Secreted inhibitors drive the loss of regeneration competence inXenopuslimbs

Absence of a specialised wound epidermis is hypothesised to block limb regeneration in higher vertebrates. To elucidate the cellular and molecular determinants of this tissue, we performed single-cell transcriptomics in regeneration-competent, -restricted, and -incompetentXenopustadpoles. We identified apical-ectodermal-ridge (AER) cells as the specialised wound epidermis, and found that their abundance on the amputation plane correlates with regeneration potential and injury-induced mesenchymal plasticity. By usingex vivoregenerating limb cultures, we demonstrate that extrinsic cues produced during limb development block AER cell formation. We identifyNoggin, a morphogen expressed in cartilage/bone progenitor cells, as one of the key inhibitors of AER cell formation in regeneration-incompetent tadpoles. Extrinsic inhibitory cues can be overridden byFgf10, which operates upstream ofNogginand blocks chondrogenesis. Together, these results indicate that manipulation of the extracellular environment and/or chondrogenesis may provide a strategy to restore regeneration potential in higher vertebrates.