Abstract
Introduction: Neonatal heart can regenerate after myocardial injury unlike adult heart. Its capacity diminishes and disappears by post neonatal day 7 (P7). Recent studies have shown that immune cells especially T cells plays an important role to regulate inflammation, however, their role in cardiac regeneration/repair after injury is understudied. Therefore, in the present study we will characterize the temporal dynamics of T cells in neonatal and adult heart after injury and will study how temporal regulation is essential to maintain repair processes. Hypothesis: Regulatory T cells plays an important role in mediating reparative processes after ischemic cardiac injury. Methods and Results: Myocardial infarction (MI) was induced in neonatal mice at P2 (n=30) and in 8-week-old (n=10) C57BL/6 mice by ligating the left anterior descending artery (LAD). CD4+, CD8+ and Foxp3+ T cells were sorted by FACS at post MI day 2, 3, 4, 5 and 7 in neonatal mice and post MI day 7 in adult mice and analyzed for the differences in transcriptome by ultra-low input RNA sequencing. Flow cytometry analysis showed CD4+ T cells peaked at post MI day 4 compared to CD8+ T cells that peaked at post MI day 7. FoxP3+ T cells increased at post MI day 2 and diminished by post MI day 7 which coincides with the non-regenerative window of the heart. CD4+ and Foxp3+ T subsets showed increased expression of transcript in anatomical structure morphogenesis and regulation of response to stimulus. Our data showed 11.2%, 12.8% and 13.4% genes in CD4+, CD8+ and Foxp3+ T cells subsets were upregulated in neonatal mice versus adult animals. Enrichment analysis resulted that cellular component morphogenesis and cell development were activated in CD4+ T cells, and cellular component biogenesis and organelle organization were elevated in Foxp3+ T cells in neonatal mice. In addition, chromosome organization and cell cycle were upregulated in CD8+ T cells. Additionally, Foxp3+ T cells showed 198 genes uniquely expressed in neonatal hearts which are involved in cardiomyocytes proliferation and myofibroblasts phenotype transition. Conclusions: CD4+/CD8+/Foxp3+ regulate inflammation and mediate reparative processes in cardiac cells including myocytes and fibroblast after myocardial ischemic injury.
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