Despite the requirement for Scleraxis-lineage (Scx Lin ) cells during tendon development, the function of Scx Lin cells during adult tendon repair, post-natal growth, and adult homeostasis have not been defined. Therefore, we crossed Scx-Cre and Diphtheria Toxin Receptor (DTR) mouse models to inducibly deplete Scx Lin cells prior to acute flexor tendon injury and repair (ScxLin DTR ) and hypothesized that ScxLin DTR mice would exhibit worse healing than wildtype littermates. Surprisingly, depletion of Scx Lin cells resulted in increased biomechanical properties without detriments to tendon gliding function at 28 days post-repair, indicative of regeneration. These improvements in biomechanical properties correspond to increased αSMA+ myofibroblasts in ScxLin DTR repairs, indicating that increased myofibroblast-mediated matrix remodeling may be responsible for accelerated recovery of tensile strength. Furthermore, we have defined the relative timing of Scx Lin cell localization relative to collagen deposition in bridging tissue of the repair and demonstrated a predominance of non-Scx Lin cells in the early bridging tissue, consistent with lack of bridging tissue disruption in ScxLin DTR repairs. Lastly, we utilized ScxLin DTR mice to assess effects of tendon cell depletion on post-natal tendon growth and adult tendon homeostasis. Collectively, these findings enhance our understanding of tendon cell localization, function, and fate during healing, growth, and homeostasis.3
Introduction:Despite the significant efforts toward improving tendon healing and regeneration, the specific cellular contributions during tendon healing have not been extensively characterized(1). While many studies have examined the potential of using various stem cell populations to promote healing, originating from both tendon intrinsic(2) and extrinsic sources(3), little focus has been directed toward defining the functions and therapeutic potential of tendon cells during tendon healing following an acute injury. Tendon cells are increasingly being recognized as a heterogenous population of cells where many, but not all, express the gene Scleraxis (Scx)(4-6).Understanding the localization and function of tendon cell subpopulations during healing could be instrumental in discovering why tendon heals using scar-mediated processes, resulting in poor patient outcomes, and could be used to develop pro-regenerative approaches to improve healing.Scx, a basic helix-loop-helix transcription factor, is currently the most well-characterized marker that the field possesses to study tendon (7). Scx has been utilized to examine tendon biology and development(8-10), healing and regeneration(4, 11-13), differentiation(14-17), and mechano-transduction (18,19). Functionally, Scx expression has previously been shown to drive matrix production and remodeling (11,20,21), epithelial-tomesenchymal transition(22), development of force-transmitting tendons(8), and effect focal adhesion morphology (19). Despite the effort to understand the functions of Scx as a transcr...