TrkA+ sensory nerves coordinate regeneration through NGF-associated regulation of mitochondrial homeostasis

Sensory nerves are emerging as critical regulators of musculoskeletal repair through neurotrophic signaling, vascular interactions, and direct communication with bone-resident cells. While their requirement for regeneration is well established, the specific contributions of distinct sensory nerve subtypes and their underlying mechanisms remain poorly defined. Mammalian digit tip regeneration provides a unique model to study this process, as it recapitulates complete tissue replacement, including bone, nail organ, and marrow. Previous studies using denervation or altered mechanical loading demonstrate that neural input controls regeneration but do not resolve subtype-specific functions. Here, we identify TrkA/NGF signaling as a dominant sensory nerve-associated pathway during digit regeneration using spatial transcriptomics and functional interrogation in TrkA F592A mice. Selective inhibition of TrkA signaling reduced regeneration, decreasing proliferation while accelerating osteogenic differentiation during the patent blastema phase, resulting in a shortened regenerate. Mechanistically, TrkA/NGF disruption induced a compensatory increase in NGF expression within the blastema, associated with increased mitochondrial fusion and fatty acid oxidation (FAO). This NGF-associated shift in mitochondrial dynamics promoted osteogenic differentiation, linking neurotrophin signaling to cellular metabolism and fate decisions. Together, these findings establish a central role for TrkA + sensory nerves in coordinating regenerative timing and patterning and identify NGF-mediated regulation of mitochondrial homeostasis as a potential therapeutic target for enhancing bone repair.