Characterizing Hypoxia-Orchestrated Post-Stroke Changes in Oligodendrocyte Precursor Cells for Improved Stroke Cell Therapy
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. Overall design: To investigate the effect of a mild hypoxic preconditioning on ex vivo POCs, we conducted comparative bulk RNAseq of these mild hypoxic-preconditioned OPCs and normally-treated OPCs.