Abstract
Most of the mammalian heart is formed from mesodermal progenitors in the first and second heart fields (FHF and SHF), whereby the FHF gives rise to the left ventricle and parts of the atria and the SHF to the right ventricle, outflow tract and parts of the atria. Whereas SHF progenitors have been characterized in detail, using specific molecular markers, comprehensive studies on the FHF have been hampered by the lack of exclusive markers. Here, we present Hcn4 (hyperpolarization-activated cyclic nucleotide-gated channel 4) as an FHF marker. Lineage-traced Hcn4+/FHF cells delineate FHF-derived structures in the heart and primarily contribute to cardiomyogenic cell lineages, thereby identifying an early cardiomyogenic progenitor pool. As a surface marker, HCN4 also allowed the isolation of cardiomyogenic Hcn4+/FHF progenitors from human embryonic stem cells. We conclude that a primary purpose of the FHF is to generate cardiac muscle and support the contractile activity of the primitive heart tube, whereas SHF-derived progenitors contribute to heart cell lineage diversification.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biomarkers / metabolism
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Cell Differentiation
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Cell Lineage
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Cyclic Nucleotide-Gated Cation Channels / genetics*
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Cyclic Nucleotide-Gated Cation Channels / metabolism
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Embryo, Mammalian
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Embryonic Stem Cells / cytology*
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Embryonic Stem Cells / metabolism
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Gene Expression Regulation, Developmental
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Heart Atria / cytology
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Heart Atria / embryology
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Heart Atria / metabolism
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Heart Ventricles / cytology
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Heart Ventricles / embryology
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Heart Ventricles / metabolism
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Humans
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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
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Mesoderm / cytology
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Mesoderm / metabolism
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Mice
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Morphogenesis*
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Muscle Proteins / genetics*
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Muscle Proteins / metabolism
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Myocardium / cytology*
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Myocardium / metabolism
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Myocytes, Cardiac / cytology*
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Myocytes, Cardiac / metabolism
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Pluripotent Stem Cells / cytology*
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Pluripotent Stem Cells / metabolism
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Potassium Channels
Substances
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Biomarkers
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Cyclic Nucleotide-Gated Cation Channels
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HCN4 protein, human
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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
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Muscle Proteins
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Potassium Channels