Exploring the cellular and molecular landscape underlying tendon fibrosis in horses

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The equine industry contributes nearly $20B annually to the Canadian economy, supporting >150K jobs. Across all equine disciplines, musculoskeletal injuries have been consistently reported as a leading cause of poor performance, early retirement and premature loss of life. Of these, tendon injuries are among the most common and challenging to treat. Similar to humans, a gradual shift from regenerative to fibrotic tendon repair leads to progressive weakness with advancing age and repetitive use. This "degenerative tendinopathy", predisposes the tissue to acute injury with continued performance resulting in the production of further biomechanically inferior scar tissue (fibrosis) at the injury site. As tendons typically function at near their biomechanical limits during athletic activity, fibrosis represents a substantial weakness, predisposing to chronic re-injury following typical endogenous repair1. Despite the significance to the equine industry, the underlying causes of this decline in regenerative capacity and switch to fibrotic response of tendons have not been elucidated2. With my well-established network within the equine industry of western Canada, my program will be uniquely positioned to collect tissues from horses (euthanized for reasons unrelated to research) representing a wide spectrum of tendon health, ranging from regeneration competent (neonatal and young horses entering athletic training) through degenerative (aging athletes) and ultimately to injured. Tendon health will be structurally characterized by magnetic resonance imaging; thereafter, tissue will harvested from the tendon's central, load-bearing region and rigorously interrogated using our established single cell RNA-sequencing pipeline, followed by in situ validation and second harmonic generation imaging of microstructure3. Next, we will deploy these new insights to conduct in vivo monitoring of cellular activities underlying early tendon healing, thus providing detailed, temporal data regarding fibrotic healing in natural tendon injuries of equine athletes. Lastly, we will use an experimental tendon injury model to compare healing outcomes in aged horses (known to produce a fibrotic response to injury) with ponies (known to exhibit superior healing in other connective tissues). In doing so, we will develop and define a novel model of superior adult tendon healing closely simulating naturally occurring injury in equines. Together, my research program will describe, in detail, currently unknown events associated with the gradual onset of degenerative tendinopathy as well as subsequent tendon injury and develop robust adult models of both regenerative and fibrotic healing after tendon injury in equine athletes. Ultimately, these studies will provide the foundational knowledge for future development of veterinary therapeutics capable of fostering a pro-regenerative (anti-fibrotic) response during musculoskeletal healing in horses.