Sensory nerves protect against tendon degeneration via FGF1/FGFR signaling

Chronic tendinopathy is typified by persistent tendon-associated pain, transmitted by local nociceptive neurons. However, the function of somatosensory neurons in the development of tendinopathy is entirely unknown. Here, we show that sensory neurons grow into the tendon proper across models of chronic tendinopathy. Three complementary surgical and transgenic mice models of disrupted sensory nerve growth were next utilized. Conditional deletion of Nerve growth factor (NGF) in macrophages (Ngf Csfr1) or inactivation of its high affinity receptor Tropomyosin receptor kinase A (TrkA) on sensory neurons led to severely worsened tendinopathy. A sensory-only sural nerve denervation model phenocopied these results, including heightened macrophage infiltration and tenocyte apoptosis. Single-cell RNA sequencing (scRNA-seq) of tendinous tissue identified defective tenocyte differentiation and altered macrophage migration and polarization with surgical denervation. Retrograde neuronal tracing in combination with scRNA-seq of corresponding dorsal root ganglia (DRG) tissues identified the profile of tendon-specific innervation, which included CGRP+ nociceptors among other neuron types. Finally, neuron-tendon interaction analyses implicated neuron-derived fibroblast growth factor 1 (FGF1) as a potent regulator of tendon repair, a finding experimental confirmed with tendon organ culture. Collectively, our findings demonstrate that peripheral afferent neural networks induce a protective effect in chronic tendinopathy by secreting FGF1, and that targeting this pathway may offer therapeutic strategies to enhance tendon repair.