Integrative multi-omics analysis of Polypterus fin regeneration reveals shared and derived fin and limb regeneration mechanisms

Comparative studies of salamander limbs and fish fins may reveal shared components of an ancestral vertebrate appendage regeneration toolkit. However, traditional fish models, such as zebrafish, regenerate only dermal fin rays, which are neither homologous to limbs nor as cellularly complex. To address this, we employed a multi-omics approach leveraging the regenerative capacity of Polypterus senegalus , a fish species capable of full fin regeneration. Single-nucleus RNA-sequencing revealed extensive erythrocyte and myeloid cell infiltration during Polypterus fin regeneration. Spatial transcriptomics identified key cellular contributors to the blastema, while cross-species comparisons with axolotl limbs uncovered both common and divergent expression patterns of wound epidermis and blastema markers. Fin amputation triggered a conserved injury response, including sequential activation of pro- and anti-inflammatory programs and DNA damage repair in cycling cells. Hypoxia responses involved hif1a modulation, consistent with other regenerative models, but uniquely included the expression of hif4a in erythrocytes and the upregulation of a myoglobin gene in the wound epidermis. Furthermore, genome-wide chromatin profiling identified candidate regeneration-responsive elements. Together, these findings establish Polypterus as a powerful comparative model for identifying shared and derived mechanisms of limb and fin regeneration.