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<p>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 <i>ABCA1</i> and adhesion-related genes and is associated with edema progression. In vitro experiments support an <i>ABCA1</i>-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 <i>CALM2–HMGB1</i> signaling to oligodendrocyte <i>ABCA1</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月27日

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  • Jiatong Ji,
  • Honglu Chao,
  • Chengzhi Chen,
  • Xinyue Wang,
  • Wenqian Shi,
  • Jun Liao,
  • Hai Qian,
  • Hao Shi,
  • Jingming Hu,
  • Yangfan Ye,
  • Yiming Tu,
  • Xiao Xu,
  • Zheng Li,
  • Zhen Yue,
  • Wei Yan,
  • Xunning Hong,
  • Huibo Wang,
  • Huimei Chen,
  • Enrico Petretto,
  • Jing Ji

摘要

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.