Stage specific transcriptome profiles at cardiac lineage commitment during cardiomyocyte differentiation from mouse and human pluripotent stem cells
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Cardiomyocyte differentiation occurs through complex andfinely regulated processes including cardiac lineage commitmentand maturation from pluripotent stem cells (PSCs). To gainsome insight into the genome-wide characteristics of cardiaclineage commitment, we performed transcriptome analysis onboth mouse embryonic stem cells (mESCs) and human inducedPSCs (hiPSCs) at specific stages of cardiomyocyte differentiation. Specifically, the gene expression profiles and the protein–protein interaction networks of the mESC-derived plateletderivedgrowth factor receptor-alpha (PDGFRα)+ cardiac lineagecommittedcells (CLCs) and hiPSC-derived kinase insert domainreceptor (KDR)+ and PDGFRα+ cardiac progenitor cells (CPCs)at cardiac lineage commitment were compared with those ofmesodermal cells and differentiated cardiomyocytes. GeneOntology and Kyoto Encyclopedia of Genes and Genomes pathwayanalyses revealed that the genes significantly upregulatedat cardiac lineage commitment were associated with responsesto organic substances and external stimuli, extracellular andmyocardial contractile components, receptor binding, gatedchannel activity, PI3K‑AKT signaling, and cardiac hypertrophyand dilation pathways. Protein–protein interaction networkanalysis revealed that the expression levels of genes thatregulate cardiac maturation, heart contraction, and calciumhandling showed a consistent increase during cardiac differentiation;however, the expression levels of genes that regulatecell differentiation and multicellular organism developmentdecreased at the cardiac maturation stage following lineagecommitment. Additionally, we identified for the first time theprotein–protein interaction network connecting cardiac development,the immune system, and metabolism during cardiac lineagecommitment in both mESC-derived PDGFRα+ CLCs andhiPSC-derived KDR+PDGFRα+ CPCs. These findings shedlight on the regulation of cardiac lineage commitment and thepathogenesis of cardiometabolic diseases.
Abstract
Cardiomyocyte differentiation occurs through complex andfinely regulated processes including cardiac lineage commitmentand maturation from pluripotent stem cells (PSCs). To gainsome insight into the genome-wide characteristics of cardiaclineage commitment, we performed transcriptome analysis onboth mouse embryonic stem cells (mESCs) and human inducedPSCs (hiPSCs) at specific stages of cardiomyocyte differentiation. Specifically, the gene expression profiles and the protein–protein interaction networks of the mESC-derived plateletderivedgrowth factor receptor-alpha (PDGFRα)+ cardiac lineagecommittedcells (CLCs) and hiPSC-derived kinase insert domainreceptor (KDR)+ and PDGFRα+ cardiac progenitor cells (CPCs)at cardiac lineage commitment were compared with those ofmesodermal cells and differentiated cardiomyocytes. GeneOntology and Kyoto Encyclopedia of Genes and Genomes pathwayanalyses revealed that the genes significantly upregulatedat cardiac lineage commitment were associated with responsesto organic substances and external stimuli, extracellular andmyocardial contractile components, receptor binding, gatedchannel activity, PI3K‑AKT signaling, and cardiac hypertrophyand dilation pathways. Protein–protein interaction networkanalysis revealed that the expression levels of genes thatregulate cardiac maturation, heart contraction, and calciumhandling showed a consistent increase during cardiac differentiation;however, the expression levels of genes that regulatecell differentiation and multicellular organism developmentdecreased at the cardiac maturation stage following lineagecommitment. Additionally, we identified for the first time theprotein–protein interaction network connecting cardiac development,the immune system, and metabolism during cardiac lineagecommitment in both mESC-derived PDGFRα+ CLCs andhiPSC-derived KDR+PDGFRα+ CPCs. These findings shedlight on the regulation of cardiac lineage commitment and thepathogenesis of cardiometabolic diseases.
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