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The deployment of cell lineages that form the mammalian heart

Abstract

The function of the mammalian heart depends on the interplay between different cardiac cell types. The deployment of these cells, with precise spatiotemporal regulation, is also important during development to establish the heart structure. In this Review, we discuss the diverse origins of cardiac cell types and the lineage relationships between cells of a given type that contribute to different parts of the heart. The emerging lineage tree shows the progression of cell fate diversification, with patterning cues preceding cell type segregation, as well as points of convergence, with overlapping lineages contributing to a given tissue. Several cell lineage markers have been identified. However, caution is required with genetic-tracing experiments in comparison with clonal analyses. Genetic studies on cell populations provided insights into the mechanisms for lineage decisions. In the past 3 years, results of single-cell transcriptomics are beginning to reveal cell heterogeneity and early developmental trajectories. Equating this information with the in vivo location of cells and their lineage history is a current challenge. Characterization of the progenitor cells that form the heart and of the gene regulatory networks that control their deployment is of major importance for understanding the origin of congenital heart malformations and for producing cardiac tissue for use in regenerative medicine.

Key points

  • Clonal analysis shows that two myocardial cell lineages, which segregate early at gastrulation, form the heart, with cell sublineages contributing to the arterial and venous poles, with early left–right delineation.

  • The origin and cell fate choices of non-myocardial progenitors, such as those that give rise to cardiac interstitial fibroblasts or the coronary vasculature, are now clearer.

  • Overlapping cell sources provide potential for compensatory mechanisms, and thus developmental robustness, a process that is just beginning to be characterized.

  • As the heart begins to form, cardiac progenitors are located in the first and second heart fields, with characteristic and diverse gene expression patterns marking their cardiac contributions, which correspond to the first and second myocardial lineages.

  • Gene regulatory networks, governed by transcription factors, cofactors and chromatin modifications, in which non-coding RNAs also participate, control the deployment of cardiac progenitor cells during cardiogenesis.

  • Single-cell analyses have identified early cardiac progenitor cell types, providing new insights into cell heterogeneity and developmental trajectories of cardiac cells as the heart develops.

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Fig. 1: Cardiogenesis stages in the mouse.
Fig. 2: Cell lineage tree of cardiac and associated skeletal muscles.
Fig. 3: Location of cardiac progenitors and their derivatives.
Fig. 4: Gene regulatory networks in cardiac development.
Fig. 5: Sources of the different cardiac cell types.

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Acknowledgements

Work in the group of S.M.M. is supported by the Institut Imagine, the Institut Pasteur, INSERM and the Université Paris Descartes. M.E.B. acknowledges support from the Institut Pasteur and the Centre National de la Recherche Scientifique (CNRS; UMR 3738). The authors thank R. Kelly (Institut de Biologie du Développement de Marseille, France) and S. Zaffran and F. Lescroart (Marseille Medical Genetics, France) for helpful comments on the manuscript.

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Meilhac, S.M., Buckingham, M.E. The deployment of cell lineages that form the mammalian heart. Nat Rev Cardiol 15, 705–724 (2018). https://doi.org/10.1038/s41569-018-0086-9

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