Coordination of endothelial cell positioning and fate specification by the epicardium

Pearl Quijada, Michael A. Trembley, Adwiteeya Misra, Jacquelyn A. Myers, Cameron D. Baker, Marta Pérez-Hernández, Jason R. Myers, Ronald A. Dirkx, Ethan David Cohen, Mario Delmar, John M. Ashton and Eric M. Small ()
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Pearl Quijada: University of Rochester School of Medicine and Dentistry
Michael A. Trembley: University of Rochester School of Medicine and Dentistry
Adwiteeya Misra: University of Rochester School of Medicine and Dentistry
Jacquelyn A. Myers: University of Rochester School of Medicine and Dentistry
Cameron D. Baker: University of Rochester School of Medicine and Dentistry
Marta Pérez-Hernández: New York University School of Medicine
Jason R. Myers: University of Rochester School of Medicine and Dentistry
Ronald A. Dirkx: University of Rochester School of Medicine and Dentistry
Ethan David Cohen: University of Rochester School of Medicine and Dentistry
Mario Delmar: New York University School of Medicine
John M. Ashton: University of Rochester School of Medicine and Dentistry
Eric M. Small: University of Rochester School of Medicine and Dentistry

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract The organization of an integrated coronary vasculature requires the specification of immature endothelial cells (ECs) into arterial and venous fates based on their localization within the heart. It remains unclear how spatial information controls EC identity and behavior. Here we use single-cell RNA sequencing at key developmental timepoints to interrogate cellular contributions to coronary vessel patterning and maturation. We perform transcriptional profiling to define a heterogenous population of epicardium-derived cells (EPDCs) that express unique chemokine signatures. We identify a population of Slit2+ EPDCs that emerge following epithelial-to-mesenchymal transition (EMT), which we term vascular guidepost cells. We show that the expression of guidepost-derived chemokines such as Slit2 are induced in epicardial cells undergoing EMT, while mesothelium-derived chemokines are silenced. We demonstrate that epicardium-specific deletion of myocardin-related transcription factors in mouse embryos disrupts the expression of key guidance cues and alters EPDC-EC signaling, leading to the persistence of an immature angiogenic EC identity and inappropriate accumulation of ECs on the epicardial surface. Our study suggests that EC pathfinding and fate specification is controlled by a common mechanism and guided by paracrine signaling from EPDCs linking epicardial EMT to EC localization and fate specification in the developing heart.

Date: 2021
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DOI: 10.1038/s41467-021-24414-z

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