Transcriptional remodeling of cardiomyocytes and fibroblasts during post-myocardial infarction recovery

Figures

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  Fig. 1. Alteration in surface electrogram and Impairment of Left ventricular function at Wk-1 and Wk-4 Post-MI mice. A Electrocardiogram showing the ST elevation after ligation demonstrated by ECG traces and waterfall plots. B The ECG traces and waterfall plots at post-MI Wk-1 and Wk-4. C Masson’s trichrome (MT) staining of longitudinal sections at the point of ligation of the left ventricle from Control, Wk-1, and Wk-4 post-MI mice hearts. D Echocardiogram recording from Control, Wk-1, and Wk-4 post-MI mouse. E, F Changes in echocardiographic parameters during post-MI Wk-1 and Wk-4. Statistical significance of the difference between control and WK-1 & WK-4 of MI mice was assessed by one-way ANOVA test (Tukey’s multiple comparison); **p < 0.01 and ****p < 0.0001).

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  Fig. 2. Compositional changes in cardiac cells post-MI. A Schematic representation of experimental plan showing the collection of the left ventricle from the control mice heart and post-MI Wk-1 & Wk-4 subjected to snRNA sequencing. B The UMAP plot showing 9 annotated cell clusters. C The proportional distribution of the number of cells across samples for each cell type. D Distribution of subclusters for each annotated cell type. E UMAP plots demonstrate the change in cluster composition for cardiomyocytes and fibroblasts across different samples. F, G The distribution (counts and proportions) of cells in subclusters across different samples for cardiomyocytes and fibroblasts. CM: Cardiomyocytes; FB: Fibroblasts; ET: Endothelial cells; EC: Endocardial cells; SM: Smooth Muscle cells; VC: Valve cells; TC: T-Cells; and BC: B-Cells.

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  Fig. 3. Transcriptional variations during the disease state in CMs post-MI. A Venn diagram showing the overlap and distinct sets of differentially expressed genes (DEGs) in CMs across control, Wk-1, and Wk-4 post-MI conditions. B Hierarchical clustering heatmap of CM transcriptomes indicating distinct gene expression profiles among control, Wk-1, and Wk-4 samples. C Violin plots demonstrating increased expression of Nppa, Nppb, Myh6, Myh7, Ttn, Ankrd1, Mybpc3, and Mylk4 in CM clusters post-MI. D Violin plot showing the change in Myh6/7 ratio post-MI. E The gene set enrichment analysis (GSEA plots) for DEGs shows a significant enrichment in mitochondrial protein subunits and oxidative phosphorylation pathways. Most genes were downregulated in Wk-1 and then restored their expression by Wk-4. F The heatmap shows the expression pattern of mitochondrial subunit & oxidative phosphorylation proteins. G The expression of ECM genes (Fn1, Col1a1, Col1a2, Col3a1) was found to increase during Wk-1 post-MI in CMs. H The DEGs patterns demonstrate that there is a decline in mitochondrial protein subunits and oxidative phosphorylation genes during Wk-1, which is gradually restored during Wk-4. The…

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  Fig. 4. Differential gene expression analysis in FBs. A Venn diagram showing the overlap and distinct sets of differentially expressed genes (DEGs) in FBs across control, Wk-1, and Wk-4 post-MI conditions. B Hierarchical clustering heatmap of FB transcriptomes indicating distinct gene expression profiles among control, Wk-1, and Wk-4 samples. C Violin and feature plots illustrating the expression of key FB activation markers (Postn, Tgfb3, Fn1) across conditions, with highest expression observed at Wk-1 post-MI. D GO enrichment analysis of DEGs in FBs at Wk-1 (top) and Wk-4 (bottom). Wk-1 FBs were enriched for extracellular matrix (ECM)-related processes, while Wk-4 FBs showed enrichment for pathways related to vascular and chondrocyte differentiation. E Violin plots showing expression levels of genes involved in collagen fibril organization (Col1a1, Col3a1, Col1a2, Col5a2, Col27a1, Col14a1), ECM regulation (Loxl3, Serpinh1), which are upregulated at Wk-1. F Violin plots displaying increased expression of genes associated with vascular-associated smooth muscle cell differentiation (Cfh, C3, Comp, Smad6) at Wk-4. G Violin plots showing expression of genes involved in regulation of…

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  Fig. 5. Differential secretory signaling between cardiac cells post-MI. A The total number of ligand-receptor interactions and their strength (as predicted by CellChat) for all cell types gradually increased in post-MI Wk-1 to Wk-4. B The scatter plot shows the change in outgoing and incoming interaction strength for different cell types in control, post-MI Wk-1 and Wk-4 samples. The outgoing strength of FBs was increased gradually during Wk-1 and Wk-4 post-MI as indicated by red arrow. C The interaction weight for the outgoing signaling in FBs demonstrates an overall increase in outgoing signals. D The bar plot showing the change in outgoing signaling weight/strength from FBs to all other cells. E The dot plot demonstrated outgoing signaling communications from FBs to other cell types that were significantly enriched in control, post-MI Wk-1 and Wk-4 samples. Highlighted with the red boxes are the three signaling pathways that are specifically activated during the post-MI Wk-1, demonstrating the communication between FBs and CMs. The signaling pathways from FBs to ECs that are highlighted during Wk-4 are highlighted with blue boxes. F Violin plot showing the expression change of the…