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Characterizing Hypoxia-Orchestrated Post-Stroke Changes in Oligodendrocyte Precursor Cells for Improved Stroke Cell Therapy

ABSTRACT: Oligodendrocyte precursor cells (OPCs) are traditionally known for their role in differentiating into oligodendrocytes, thereby contributing to myelination. Additionally, it has been increasingly recognized that OPCs actively modify their characteristics in response to the surrounding environment, exhibiting various other functions. However, how and when OPCs change their characteristics after acute ischemic stroke, and the contribution of these changes to post-stroke recovery, are not well understood. In this study, we aimed to transcriptionally characterize the changes in OPCs during acute ischemic stroke and develop therapies to support these changes. For this purpose, we first leveraged mouse single-cell RNA sequencing (scRNAseq) datasets to create a “middle cerebral artery occlusion (MCAO) atlas.” Crucially, we identified the distinct appearance of “angiogenic” OPCs in the subacute phase and “oligogenic” OPCs in the chronic phase after MCAO, contributing to angiogenesis and remyelination, respectively. Furthermore, we successfully induced OPCs ex vivo with similar functional characteristics to “angiogenic” OPCs through severe hypoxic preconditioning. The intravenous transplantation of these hypoxia-preconditioned OPCs more efficiently promoted post-stroke angiogenesis, reduced infarct size, and improved neurological function after MCAO compared to normally treated OPCs. Finally, we demonstrated that mild hypoxia at least partially contributes to the generation of “oligogenic” OPCs. Therefore, following acute ischemic stroke, OPCs sense oxygen levels and undergo phenotypic changes to exhibit functions required at specific times. Importantly, therapies supporting these phenotypic changes hold great promise for improving recovery from damage caused by acute ischemic stroke, for which current available treatments focus on quickly restoring blood flow.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE275670 | GEO | 2025/11/09

REPOSITORIES: GEO

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Project description:Astrogliosis is a hallmark of the response to brain ischemia, comprised of changes in gene expression and morphology. Hsp72 protects from cerebral ischemia, and although several mechanisms of protection have been investigated, effects on astrocyte activation are unknown. To identify potential mechanisms of protection, gene expression was assessed in mice subjected to middle cerebral artery (MCAO) or sham surgery, of either wildtype (WT) or Hsp72-overexpressing (Hsp72Tg) mice. After stroke, both genotypes exhibited genes related to cell death, stress response, and immune response. Furthermore, genes indicative of astrocyte activation, including cytoskeletal proteins and cytokines, were upregulated. To measure astrocyte activation after stroke, detailed histological and morphological analyses were performed in the cortical penumbra after stroke using unbiased stereology. Consistent with other reports, we observed a marked and persistent increase in glial fibrillary acidic protein (GFAP ) as soon as 3 hours after MCAO. In contrast, vimentin immunoreactivity appeared 12-24 hours after stroke, peaked at 72 hours, and returned to baseline after 30 days. Surprisingly, no change in overall astrocyte number was observed based on glutamine synthetase (GS) immunoreactivity. To determine if Hsp72Tg mice exhibited altered astrocyte activation compared to WT controls, morphological evaluation by fractal analysis was used. Overexpression of Hsp72 reduced astrocyte cell area, arbor area, and to a lesser extent fractal dimension, 72 hours following stroke. In conclusion, in vivo overexpression of Hsp72 alters gene expression following stroke, including genes involved in astrocyte activation, and decreases astrocyte activation acutely following MCAO. Thus, modulation of astrogliosis may be a neuroprotective mechanism exerted by Hsp72 after ischemia. A total of 10 samples were analyzed, with 5 of each genotype, wildtype (WT) and Hsp72-overexpressing (Hsp72Tg) mice. Of the 5 in each group, 3 received middle cerebral artery occlusion (MCAO) and 2 received a sham surgery. The sham samples serve as the controls for the MCAO samples in each genotype. All samples were taken from the ischemic or control hemisphere 24 hours after surgery.

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Characterizing Hypoxia-Orchestrated Post-Stroke Changes in Oligodendrocyte Precursor Cells for Improved Stroke Cell Therapy

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