Beta cell senescence in T1D

Senescence is a stress adaptation program involves a cell-cycle arrest that prevents the replication of damaged cells and activation of a secretory program that promotes their clearance by the immune system. However, failure of immune surveillance leads to the accumulation of senescent cells, leading to chronic inflammation and tissue dysfunction. β-cell senescence has recently emerged as a key contributor to T1D pathogenesis. Our work has identified context-dependent heterogeneity of β-cell senescence, with different cellular stressors initiating distinct senescence programs with divergent effects on T1D progression. Senescent β-cells that normally accumulate in the non-obese diabetic (NOD) mouse model of T1D promote islet inflammation and disease progression. In contrast, we made the striking discovery that NOD β-cells deficient for the UPR sensors ATF6 or IRE1 exhibit an alternative senescence program marked by a p21-driven secretome that promotes immune surveillance and is protective against diabetes (Lee et al., Cell Metab 2023). These intriguing findings highlight that β-cell senescence exhibits molecular and phenotypic heterogeneity in a context-dependent manner based on the nature of the initiating stressor and subsequent temporal progression. We aim to define the molecular and epigenetic heterogeneity of senescent β-cells in mouse and primary human islets, and track the temporal progression of senescence programs. Overall, our goal is to support the development of targeted interventions to maximize the beneficial effects of β-cell senescence programs while mitigating the pathological effects of maladaptive β-cell senescence programs in T1D.