Axin2-lineage cells contribute to neonatal tendon regeneration

Purpose: Tendon injuries are a challenging clinical problem with few treatment options. Identifying the molecular regulators of tendon is required for the development of new therapies. While the Wnt pathway is critical for the maintenance and differentiation of many tissues, the role of Wnt signaling in tendon cell biology remains largely unexplored. Methods: The effects of Wnt activation were tested in vitro using neonatal tendon-derived cells cultured in 2D and 3D conditions. The inducible Axin2CreERT2 was then used to label Axin2+ cells in vivo and cells were traced during neonatal tendon regeneration. Results: We showed that activation of Wnt signaling results in proliferation of neonatal tendon cells. While tendon marker expression was inhibited by Wnt activation under 2D conditions, Scx expression was not affected under 3D uniaxial tension, suggesting that the microenvironment contextualizes tendon cell response to Wnt signaling. Using an in vivo model of neonatal tendon regeneration, we further showed that Wnt signaling cells comprise a subpopulation of tenocyte and epitenon cells that proliferate after injury and are recruited during regeneration. Discussion: Collectively, these studies suggest that Wnt signaling may play a role in tendon cell proliferation, differentiation, and regeneration.