Abstract
Endothelial cells and mesenchymal cells are two different cell types with distinct morphologies, phenotypes, functions, and gene profiles. Accumulating evidence, notably from lineage-tracing studies, indicates that the two cell types convert into each other during cardiovascular development and pathogenesis. During heart development, endothelial cells transdifferentiate into mesenchymal cells in the endocardial cushion through endothelial-to-mesenchymal transition (EndoMT), a process that is critical for the formation of cardiac valves. Studies have also reported that EndoMT contributes to the development of various cardiovascular diseases, including myocardial infarction, cardiac fibrosis, valve calcification, endocardial elastofibrosis, atherosclerosis, and pulmonary arterial hypertension. Conversely, cardiac fibroblasts can transdifferentiate into endothelial cells and contribute to neovascularization after cardiac injury. However, progress in genetic lineage tracing has challenged the role of EndoMT, or its reversed programme, in the development of cardiovascular diseases. In this Review, we discuss the caveats of using genetic lineage-tracing technology to investigate cell-lineage conversion; we also reassess the role of EndoMT in cardiovascular development and diseases and elaborate on the molecular signals that orchestrate EndoMT in pathophysiological processes. Understanding the role and mechanisms of EndoMT in diseases will unravel the therapeutic potential of targeting this process and will provide a new paradigm for the development of regenerative medicine to treat cardiovascular diseases.
Key points
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Endothelial cells are converted to mesenchymal cells through endothelial-to-mesenchymal transition (EndoMT) during cardiovascular development.
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EndoMT also has a critical role in the development of cardiovascular diseases, including cardiac valve diseases, tissue fibrosis, pulmonary arterial hypertension, and atherosclerosis.
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The involvement of EndoMT in fibroblast contribution during cardiac fibrosis is an ongoing debate.
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Lineage-tracing studies indicate that resident fibroblasts, rather than EndoMT, give rise to the majority of myofibroblasts after injury.
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Pre-existing endothelial cells, but not mesenchymal-to-endothelial transition, are the main source that mediates neovascularization after cardiac injury.
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Acknowledgements
The authors thank L. He and H. Zhang (Shanghai Institutes for Biological Sciences, China) for providing the images of staining and other laboratory members for their valuable suggestions and insightful advice for the completion of this Review. The authors are supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS, XDB19000000, and XDA16020204), the National Science Foundation of China (31730112, 91639302, 31625019, and 81761138040), National key Research & Development Program of China (2016YFC1300600 and 2017YFC1001303), the Research Council of Hong Kong (04110515, 14111916, and C4024-16W), and the Health and Medical Research Fund (03140346 and 04152566).
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Nature Reviews Cardiology thanks J. Bischoff, E. Dejana, and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Y.L. searched for reference articles and drafted the paper. K.O.L. and B.Z. wrote and revised the article. All authors provided substantial contributions to the scientific discussion and reviewed and edited the manuscript before submission.
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Glossary
- Endothelial-to-mesenchymal transition
-
The transformation or differentiation of endothelial cells into mesenchymal cells.
- Lineage tracing
-
The tracing of the progeny of a cell.
- Cre–loxP
-
A bacteriophage recombination system that is used in mouse genetic studies.
- Rosa26
-
A mouse gene locus that is open and allows ubiquitous transcription.
- Constitutive Cre
-
A form of Cre that is constantly expressed and active for Cre–loxP recombination in the cell type targeted.
- Inducible Cre
-
A form of Cre that is expressed in the cell type targeted but is active only after the administration of a drug.
- mT/mG
-
Membrane tdTomato fluorescent protein /membrane green fluorescent protein (GFP).
- Endocardial cushion
-
Cardiac jelly formed in the heart tube during valve formation.
- Neural crest
-
A ridge of embryonic neural folds that converge to form the neural tube.
- Rainbow or Confetti reporter
-
A type of reporter line that uses multiple fluorescence proteins.
- Partial EndoMT
-
A process during which endothelial cells retain both endothelial and mesenchymal phenotypes.
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Li, Y., Lui, K.O. & Zhou, B. Reassessing endothelial-to-mesenchymal transition in cardiovascular diseases. Nat Rev Cardiol 15, 445–456 (2018). https://doi.org/10.1038/s41569-018-0023-y
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DOI: https://doi.org/10.1038/s41569-018-0023-y
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