P16+ Cells Drive Adverse Postischemic Cardiac Remodeling Through CCL8-Mediated Recruitment of Cytotoxic Lymphocytes
Lei Yan1, Jialei Zheng1, Zhengkai Lu2
1School of Life Science and Technology (L.Y., J.Z., A.Z., M.Y., J.M., H.Z.), ShanghaiTech University, China.
Insights
P16-positive cells drive heart damage after myocardial infarction by recruiting cytotoxic lymphocytes via CCL8. Targeting these cells or CCL8 may treat ischemic heart disease.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cellular Senescence
Background:
- Ischemic heart disease is a leading global cause of mortality.
- Adverse cardiac remodeling post-myocardial infarction involves inflammation and cardiomyocyte loss.
- The specific roles of P16-positive (P16+) cells in heart disease remain unclear.
Purpose of the Study:
- To investigate the heterogeneity and function of P16+ cells after myocardial infarction.
- To assess the therapeutic potential of senolytic treatments and targeting specific cell populations.
- To elucidate the mechanisms by which P16+ cells contribute to cardiac remodeling.
Main Methods:
- Utilized p16-CreER reporter mice to map P16+ cell populations.
- Employed dasatinib and quercetin for senolytic therapy assessment.
- Conducted bulk and single-cell RNA sequencing for transcriptomic profiling.
- Analyzed intercellular communication using CellChat and validated findings through genetic manipulations and neutralization studies.
Main Results:
- P16 expression was observed in fibroblasts, macrophages, endothelial cells, and cardiomyocytes post-myocardial infarction.
- Senolytic treatment selectively eliminated P16+ macrophages and fibroblasts, improving cardiac function.
- P16+ fibroblasts and macrophages were identified as major sources of CCL8.
- CCL8 blockade reduced cytotoxic lymphocyte infiltration, decreased cardiomyocyte apoptosis, and enhanced cardiac repair.
Conclusions:
- P16+ cells orchestrate maladaptive cardiac remodeling via CCL8-mediated recruitment of cytotoxic lymphocytes, particularly CD8+ T cells.
- This recruitment drives cardiomyocyte apoptosis and contributes to adverse remodeling.
- Targeting P16+ fibroblasts or inhibiting CCL8 presents a promising therapeutic strategy for ischemic heart disease.
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.
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