Single-Cell Resolution of Temporal Gene Expression during Heart Development

• Published in: Developmental cell Vol. 39; no. 4; pp. 480 - 490
• Main Authors: DeLaughter, Daniel M., Bick, Alexander G., Wakimoto, Hiroko, McKean, David, Gorham, Joshua M., Kathiriya, Irfan S., Hinson, John T., Homsy, Jason, Gray, Jesse, Pu, William, Bruneau, Benoit G., Seidman, J.G., Seidman, Christine E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.11.2016
• Subjects: Animals; atria; cardiogenesis; cardiomyocyte maturation; Cell Differentiation - genetics; Cell Lineage - genetics; ECM; Endothelial Cells - cytology; Endothelial Cells - metabolism; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Expression Profiling; Gene Expression Regulation, Developmental; Haploinsufficiency - genetics; heart; Heart - embryology; Heart Atria - cytology; Heart Ventricles - cytology; Homeobox Protein Nkx-2.5 - metabolism; Humans; Mice; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Nkx2.5; RNA-seq; Sequence Analysis, RNA; single cell; Single-Cell Analysis - methods; Time Factors; Transcriptome - genetics; ventricle; single cell; cardiogenesis; RNA-seq; ventricle; cardiomyocyte maturation; atria; Nkx2.5; heart; ECM
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2016.10.001

Activation of complex molecular programs in specific cell lineages governs mammalian heart development, from a primordial linear tube to a four-chamber organ. To characterize lineage-specific, spatiotemporal developmental programs, we performed single-cell RNA sequencing of >1,200 murine cells isolated at seven time points spanning embryonic day 9.5 (primordial heart tube) to postnatal day 21 (mature heart). Using unbiased transcriptional data, we classified cardiomyocytes, endothelial cells, and fibroblast-enriched cells, thus identifying markers for temporal and chamber-specific developmental programs. By harnessing these datasets, we defined developmental ages of human and mouse pluripotent stem-cell-derived cardiomyocytes and characterized lineage-specific maturation defects in hearts of mice with heterozygous mutations in Nkx2.5 that cause human heart malformations. This spatiotemporal transcriptome analysis of heart development reveals lineage-specific gene programs underlying normal cardiac development and congenital heart disease. •Single-cell RNA-seq data characterizing >1,200 murine cells from E9.5–P21 hearts•Dynamic spatiotemporal gene expression defines distinct cardiomyocyte populations•Human/mouse stem-cell-derived cardiomyocytes are developmentally immature•Nkx2.5+/− mice have lineage-specific maturation defects in cardiac cells Using spatiotemporal RNA-seq analyses of single cells isolated from E9.5–P21 mouse hearts, DeLaughter, Bick et al. reveal the dynamic transcriptional programs directing cardiomyocyte maturation during heart development. These data provide benchmarks for assessing lineage-specific maturation of differentiated stem cells and a basis for interrogating how human mutations cause congenital heart malformations.