Engineering nerve-tendon crosstalk to enhance tendon repair and alleviate pain

Project Summary Tendon and ligament injuries are common diagnoses with inadequate treatments to enhance repair and to mitigate pain. Several studies, including our own, have demonstrated that sensory nerve fibers mediate the response to tendon injury, including both afferent pain responses and neurosecretory / regenerative responses. Our data show that nerve growth factor (NGF) released from injured tendons activates TrkA (Tropomyosin receptor kinase A)-expressing sensory neurons, and that this interaction is involved in promoting tendon repair. In addition, we have new data elucidating the next step in this pathway—a neurosecretory mechanism through which tendon-innervating TrkA+ sensory nerves release fibroblast growth factor 1 (FGF1) to activate FGFR1/2 signaling in tendon sheath progenitor cells (TSPCs) and tenocytes to enhance repair. We now propose work to investigate the potential to leverage these nociceptive nerves as a novel tendon repair therapy. Whether that is possible depends on the extent to which the neural `regenerative response' is separable from the `pain response' following injury. NGF-mediated nociception relies on downstream mitogen-activated protein kinase interacting kinases (MNK1 and MNK2). In preliminary studies, we find that these same kinases (MNK1 and MNK2) are activated in tendon-innervating neurons after injury and that inhibiting MNK blunted tendon pain while preserving repair. These key data lead us to our central hypothesis, that NGF-TrkA signaling after tendon injury activates two separable and therapeutically vulnerable downstream responses: 1) an FGF1-dependent regenerative response at the tendon injury site and 2) an MNK-dependent pain response at the level of the DRG neural soma. Aim 1: Determine the role of TrkA+ nerve-derived FGF1 as a critical downstream regulator controlling tendon sheath progenitor cell (TSPC) and tenocyte mediated tendon repair. Aim 2: Demonstrate the ability to locally promote neural-mediated tendon repair via a bioengineered hydrogel that percutaneously delivers a TrkA agonist precisely at the tendon injury during the key phases of repair. Aim 3: Test a combined approach for acute tendon injury to minimize pain and optimize regeneration via neural MNK signaling inhibition while promoting TrkA+ nerve-guided tendon repair. The proposed studies will provide a mechanistic understanding of how peripheral nerves regulate tendon repair and pain. By identifying new pathways of nerve-to-tendon communication, these results may reveal ways to functionally and therapeutically uncouple the neurosecretory FGF1 `regenerative response' from the MNK `pain response.' Thus, the proposed studies will provide novel insights into the neuroregulation of key processes in tendon injury, while identifying new targets for therapeutic intervention across musculoskeletal tissues.