Nail Proximal Fold Stem Cells Participate in Nail Growth, Orchestrating Enhanced Digit Regeneration via BMP Signaling Activation

The study identifies a distinct population of slow-cycling nail proximal fold stem cells (NPFSCs) that play a crucial role in nail growth and digit regeneration, with BMP signaling being a key regulatory factor. Inhibition of BMP signaling resulted in limited regeneration, while its activation enhanced NPFSC involvement in the nail matrix, promoting significant digit regeneration. Enhanced BMP activity not only accelerated nail and bone regrowth but also extended the regenerative boundary, allowing full regeneration after substantial removal of the distal phalanx. In BMP gain-of-function models, even extreme proximal amputations allowed partial nail plate regeneration. Transplanted lineage-traced NPFSCs into immunocompromised mice integrated into the nail proximal fold and contributed to nail matrix progenitors, retaining their regenerative capacity. These findings highlight the therapeutic potential of NPFSCs and the pivotal role of BMP-Wnt signaling cross-talk in enhancing regenerative outcomes following traumatic amputation.