Sengul, E.; Potts, H. G.; Stockdale, W. T.; Carter, R. D.; Bevan, L.; Nozdrina, M.; Alonaizan, R.; Hu, Z.; Goodship, A.; Ying, J.; Lekkos, K.; O Byrne, L.; Lemieux, M. E.; Richardson, R.; Mommersteeg, M. T. M.

A balanced immune response after cardiac injury is crucial to successful heart regeneration, but knowledge of what distinguishes a regenerative from a scarring response is still limited. The Mexican cavefish provides a unique comparative model to study heart regeneration and scarring within a single species. Surface-dwelling fish are capable of heart regeneration whereas their cave-dwelling counterparts lack this ability, similar to the human heart. Using single-cell transcriptomics and immune perturbations, we find significant differences in the immune response between the two populations. Unlike the transient response in the scarring cave-dwelling fish, the regenerative surface fish heart generates an unexpected functionally active prolonged innate and adaptive immune response at the late stages of regeneration. Inhibiting the overall prolonged immune response impairs regeneration and cardiomyocyte proliferation. Further characterisation of specific cell types shows that late-present macrophages are phagocytic, and their depletion disrupts regeneration but not cardiomyocyte proliferation while inhibiting B cells impairs regeneration by reducing cardiomyocyte proliferation. This B cell response is conserved in zebrafish. Our findings reveal critical immune mechanisms distinguishing regenerative and non-regenerative responses, offering insights for potential therapeutic strategies to enhance heart repair.