Identifying specific functional roles for senescence across cell types

Cellular senescence plays critical roles in aging, regeneration, and disease; yet, the ability to discern its contributions across various cell types to these biological processes remains limited. In this study, we generated an in vivo genetic toolbox consisting of three p16^Ink4a-related intersectional genetic systems, enabling pulse-chase tracing (Sn-pTracer), Cre-based tracing and ablation (Sn-cTracer), and gene manipulation combined with tracing (Sn-gTracer) of defined p16^Ink4a+ cell types. Using liver injury and repair as an example, we found that macrophages and endothelial cells (ECs) represent distinct senescent cell populations with different fates and functions during liver fibrosis and repair. Notably, clearance of p16^Ink4a+ macrophages significantly mitigates hepatocellular damage, whereas eliminating p16^Ink4a+ ECs aggravates liver injury. Additionally, targeted reprogramming of p16^Ink4a+ ECs through Kdr overexpression markedly reduces liver fibrosis. This study illuminates the functional diversity of p16^Ink4a+ cells and offers insights for developing cell-type-specific senolytic therapies in the future.