Fibrotic scarring prevents optic nerve regeneration despite preserved axonal growth potential in adult killifish.

Adult mammals exhibit limited regenerative capacity in the central nervous system (CNS), leading to irreversible deficits following injury or disease. Effective strategies to restore CNS function remain lacking. For retinal disorders, whole-eye transplantation has emerged as a promising approach, yet reinnervation of visual brain targets remains a major challenge. Here, we evaluated the killifish-a teleost fish species displaying robust regenerative capacities during young adulthood and mammalian-like regenerative traits at old age-as a translational model for whole-eye transplantation. We analyzed axonal regeneration following complete optic nerve transection (cONT), an injury paradigm relevant to whole-eye transplantation, in both young adult and aged individuals. Unexpectedly, retinal ganglion cells (RGCs) in adult killifish failed to reinnervate their brain target after cONT, in contrast to regeneration-competent zebrafish. Despite this failure, RGCs retained high intrinsic growth potential, evidenced by aberrant axonal projections within the retina. The inability to reestablish brain connectivity, combined with inflammation and intrinsic vulnerability, likely underlies the severe RGC loss (~75%) in both age groups. We identified the formation of a dense, collagen-rich gliofibrotic scar at the lesion site as a major barrier to axonal regeneration. Intriguingly, partial optic nerve transection, which markedly reduced scar formation, improved RGC survival, facilitated robust axonal regeneration and restored target reinnervation. Together, these findings establish the killifish as a powerful model to study scar-mediated inhibition of CNS regeneration, with important implications for advancing CNS repair strategies, including whole-eye transplantation.