Macrophage crosstalk with neural progenitors and fibroblasts controls regenerative neurogenesis via Sema4ab after spinal cord injury in zebrafish
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After spinal cord injury, interactions of multiple tissues inhibit neuronal regeneration in mammals, but not in anamniotes, such as zebrafish. These pivotal interactions are poorly understood. Here we analyse the role of the cell signalling molecule sema4ab in the cell communication network leading to regenerative neurogenesis after spinal injury in larval zebrafish. Sema4ab is expressed by macrophages and gene ablation doubles the rate of regenerative neurogenesis. Disruption of the sema4ab receptor plxnb1a/b , expressed by spinal progenitor cells, also moderately increases regenerative neurogenesis. In addition, single cell transcriptomics reveals altered interactions between macrophages and multiple additional cell types after sema4ab disruption. Pro-inflammatory cytokines are down-regulated and fibroblasts upregulate expression of the anti-inflammatory cytokine tgfb3. Inhibition of tgfb3 abolishes effects of sema4ab disruption on regenerative neurogenesis. This highlights sema4ab as a direct and indirect inhibitor of regenerative neurogenesis and as a potential therapeutic target in non-regenerating mammals.
