A unique macrophage subpopulation signals directly to progenitor cells to promote regenerative neurogenesis in the zebrafish spinal cord

Central nervous system injury re-initiates neurogenesis in anamniotes (amphibians and fishes), but not in mammals. Activation of the innate immune system promotes regenerative neurogenesis, but it is fundamentally unknown whether this is indirect through the activation of known developmental signaling pathways or whether immune cells directly signal to progenitor cells using mechanisms that are unique to regeneration. Using single-cell RNA-seq of progenitor cells and macrophages, as well as cell-type-specific manipulations, we provide evidence for a direct signaling axis from specific lesion-activated macrophages to spinal progenitor cells to promote regenerative neurogenesis in zebrafish. Mechanistically, TNFa from pro-regenerative macrophages induces Tnfrsf1a-mediated AP-1 activity in progenitors to increase regeneration-promoting expression of hdac1 and neurogenesis. This establishes the principle that macrophages directly communicate to spinal progenitor cells via non-developmental signals after injury, providing potential targets for future interventions in the regeneration-deficient spinal cord of mammals. [Display omitted] •A direct signaling axis from injury to regenerated neurons is established•scRNA-seq reveals a pro-regenerative macrophage•Spinal progenitors directly react to human TNF with enhanced neurogenesis•hdac1 in spinal progenitors promotes regenerative neurogenesis in vivo Cavone et al. show that after a spinal injury, neural progenitor cells read TNF, a cytokine derived from specific infiltrating macrophages, to promote regeneration of destroyed neurons in larval zebrafish. This mechanism of regenerative neurogenesis, not seen in spinal development, could provide therapeutic targets for non-regenerating vertebrates.