Regenerative Potential of Neonatal Tendons Is Regulated by Intrinsic Resistance to Inflammation and Supportive...

Tendons mediate force transmission from muscle to bone to allow movement. Upon injury, adult tendons heal by scar formation with persistent functional deficits. While the immune response is a key regulator of healing, the roles of specific immune cells and their interactions with resident tendon cells remain understudied. While it is well appreciated that macrophages drive both inflammation and its resolution, other immune cells such as T cells have also been implicated. Here, we apply in vitro culture of CD4+ helper T-cell supernatants to determine the role of neonatal vs. adult T cells in regulating key tendon cell properties previously associated with neonatal tendon regeneration. While T cells were dominated by inflammatory Th1 cells regardless of source, neonatal T cells were less inflammatory compared to adults. Proliferation and migration potential were also properties intrinsic to neonatal tendon cells. While adult tendon cells were more sensitive to secreted T-cell factors, neonatal T-cell factors generally supported regenerative properties in adult tendon cells. Using RNA sequencing, we further identified a role for JAK/STAT signaling specific to treatment with adult T-cell supernatants; using a small molecule inhibitor of JAK/STAT, we confirmed that suppression of adult tendon cell migration by adult T-cell factors can be rescued by JAK/STAT inhibition. Altogether, these data show that regenerative tendon healing in neonates is due to both intrinsic neonatal tendon cell resistance to T-cell-mediated inflammation as well as a more favorable environment for tendon phenotype induced by neonatal CD4+ T cells.