Endogenous stem cells promote regeneration of muscle in rotator cuff repair

Rotator cuff (RC) tears are the most common upper extremity injury, with over two million Americans seeking medical attention annually. With the increased age of our veterans' population, RC tears are becoming a vital health issue for the VA patients. Secondary muscle degradation following tears, including atrophy and fatty infiltration (FI) are critical factors that directly determine the clinical outcome of patients with this injury. Muscle residential fibro/adipogenic progenitor (FAP) cells have been found to be the major cellular source of fat in RC muscle after massive tendon tears. We recently discovered that these cells represent a heterogeneous cell population capable of both regenerative and pathologic responses to muscle injury. Importantly, FAPs can differentiate into a beige adipose tissue (BAT) phenotype that may have a role in promoting muscle recovery and regeneration in chronic injury states. However, at this time, no studies have evaluated factors that influence the fate of FAPs in human cuff tears, nor what FAP regenerative capabilities could be in clinical scenarios such as rotator cuff repair. Clinically, both patient age and size of the rotator cuff tear have been found to be independent factors that associate with poorer muscle quality and worse patient outcomes. However, the interplay between patient and rotator cuff tear size and their influence on muscle stem cell proliferation, differentiation, and regenerative capabilities is not known at this time. To address this problem, we will perform the first large-scale clinical study evaluating FAP phenotypic properties in patients with rotator cuff tears. Expanding on our promising mouse studies that show FAPs are capable of stimulating muscle regeneration, we will perform a rigorous set of studies that will determine the regenerative capabilities of human FAPs in this clinically relevant scenario to confirm our hypothesis that the ability of FAPs to promote healthy muscle regeneration is dependent on the size of the tear and age of the patient due to changes in FAP gene expression. By the end of this study, we will understand how clinically important factors (age, tear size) affect the degeneration and regeneration potential of human FAPs, which should provide critical information on how these endogenous stem cells can be leveraged to improve precision guided patient outcomes with targeted therapeutic strategies in the near future.