Single-nucleus analysis reveals human-specific oligodendrocyte polarization and conserved neuronal responses after severe traumatic brain injury.

Severe traumatic brain injury (sTBI) is a leading cause of edema and neurological dysfunction. However, the molecular mechanisms driving injury progression remain poorly understood. Here, we present a single-nucleus transcriptomic atlas of human and male mouse cortex across multiple sTBI stages, providing a systematic landscape of dynamic, cell-type-specific responses to injury and edema. Cross-species analyses reveal both conserved and human-specific programs, including a polarized oligodendrocyte state absent in murine sTBI. This state shows increased ABCA1 and adhesion-related genes and is associated with edema progression. In vitro experiments support an ABCA1-linked role in lipid handling that may support oligodendrocyte-lineage cell function, reflected by the maintenance of myelin-associated marker expression. Analyses combining ligand-receptor interactions, co-expression, and perturbation experiments link microglial CALM2-HMGB1 signaling to oligodendrocyte ABCA1-associated lipid regulation during injury progression. These human-specific programs indicate that rodent models may not fully recapitulate human sTBI mechanisms, underscoring the need for caution when extrapolating cross species findings.