Molecular Drivers of MSC Senescence in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent joint inflammation, immune dysregulation, and progressive tissue destruction. Increasing evidence implicates mesenchymal stromal cell (MSC) senescence and its pathological interaction with immune cells, particularly T-cells, in sustaining inflammation and promoting joint degeneration. However, the molecular drivers of MSC senescence and their reciprocal interaction with T-cells remain incompletely defined. In this study we aim to uncover key molecular mechanisms of cellular senescence in RA, providing novel biomarkers and therapeutic targets. We hypothesize that oxidized lipids enriched in RA serum induce premature MSC senescence, leading to a dysfunctional secretome that disrupts T-cell immunoregulation, enhances inflammation, and contributes to cartilage degradation. Senescent MSCs may further promote paracrine tissue damage, alter extracellular matrix remodeling, and impair the regenerative capacity of surrounding joint cells. In parallel, T-cells in RA are proposed to acquire a distinct senescent phenotype with pro-inflammatory and tissue-invasive properties. To investigate these processes, we will combine coculture models with bulk and single-cell omics approaches to identify RA-associated factors that induce MSC senescence and impair immunoregulation. We will also characterize the senescent MSC secretome, assess its impact on ECM remodeling, and define senescent T-cell subsets and their interactions with synovial MSCs.