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. Traumatic brain injury induces edema and widespread cellular damage. Here, the authors present a time-resolved, cross-species single-cell atlas that identifies human-specific ABCA1⁺ oligodendrocytes associated with edema, microglial signaling, and neural responses.