Spatiotemporal orchestration of multicellular transcriptional programs and communications in the early stage of spinal cord injury

Abstract

While spinal cord injury (SCI) involves a complex cascade of cellular and pathological changes that last for months to years, the most dramatic and comprehensive molecular rewiring and multicellular re-organization occur in the first few days, which determine the overall progression and prognosis of SCI, yet remain poorly understood. Here, we resolved the spatiotemporal architecture of multicellular gene expression in a mouse model of acute SCI, and revealed the coordinated gene co-expression networks, the upstream regulatory programs, and in situ cell-cell interactions that underlay the anatomic disorganization as well as the immune and inflammatory responses conferring the secondary injury. The spatial transcriptomic analysis highlights that the genes and cell types in the white matter (WM) play a more active and predominant role in the early stage of SCI. In particular, we identified a distinct population of WM-originated, Igfbp2-expressing reactive astrocytes, which migrated to the grey matter and expressed multiple axon/synapse-supporting molecules that may foster neuron survival and spinal cord recovery in the acute phase. Together, our dataset and analyses not only showcase the spatially-defined molecular features endowing the cell (sub)types with new biological significance but also provide a molecular atlas for disentangling the spatiotemporal organization of the mammalian SCI and advancing the injury management.