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High-resolution transcriptomic profiling of the heart during chronic stress reveals cellular drivers of cardiac fibrosis and hypertrophy

Version 2 2023-10-19, 05:53
Version 1 2020-12-14, 04:07
journal contribution
posted on 2023-10-19, 05:53 authored by Micheal A McLellan, Daniel A Skelly, Malathi SI Dona, Galen T Squiers, Gabriella FarrugiaGabriella Farrugia, Taylah GaynorTaylah Gaynor, Charles Cohen, Raghav Pandey, Henry DiepHenry Diep, Antony VinhAntony Vinh, Nadia A Rosenthal, Ruvantha PintoRuvantha Pinto
© 2020 Lippincott Williams and Wilkins. All rights reserved. Background: Cardiac fibrosis is a key antecedent to many types of cardiac dysfunction including heart failure. Physiological factors leading to cardiac fibrosis have been recognized for decades. However, the specific cellular and molecular mediators that drive cardiac fibrosis, and the relative effect of disparate cell populations on cardiac fibrosis, remain unclear. Methods: We developed a novel cardiac single-cell transcriptomic strategy to characterize the cardiac cellulome, the network of cells that forms the heart. This method was used to profile the cardiac cellular ecosystem in response to 2 weeks of continuous administration of angiotensin II, a profibrotic stimulus that drives pathological cardiac remodeling. Results: Our analysis provides a comprehensive map of the cardiac cellular landscape uncovering multiple cell populations that contribute to pathological remodeling of the extracellular matrix of the heart. Two phenotypically distinct fibroblast populations, Fibroblast-Cilp and Fibroblast-Thbs4, emerged after induction of tissue stress to promote fibrosis in the absence of smooth muscle actin-expressing myofibroblasts, a key profibrotic cell population. After angiotensin II treatment, Fibroblast-Cilp develops as the most abundant fibroblast subpopulation and the predominant fibrogenic cell type. Mapping intercellular communication networks within the heart, we identified key intercellular trophic relationships and shifts in cellular communication after angiotensin II treatment that promote the development of a profibrotic cellular microenvironment. Furthermore, the cellular responses to angiotensin II and the relative abundance of fibrogenic cells were sexually dimorphic. Conclusions: These results offer a valuable resource for exploring the cardiac cellular landscape in health and after chronic cardiovascular stress. These data provide insights into the cellular and molecular mechanisms that promote pathological remodeling of the mammalian heart, highlighting early transcriptional changes that precede chronic cardiac fibrosis.


This work is supported by National Health and Medical Research Council (Australia) Ideas Grant (GNT1188503) to Dr Pinto. JAX Cores are supported by the Jackson Laboratory Cancer Center Core grant and the Leducq Foundation Transatlantic Network of Excellence in Cardiac Research to Dr Rosenthal. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by National Cancer Institute, National Human Genome Research Institute, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke.


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Article Number



16p. (p. 1448-1463)


Wolters Kluwer Health



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