A Single Cell Atlas of Spared Tissue Below a Spinal Cord Injury Reveals Cellular Mechanisms of Repair

Abstract

After spinal cord injury (SCI), the spared tissue below the lesion contains undamaged cells that could support or augment recovery, but targeting these cells requires a clearer understanding of their injury responses and capacity for repair. Here, we used single nucleus sequencing to profile how each cell type in the lumbar spinal cord changes over time after a thoracic injury. We present an atlas of these dynamic responses and explore two unexpected findings. Amongst neurons, rare cell types expressed a molecular signature of regeneration and amongst microglia, we identified a population of trauma associated microglia (TAM). These TAM cells were present in the white matter near degenerating axons and expressed the trophic factors Igf1 and Spp1(OPN). Viral over-expression of Igf1 and Spp1(OPN) expanded the TAM population and promoted the clearance of myelin debris. These findings expose endogenous mechanisms of repair in spared neural tissue, uncovering potential candidates for targeted therapy.

A harmonized atlas of mouse spinal cord cell types and their spatial organization

“…As more data become available from studies that include more specific regions of the spinal cord, more biological conditions, more developmental stages, more species, more specific cellular features, and more -omics modalities, we anticipate that this work will reveal exciting insights from singlecell data. Future work could incorporate genetic lineage tracing to test developmental origins for postnatal cell types 2 , could track cell-type-specific changes in different biological conditions 8,9,128 , or could focus deeply on specific spinal cord regions and cell types 10,11,39,40,77,129 . Relatedly, the in situ hybridization experiments here are also limited in scope, being specific to the adult lumbar spinal cord.…”

A Time-Course Study of the Expression Level of Synaptic Plasticity-Associated Genes in Un-Lesioned Spinal Cord and Brain Areas in a Rat Model of Spinal Cord Injury: A Bioinformatic Approach

“…This result is in line with our observations of the activation of ECM reorganization genes in the context of the synaptic plasticity pathway. Interestingly one of the main genes involved in recovery, Igf1, identified in mouse SCI scRNA-seq, resulted downregulated in the acute phase in our rat model [62].…”

Advances in Biomaterial‐Based Spinal Cord Injury Repair

“…used a single nuclear RNA sequencing technique to profile cell type changes in lumbar spinal cord tissues after thoracic SCI. [ 42 ] Seven clusters of microglia/macrophages were identified, including three homeostatic microglia populations, two activated microglia populations, and a cluster of macrophages, suggesting abundant microglial phenotypes in the SCI and providing potential immunotherapeutic targets to control microglia‐induced pathological changes.…”