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Yang, Donghe; Gomez-Garcia, Juliana; Funakoshi, Shunsuke; Tran, Thinh; Fernandes, Ian; Bader, Gary D.; Laflamme, Michael A.; Keller, Gordon M.
Cell stem cell, 09/2022, Volume: 29, Issue: 9Journal Article
The cardiomyocyte (CM) subtypes in the mammalian heart derive from distinct lineages known as the first heart field (FHF), the anterior second heart field (aSHF), and the posterior second heart field (pSHF) lineages that are specified during gastrulation. We modeled human heart field development from human pluripotent stem cells (hPSCs) by using single-cell RNA-sequencing to delineate lineage specification and progression. Analyses of hPSC-derived and mouse mesoderm transcriptomes enabled the identification of distinct human FHF, aSHF, and pSHF mesoderm subpopulations. Through staged manipulation of signaling pathways identified from transcriptomics, we generated myocyte populations that display molecular characteristics of key CM subtypes. The developmental trajectory of the human cardiac lineages recapitulated that of the mouse, demonstrating conserved cardiovascular programs. These findings establish a comprehensive landscape of human embryonic cardiogenesis that provides access to a broad spectrum of cardiomyocytes for modeling congenital heart diseases and chamber-specific cardiomyopathies as well as for developing new therapies to treat them. Display omitted •ScRNA-seq profiling of human heart field development spanning various stages•Comparisons of hPSC-derived, human fetal-, and mouse fetal-cardiac populations•Identification of pathways involved in the development of heart field lineages•Generation of functionally and transcriptionally distinct cardiomyocyte (CM) subtypes We describe hPSC-derived models of FHF, aSHF, and pSHF development spanning the mesoderm, progenitor, and cardiomyocyte stages. Comparison between the hPSC-derived and the corresponding mouse populations revealed conserved developmental trajectories across the species. Access to cardiomyocyte subtypes derived from different heart fields enables modeling chamber-specific diseases and developing new therapies.
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