Identifying specific functional roles for senescence across cell types

Abstract

<h2>Summary</h2> 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 <i>in vivo</i> genetic toolbox consisting of three <i>p16</i>^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 <i>p16</i>^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 <i>p16</i>^Ink4a+ macrophages significantly mitigates hepatocellular damage, whereas eliminating <i>p16</i>^Ink4a+ ECs aggravates liver injury. Additionally, targeted reprogramming of <i>p16</i>^Ink4a+ ECs through <i>Kdr</i> overexpression markedly reduces liver fibrosis. This study illuminates the functional diversity of <i>p16</i>^Ink4a+ cells and offers insights for developing cell-type-specific senolytic therapies in the future.