The Tabulae Paralytica: Multimodal single-cell atlas of spinal cord injury

Spinal cord injury (SCI) is a complex disorder that triggers a cascade of biochemical processes interwoven by cell-type specific responses after the initial injury. This progressive cascade is collectively termed the "secondary injury", and involves inflammatory cell infiltration and cytokine release, apoptosis, demyelination, excitotoxicity, ischemia, and the formation of a fibrotic scar with an astrocyte border. Here, we turn to single-cell technology to unravel the underlying cellular and molecular tapestry of SCI. We compiled a series of comprehensive single-cell atlases of the injured mouse spinal cord; namely a single-cell transcriptomics (scRNA-seq) atlas that comprises 400,000 cells spanning 18 experimental conditions, a multi-omic paired scRNA-seq and chromatin accessibility data (scATAC-seq) atlas of 40,000 cells, and a spatial transcriptomic atlas with 60,000 spatial barcodes. These served as the most comprehensive atlases to date, and have provided us with an unprecedented opportunity to characterize the SCI at a molecular and cellular level. These atlases have unveiled numerous novel biological principles that underlie the molecular nature of SCI. We leveraged on this multimodal atlas to explore these narratives at the transcriptional and epigenomic levels. Our analyses showed the conserved and divergent neuronal responses to injury; the priming of specific neuronal subpopulations to become circuit-reorganizing neurons after injury; an inherent trade-off between neuronal stress responses and the activation of circuit reorganization programs; and a catastrophic failure to form a tripartite neuroprotective barrier in old mice. Overall, these new findings enable a better mechanistic understanding of SCI and consequent effective therapeutics.