<i>Editorial Commentary</i> : Cellular Senescence, Immune Targeting and Exosome Translational Research Requires Methodological Rigor

Aging is associated with increased pathology in musculoskeletal tissues. Aging results in the accumulation of senescent cells, stem cell exhaustion, sterile inflammation, and immune cell dysfunction systemically and locally. Improving healing and regeneration during musculoskeletal aging is a significant area of clinical need. Recently, the targeting of senescent cells has become an exciting area of research. Pathological accumulation of senescent cells in tissues is associated with tissue dysfunction. Immune system dysfunction has also been a proposed mechanism for the accumulation of senescent cells, where the immune system fails to clear senescent cells from tissues. Therapeutics that target senescent cells are an active area of research. Additionally, stem cell exhaustion is one proposed mechanism for the decline in regeneration and healing that is found with aging. Declines in stem cells have been noted in patients with musculoskeletal injuries, including rotator cuff tears. The systemic increase in sterile inflammation is also associated with this shift in immune cell function. Polarized regenerative macrophages have been suggested to attenuate inflammation and promote healing. Exosomes from mesenchymal stem cells and immune cells, such as macrophages, are actively being pursued as important biologic therapies to improve regeneration and healing. Exosomes are small extracellular vesicles that are released from cells and carry DNA, RNA, lipids, and metabolites. It is essential in this work to thoroughly define the cell sources of exosomes and determine their mechanistic responses in tissues. Rigorous evidence-based research is needed to determine the potential efficacy of exosomes to improve tissue healing for patients.