Single-cell and spatial atlases of spinal cord injury in the Tabulae Paralytica

• 成果类型: Article
• 署名作者: Skinnider, Michael A.; Gautier, Matthieu; Teo, Alan Yue Yang; Kathe, Claudia; Hutson, Thomas H.; Laskaratos, Achilleas; de Coucy, Alexandra; Regazzi, Nicola; Aureli, Viviana; James, Nicholas D.; Schneider, Bernard; Sofroniew, Michael V.; Barraud, Quentin; Bloch, Jocelyne; Anderson, Mark A.; Squair, Jordan W.; Courtine, Gregoire
• 署名单位: Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Swiss School of Public Health (SSPH+); Princeton University; Ludwig Institute for Cancer Research; Princeton University; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); University of Lausanne; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6829
• DOI: 10.1038/s41586-024-07504-y
• 发表日期: 2024-07-04
• 页码: 150-+
• 关键词: fluid-contacting neurons; scar formation; RECOVERY; methylprednisolone; astrocytes; walking; SYSTEM

摘要

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 cord(1). 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.