Fig. 5: CCNA2 expression induces reprogramming, cytokinesis, and proliferation in mouse cardiomyocytes.
From: Cyclin A2 induces cytokinesis in human adult cardiomyocytes and drives reprogramming in mice
A t-SNE projection showing Ryr2 expression across cardiomyocyte subpopulations in nTg and CCNA2-Tg mice. Ryr2+ cardiomyocytes correspond to a more mature ventricular cardiomyocyte (vCM) state, whereas Ryr2 low-expression cardiomyocytes represent less mature, or proliferative cardiomyocytes. Quantification of Ryr2 expression levels among cardiomyocyte subpopulations is shown in the accompanying violin plot, highlighting differences in Ryr2 expression across conditions. B t-SNE plots and representative scatter plots and Violin plots representing the expression of key proliferation, (C) cytokinesis, and (D) reprogramming gene markers in both CCNA2-Tg and nTg mice. Individual points represent median-normalized expression values for proliferation genes in Pro-vCMs. Two values were flagged as statistical outliers; these are retained to reflect biological heterogeneity within the proliferative program. E Representative dot plot of the differential gene expression analysis showing the upregulation of proliferation, cytokinesis, and reprogramming genes in CCNA2-Tg versus nTg cardiomyocytes. F Heatmaps of log-transformed gene expression changes in human fetal versus adult hearts, (G) and in CCNA2-Tg versus nTg cardiomyocytes. H Venn diagram showing shared upregulated genes between CCNA2-transgenic mouse hearts and human fetal hearts. The diagram displays the overlap of upregulated genes from CCNA2-Tg versus nTg mouse cardiomyocytes and human fetal versus adult heart RNA-seq datasets. These shared genes are further associated with cell cycle, cytokinesis, and cardiac development, supporting a dedifferentiation and reprogramming phenotype induced by CCNA2. I Heatmap showing expression z-scores of canonical hypertrophic markers alongside genes associated with EMT and cell cycle /cytokinesis across different conditions: non-transgenic nTg, CCNA2-Tg, Sham-operated, and (8 weeks) transverse aortic banding (TAB) cardiomyocytes. The heatmap illustrates distinct gene expression patterns differentiating CCNA2-induced regenerative reprogramming from hypertrophic remodeling in pathological pressure overload. J Pathway enrichment analysis showing significantly enriched pathways in the human adult (top) and fetal (bottom) heart. In the adult heart, pathways related to metabolism and energy are enriched, based on 4348 downregulated genes and 3713 upregulated genes (P < 0.05). In the fetal heart, cell cycle, DNA/RNA processing, and signaling pathways are enriched (P < 0.05).
