Hanyou Liu, Zhenwei Li, Ruxu Geng, Lingui Gu, Xinjie Bao
Our analysis suggests that post-ischemic brain repair involves time-associated multicellular programs integrating inflammation resolution, astrocyte-mediated repair, oligodendrocyte maturation, and neurovascular remodeling. These findings provide a hypothesis-generating transcriptomic framework for understanding stage-associated brain repair after ischemic stroke and may inform the development of time-aware therapeutic strategies targeting cell-state transitions and intercellular communication.
BACKGROUND: Ischemic stroke triggers complex multicellular responses across neurons, glia, and the neurovascular unit, but the temporal coordination among these cell types remains incompletely understood. In this study, we integrated five publicly available mouse single-cell RNA sequencing datasets spanning the acute, subacute, and recovery phases after middle cerebral artery occlusion (MCAO), together with complementary rat single-nucleus RNA-seq data, to establish a time-resolved transcriptomic framework of post-ischemic brain repair.
RESULTS: Integrative single-cell analysis identified candidate multicellular communication patterns linking microglia, astrocytes, oligodendrocyte lineage cells, endothelial cells, and neurons during post-ischemic remodeling. Microglia exhibited an early transition from inflammatory activation toward lipid metabolic and neuroprotective programs. Astrocytes shifted from injury-associated reactive states to reparative phenotypes and emerged as central coordinators of intercellular communication. Oligodendrocyte progenitor cells activated maturation programs associated with remyelination, while the neurovascular unit underwent coordinated remodeling characterized by dynamic signaling interactions among astrocytes, microglia, endothelial cells, and neurons. Selected glial and neurovascular signaling patterns were also detectable in the complementary rat snRNA-seq data.
CONCLUSIONS: Our analysis suggests that post-ischemic brain repair involves time-associated multicellular programs integrating inflammation resolution, astrocyte-mediated repair, oligodendrocyte maturation, and neurovascular remodeling. These findings provide a hypothesis-generating transcriptomic framework for understanding stage-associated brain repair after ischemic stroke and may inform the development of time-aware therapeutic strategies targeting cell-state transitions and intercellular communication.