Shared inflammatory glial cell signature after stab wound injury, revealed by spatial, temporal, and cell-type-specific profiling of the murine cerebral cortex

Abstract

Traumatic brain injury leads to a highly orchestrated immune- and glial cell response partially responsible for long-lasting disability and the development of secondary neurodegenerative diseases. A holistic understanding of the mechanisms controlling the responses of specific cell types and their crosstalk is required to develop an efficient strategy for better regeneration. Here, we combine spatial and single-cell transcriptomics to chart the transcriptomic signature of the injured male murine cerebral cortex, and identify specific states of different glial cells contributing to this signature. Interestingly, distinct glial cells share a large fraction of injury-regulated genes, including inflammatory programs downstream of the innate immune-associated pathways Cxcr3 and Tlr1/2. Systemic manipulation of these pathways decreases the reactivity state of glial cells associated with poor regeneration. The functional relevance of the discovered shared signature of glial cells highlights the importance of our resource enabling comprehensive analysis of early events after brain injury.

Unlocking the Potential: immune functions of oligodendrocyte precursor cells

“…However, not all polarized OPCs migrate, indicating that polarization does not necessarily imply migration. Interestingly, a recent study using a combination of spatial and single-cell RNA transcriptomics identified a subset of OPCs (cluster 15) in the injury core and another group of OPCs (cluster 10) at the periphery ( 39 ). These cluster 15 OPCs may be the polarized cells.…”

“…Interestingly, OPCs also change the expression of TGFβ2 after acute brain injury. Single-cell RNA sequencing of glial cells at the injury site has revealed that both clusters of OPCs (OPC1 and OPC2) upregulate Tgfb2 mRNA ( 39 ). Hence, depleting reactive OPCs at the lesion site may enhance microglial response and inflammation, thereby impeding wound healing.…”

“…The study from Koupourtidou et al. has revealed that a cluster of inflammatory genes, exceeding 140 in number, exhibited common alterations in all reactive glial cells surrounding the lesion, including microglia, OPCs, and astrocytes, following a stab wound injury in the mouse cerebral cortex—a model for traumatic brain injury (TBI) ( 39 ). Among the 241 upregulated genes, those involved in cell proliferation predominated.…”