscopy, diffusion tensor imaging, and electrophysiology. The selective effect of IL-4 on remyelination was verified in an ex vivo organotypic model of demyelination. By leveraging primary oligodendrocyte progenitor cells (OPCs), microglia-depleted mice, and conditional OPC-specific PPARγ knockout mice, we discovered a direct salutary effect of IL-4 on oligodendrocyte differentiation that was mediated by the PPARγ axis. Our findings reveal a new regenerative role of IL-4 in the CNS, which lies beyond its known immunoregulatory functions on microglia/macrophages or peripheral lymphocytes. Therefore, intranasal IL-4 delivery may represent a novel therapeutic strategy to improve white matter integrity in stroke and other brain injuries.
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Project description:The precise mechanisms underlying the salutary effects of regulatory T cells (Tregs) on long-term tissue repair after stroke remain elusive. Here, , we performed RNAseq analysis on sorted CD4+CD25+Foxp3(GFP)+ Tregs from the ischemic brain and blood of DTR stroke mice 14d after surgery and from the blood of sham DTR mice. The unique patterns of gene expression of brain-infiltrating Tregs exhibited a significant enrichment for genes with functions in immunoregulation and cell-cell interactions, especially the activation of phagocytes.
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Project description:The proteome of cerebral thrombi from patients recanalized by mechanical thrombectomy in an acute phase of stroke was carried out to determine biomarkers of stroke radio-clinical outcomes for stroke physicians (clinical outcome and mortality at 3 months, intracranial hemorrhagic transformation, etc.). Proteome of cerebral thrombi was also used to elucidate stroke physiopathology (paradoxical effect of glucose in acute phase of stroke) and evaluate recanalization treatments (intravenous thrombolysis by rt-PA and/or thrombectomy efficiency). Retro-MATISSE (Molecular Analysis of Thrombus in Ischemic Stroke prognosiS and Etiology) database was incremented by proteomic analyses of cerebral thrombi successfully retrieved from all consecutive stroke patients (n=47) with large vessel occlusion treated by mechanical thrombectomy in acute phase between December 2020 and May 2021 in the intensive care stroke unit of the University Hospital of Marseille (France).
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