Achilles tendinopathy is a common degenerative change seen in athletes and elderly individuals. Tendons have limited regenerative capacity and heal via the formation of a disorganized, fibrotic scar. Surgical options for tendinopathy are often ineffective and rates of re- injury after surgical intervention are high. While the clinical changes associated with tendinopathy are well characterized, the mechanisms that underpin tendon healing remain poorly understood. In an effort to understand the cellular and molecular mechanisms that control tendon healing, our lab has developed a regenerative model of tendon healing in neonatal mice to complement existing fibrotic models of tendon healing in adult mice. Interestingly, a growing body of evidence has demonstrated that neonatal immunity uniquely supports a pro- regenerative, anti-fibrotic phenotype. Preliminary work from our lab similarly suggests that the immune response is critical to tendon healing. Moreover, neonatal response to injury in tendon differs dramatically from adult, and Tregs may underlie this difference in immune landscape. Therefore, we hypothesize that tendon specific Tregs involved in neonatal regeneration represent a special population of Tregs, unique in their capacity to promote regeneration (Aim 1). Next, we hypothesize that Tregs are necessary for neonatal tendon regeneration (Aim 2), and that establishment of a neonatal immune landscape in adult mice using dexamethasone, can rescue tendon regeneration in adults (Aim 3).
The parent grant investigates the hypothesis that with respect to tendon, Tregs mediate a pro- regenerative type 2 immune environment in neonates that when absent in adults, leads to scar formation. This fellowship plans to use transcriptomic profiling to investigate if tendon Tregs are unique in their capacity to promote regeneration, will use a Treg ablation mouse model (Foxp3- DTR/EGFP) to test if Tregs are required for tendon regeneration, and lastly will test if recapitulation of the neonatal type 2 immune landscape using dexamethasone in adults, rescues tendon regeneration in adult injured mice. This fellowship will aid in our ability to treat tendinopathies by identifying the immune mediators which underpin regeneration in tendon.
