Innate tissue properties drive improved tendon healing in MRL/MpJ and harness cues that enhance behavior of canonical healing cells

Development of tendon therapeutics has been hindered by the lack of informative adult mammalian models of regeneration. Murphy Roth's Large (MRL/MpJ) mice exhibit improved healing following acute tendon injuries, but the driver of this regenerative healing response remains unknown. The tissue-specific attributes of this healing response, despite a shared systemic environment within the mouse, support the hypothesis of a tissue-driven mechanism for scarless healing. Our objective was to investigate the potential of MRL/MpJ tendon extracellular matrix (ECM)-derived coatings to regulate scar-mediated healing. We found that deviations in the composition of key structural proteins within MRL/MpJ vs C57Bl/6 tendons occur synergistically to mediate the improvements in structure and mechanics following a 1-mm midsubstance injury. Improvement in mechanical properties of healing MRL/MpJ vs C57Bl/6 tendons that were isolated from systemic contributions via organ culture, highlighted the innate tendon environment as the driver of scarless healing. Finally, we established that decellularized coatings derived from early-deposited MRL/MpJ tendon provisional extracellular matrix (provisional-ECM), can modulate canonical healing B6 tendon cell behavior by inducing morphological changes and increasing proliferation in vitro. This study supports that the unique compositional cues in MRL/MpJ provisional-ECM have the therapeutic capability to motivate canonically healing cells toward improved behavior; enhancing our ability to develop effective therapeutics.