Poster Presentation: Emma Stowe

ABSTRACT

Senescent cells disrupt ECM remodeling in response to exercise

Emma Stowe1 & Brianne Connizzo1,2

1Department of Biomedical Engineering, Boston University, Boston, MA 02215

2Department of Mechanical Engineering, Boston University, Boston, MA 02215

Aging is a primary risk factor for degenerative tendon injuries and is strongly linked to dysfunctional extracellular matrix (ECM) remodeling. Prior work from our group demonstrates that aged tendons show impaired ECM remodeling in response to mechanical unloading, compression, and tensile strain. Our current focus is on why this occurs and how we can prevent or reverse it. Senescent cells, which accumulate in aged tissues and are characterized by chronic growth arrest and increased secretion of pro-inflammatory markers, have strong potential to disrupt tissue remodeling. We recently developed an microphysiologic senescence model in live murine tendon explants that enables direct study of senescence and tissue remodeling. In the present study, we focus on the ability of naturally-aged and induced-senescent cells to synthesize and remodel tissue structure in response to exercise. Young, aged, and induced-senescent flexor tendon explants were stimulated with an ex vivo loading protocol designed to increase matrix turnover and simulate exercise. The first week established a homeostatic baseline, after which half of the samples were subjected to an increase in loading for the next week. As expected, young tendons exhibit robust expression of ECM-related genes and increases in protein synthesis with exercise. Interestingly, aged and induced-senescent explants exhibit no adaptive increases in most of the ECM genes, especially proteoglycans and MMPs. In some cases, senescent explants actively downregulate important ECM turnover genes, like TGF-β. This lack of response may reflect an impaired ability to initiate matrix repair, leaving aged or senescent tissues vulnerable to injury and chronic degeneration. Together, these results highlight the detrimental impact of senescent cells on tendon adaptation to exercise and support senescence as a promising therapeutic target for mitigating age-related extracellular matrix dysfunction.