311 Modeling and Rescue of PLN-R14del Cardiomyopathy Phenotype in Human iPSC-Derived Cardiac Spheroids 12 Figure 4. Single-cell transcriptional profiling of cardiac spheroids from PLN-R14del spheroids and healthy controls. (A) Bright-field images of the spheroids used for split-pool ligation-based transcriptome sequencing (SPLiT-seq). (B) UMAP of single cell profile with each cell color-coded for cells from healthy controls (WT, blue) and PLN-R14del spheroids (R14del, red). (C) Unsupervised Uniform Manifold Approximation and Projection (UMAP) clustering of single cells after QC and data filtering using Harmony integration. Expression patterns of hiPSC-derived cardiac spheroids from 374 healthy control and 384 PLN-R14del single cells were clustered using the Jaccard-Louvain method (3 clusters indicated by colors) and visualized using Uniform Manifold Approximation and Projection (UMAP). Cluster IDs were assigned after clustering based on cluster size, with Cluster 1 containing the most cells and Cluster 3 containing the least. (D) Gene Ontology (GO) enrichment analyses with the top hundred biological processes, cellular components, and molecular functions of the differentially expressed genes between PLN-R14del and healthy cardiac spheroid cells. GO-pathways are selected for 5 PLN-R14del phenotype classes; mitochondrial function (yellow), Unfolded protein Response (Red), Contractility (blue), Ca2+ handling (Purple), and Fibrosis (orange). A vertical black dotted line indicates the cut-off level for significance (P < 0.05). P-values were adjusted by Benjamini-Hochberg correction for multiple testing. (E) The differential expression levels of 5 PLN-R14del phenotype classes genes in
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