The nail mesenchyme creates a regeneration-specific ligand environment that orchestrates mammalian regeneration versus fibrotic wound healing

The adult digit tip is one of a few privileged mammalian tissues that regenerate. Here, we asked why this is so. Using single cell spatial transcriptomics and genetic mouse models we show regeneration requires the nail organ and associated nail mesenchyme, and that in their absence fibrotic wound-healing occurs. We show the nail organ/mesenchyme orchestrates a highly-organized regenerative response that includes reprogramming of tissue-resident mesenchymal cells to a blastema state. It does this by creating a regeneration-specific ligand environment that includes multiple BMPs. Loss of the resultant downstream BMP signaling by genetic deletion of Smad4 in all mesenchymal cells or specifically in the nail mesenchyme inhibits multiple aspects of the regenerative response, including expression of regeneration-specific ligands. Thus, the nail mesenchyme creates a BMP-rich local ligand environment that reprograms mesenchymal cells and orchestrate tissues regeneration versus fibrotic wound-healing, findings with implications for tissue repair and anti-fibrosis strategies.