P16+ cells drive adverse cardiac remodeling after myocardial infarction through CCL8-mediated recruitment of cytotoxic CD8+ T cells that cause cardiomyocyte apoptosis.
Targeting P16+ fibroblasts or blocking CCL8 represents a promising therapeutic approach to prevent maladaptive cardiac remodeling after myocardial infarction.
BACKGROUND: Ischemic heart disease remains a leading cause of mortality worldwide, with adverse remodeling after myocardial infarction driven by inflammation and cardiomyocyte loss. Although cytotoxic lymphocytes exacerbate myocardial injury and P16 marks cellular senescence in diseased hearts, the cell type-specific functions of P16+ populations remain unclear. METHODS: Using p16-CreER;R26-tdT reporter mice, we mapped P16+ cell heterogeneity after myocardial infarction. Senolytic effects were assessed with combined dasatinib and quercetin treatment. Transcriptomic profiling (bulk and single-cell RNA sequencing) of sorted P16+ cells identified secreted factors, validated through in silico predictions and quantitative polymerase chain reaction. Intercellular communication was analyzed using CellChat. Functional relevance was tested through CCL8 (cytokine C-C motif ligand 8) neutralization, Ccl8 deletion in P16+ cells, lymphocyte depletion, and intersectional genetic ablation of P16+ fibroblasts or macrophages using dual-recombinase systems (p16-DreER;Pdgfra-CreER;R26-lr-tdT-DTR and p16-DreER;Cx3cr1-CreER;R26-lr-tdT-DTR). RESULTS: P16 was induced in fibroblasts, macrophages, coronary endothelial cells, and cardiomyocytes after myocardial infarction. Dasatinib and quercetin treatment selectively eliminated P16+ macrophages and fibroblasts, improving cardiac function. Transcriptomic analysis identified P16+ fibroblasts and macrophages as the main sources of CCL8. CCL8 blockade reduced infiltration of cytotoxic lymphocytes (CD8+ T cells and natural killer cells), decreased cardiomyocyte apoptosis, and enhanced repair. Genetic deletion of Ccl8 in P16+ cells reproduced these benefits. It is important to note that ablation of P16+ fibroblasts, but not macrophages, diminished fibrosis and improved function, and depletion of CD8+ T cell attenuated adverse remodeling. CONCLUSIONS: P16+ cells orchestrate maladaptive remodeling after myocardial infarction through CCL8-dependent recruitment of cytotoxic lymphocytes, particularly CD8+ T cells, which drive cardiomyocyte apoptosis. Targeting P16+ fibroblasts or blocking CCL8 offers a promising therapeutic approach for ischemic heart disease.
Yan et al. (2026) studied this question. P16+ cells drive adverse cardiac remodeling after myocardial infarction through CCL8-mediated recruitment of cytotoxic CD8+ T cells that cause cardiomyocyte apoptosis.