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. [Display omitted] • Intersectional genetics enables tracing, ablation, and manipulation of defined p16 Ink4a + cell types • Ablation of p16 Ink4a + macrophages ameliorates liver fibrosis • p16 Ink4a + endothelial cells play a reparative role in liver injury • Reprogramming of p16 Ink4a + endothelial cells ameliorates liver fibrosis A dual recombinase-mediated genetic system for cell-type-specific lineage tracing, ablation, and gene manipulation of senescent cells reveals distinct roles of senescence across cell types. [ABSTRACT FROM AUTHOR]