Journal
DEVELOPMENT
Volume 142, Issue 1, Pages 21-30Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.116418
Keywords
Heart; Epicardium; Migration; Progenitor; Pericyte; Transcription
Categories
Funding
- National Institutes of Health (NIH) [R01HL120919]
- American Heart Association [10SDG4350046]
- University of Rochester CTSA award from the NIH [UL1 TR000042]
- Aab CVRI
- Howard Hughes Medical Institute Med-Into-Grad Initiative
- Institutional Ruth L. Kirschstein National Research Service Award from the NIH [GM068411]
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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)-beta 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 subepicardial 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.
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