Newly repopulated spinal cord microglia exhibit a unique transcriptome and correlate with pain resolution

Abstract

Microglia contribute to the initiation of pain, however, a translationally viable approach addressing how or when to modulate these cells remains elusive. We used a targeted, inducible genetic microglial depletion strategy at both the acute and acute-to-chronic transition phases in the clinically-relevant tibial fracture/casting model to determine the contribution of microglia to the initiation and maintenance of pain. We observed complete resolution of pain after transient microglial depletion at the acute-to-chronic phase, which coincided with the timeframe of full repopulation of microglia. These repopulated microglia were morphologically distinct from control microglia, suggesting they may exhibit a unique transcriptome. RNA sequencing of repopulated spinal cord microglia identified genes of interest using weighted gene co-expression network analysis (WGCNA). We intersected these genes with a newly-generated single nuclei microglial dataset from human dorsal horn spinal cord to identify human-relevant genes that may promote homeostatic features of microglia and ultimately promote pain resolution after injury.