Project description: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.
Project description:Tendon injuries are common, affecting both athletes and the general population. Healing is often poor, with deposition of fibrotic, disorganised scar-like tissue leading to continued pain, dysfunction and reinjury. While a variety of therapeutics are available clinically to treat tendon injuries, outcomes remain variable and no treatments are able to fully restore tendon structure and function, hence novel regenerative therapies are required. The pathogenesis of many fibrotic diseases is influenced by the mammalian target of rapamycin (mTOR) signalling pathway, which modulates processes required for cell growth and proliferation. Rapamycin, an mTOR inhibitor, is a promising therapeutic for several fibrotic diseases, and can facilitate musculoskeletal tissue repair. Therefore, we used a needle injury model in the rat Achilles tendon to test the hypothesis that rapamycin treatment during the early stages of tendon injury enhances tendon healing via modulation of resident tendon cell populations and autophagy. The results demonstrate that, while rapamycin treatment decreased peritendinous fibrosis and appeared to modulate cell recruitment, it did not enhance healing of lesions within the tendon core, up to three weeks post-injury. Therefore, rapamycin is not an effective therapeutic for tendon injury in young adults. Future studies should establish if rapamycin is able to improve tendon healing in aged animals or with longer-term administration.