title: Myocardin-related transcription factors control the motility of epicardium-derived cells and the maturation of coronary vessels.
abstract: An important pool of cardiovascular progenitor cells arises from the epicardium, a single layer of mesothelium lining the heart. Epicardium-derived progenitor cell (EPDC) formation requires epithelial-to-mesenchymal transition (EMT) and the subsequent migration of these cells into the sub-epicardial space. Although some of the physiological signals that promote EMT are understood, the functional mediators of EPDC motility and differentiation are not known. Here, we identify a novel regulatory mechanism of EPDC mobilization. Myocardin-related transcription factor (MRTF)-A and MRTF-B (MKL1 and MKL2, respectively) are enriched in the perinuclear space of epicardial cells during development. Transforming growth factor (TGF)-β signaling and disassembly of cell contacts leads to nuclear accumulation of MRTFs and the activation of the motile gene expression program. Conditional ablation of Mrtfa and Mrtfb specifically in the epicardium disrupts cell migration and leads to sub-epicardial hemorrhage, partially stemming from the depletion of coronary pericytes. Using lineage-tracing analyses, we demonstrate that sub-epicardial pericytes arise from EPDCs in a process that requires the MRTF-dependent motile gene expression program. These findings provide novel mechanisms linking EPDC motility and differentiation, shed light on the transcriptional control of coronary microvascular maturation and suggest novel therapeutic strategies to manipulate epicardium-derived progenitor cells for cardiac repair.
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Trembley
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA.
authors.forename: Lissette S
authors.initials: LS
authors.lastname: Velasquez
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: de Mesy Bentley
authors.affiliation: Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14624, USA Eric_Small@URMC.Rochester.edu.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Small
mesh_terms: D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D003331:Coronary Vessels / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010496:Pericardium / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D020286:Pericytes / Q000166:cytology / Q000187:drug effects; D026362:Serum Response Factor / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: C511173:Mrtfa protein, mouse; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C503315:myocardin-related transcription factor B, mouse
keywords: Epicardium; Heart; Migration; Pericyte; Progenitor; Transcription