Here, we introduce the Tabulae Paralytica—a compilation of four atlases of spinal cord injury (SCI) comprising a single-nucleus transcriptome atlas of half a million cells, a multiome atlas pairing transcriptomic and epigenomic measurements within the same nuclei, and two spatial transcriptomic atlases of the injured spinal cord spanning four spatial and temporal dimensions. We integrated these atlases into a common framework to dissect the molecular logic that governs the responses to injury within the spinal cord¹. The Tabulae Paralytica uncovered new biological principles that dictate the consequences of SCI, including conserved and divergent neuronal responses to injury; the priming of specific neuronal subpopulations to upregulate circuit-reorganizing programs after injury; an inverse relationship between neuronal stress responses and the activation of circuit reorganization programs; the necessity of re-establishing a tripartite neuroprotective barrier between immune-privileged and extra-neural environments after SCI and a failure to form this barrier in old mice. We leveraged the Tabulae Paralytica to develop a rejuvenative gene therapy that re-established this tripartite barrier, and restored the natural recovery of walking after paralysis in old mice. The Tabulae Paralytica provides a window into the pathobiology of SCI, while establishing a framework for integrating multimodal, genome-scale measurements in four dimensions to study biology and medicine.

在这里，我们介绍Tabulae Paralytica——四个脊髓损伤 (SCI) 图谱的汇编，其中包括 50 万个细胞的单核转录组图谱、同一核内配对转录组和表观基因组测量的多组图谱以及两个空间转录组图谱。跨越四个空间和时间维度的受伤脊髓图谱。我们将这些图谱整合到一个通用框架中，以剖析控制脊髓损伤反应的分子逻辑¹ 。 Tabulae Paralytica揭示了决定 SCI 后果的新生物学原理，包括对损伤的保守和不同的神经元反应；损伤后启动特定神经元亚群上调电路重组程序；神经元应激反应与回路重组程序的激活之间存在反比关系； SCI 后在免疫特权环境和神经外环境之间重建三重神经保护屏障的必要性，以及在老年小鼠中未能形成这一屏障。我们利用麻痹板开发了一种恢复活力的基因疗法，重新建立了这种三重屏障，并恢复了老年小鼠瘫痪后行走的自然恢复能力。 Tabulae Paralytica提供了了解 SCI 病理学的窗口，同时建立了一个框架，用于整合四个维度的多模式、基因组规模测量以研究生物学和医学。