NRG1/ErbB signalling controls the dialogue between macrophages and neural crest-derived cells during zebrafish fin regeneration

Some fish can regenerate appendages by formation of a structure called the blastema. Here, the authors use single-cell RNA sequencing to characterize the cells required for blastema formation and fin regeneration and identified neural crest cells that orchestrate regeneration via the NRG1/ErbB axis Fish species, such as zebrafish (Danio rerio), can regenerate their appendages after amputation through the formation of a heterogeneous cellular structure named blastema. Here, by combining live imaging of triple transgenic zebrafish embryos and single-cell RNA sequencing we established a detailed cell atlas of the regenerating caudal fin in zebrafish larvae. We confirmed the presence of macrophage subsets that govern zebrafish fin regeneration, and identified a foxd3-positive cell population within the regenerating fin. Genetic depletion of these foxd3-positive neural crest-derived cells (NCdC) showed that they are involved in blastema formation and caudal fin regeneration. Finally, chemical inhibition and transcriptomic analysis demonstrated that these foxd3-positive cells regulate macrophage recruitment and polarization through the NRG1/ErbB pathway. Here, we show the diversity of the cells required for blastema formation, identify a discrete foxd3-positive NCdC population, and reveal the critical function of the NRG1/ErbB pathway in controlling the dialogue between macrophages and NCdC.

Automated summary

This study utilized single-cell RNA sequencing to characterize the cells involved in blastema formation and fin regeneration in zebrafish, highlighting the role of neural crest cells in orchestrating regeneration through the NRG1/ErbB axis. The presence of foxd3-positive neural crest-derived cells was identified to be crucial in regulating macrophage recruitment and polarization during blastema formation and caudal fin regeneration. The findings underscore the critical function of the NRG1/ErbB pathway in controlling the communication between macrophages and neural crest-derived cells during fish fin regeneration.