Abstract
The epicardium has emerged as a multipotent cardiovascular progenitor source with therapeutic potential for coronary smooth muscle cell, cardiac fibroblast (CF) and cardiomyocyte regeneration, owing to its fundamental role in heart development and its potential ability to initiate myocardial repair in injured adult tissues. Here, we describe a chemically defined method for generating epicardium and epicardium-derived smooth muscle cells (EPI-SMCs) and CFs from human pluripotent stem cells (HPSCs) through an intermediate lateral plate mesoderm (LM) stage. HPSCs were initially differentiated to LM in the presence of FGF2 and high levels of BMP4. The LM was robustly differentiated to an epicardial lineage by activation of WNT, BMP and retinoic acid signalling pathways. HPSC-derived epicardium displayed enhanced expression of epithelial- and epicardium-specific markers, exhibited morphological features comparable with human foetal epicardial explants and engrafted in the subepicardial space in vivo. The in vitro-derived epicardial cells underwent an epithelial-to-mesenchymal transition when treated with PDGF-BB and TGFβ1, resulting in vascular SMCs that displayed contractile ability in response to vasoconstrictors. Furthermore, the EPI-SMCs displayed low density lipoprotein uptake and effective lowering of lipoprotein levels upon treatment with statins, similar to primary human coronary artery SMCs. Cumulatively, these findings suggest that HPSC-derived epicardium and EPI-SMCs could serve as important tools for studying human cardiogenesis, and as a platform for vascular disease modelling and drug screening.
Highlights
Epicardium and epicardium-derived cells (EPDCs) play crucial roles in embryonic heart formation
We investigated the effects of retinoic acid (RA) signalling, an important regulator of epicardial epithelial-to-mesenchymal transition (EMT) and coronary development in the specification of epicardium. Quantitative real-time polymerase chain reaction (qRT-PCR) revealed a substantial increase in the expression of TBX18, WT1 and TCF21 in RAtreated lateral plate mesoderm (LM) cells compared with other signalling conditions (Fig. 2A)
In this study, we report a simple chemically defined monolayer method to generate epicardium and its differentiated SMC and cardiac fibroblast (CF) progeny from the LM
Summary
Epicardium and epicardium-derived cells (EPDCs) play crucial roles in embryonic heart formation. Anne McLaren Laboratory for Regenerative Medicine and Wellcome Trust-Medical Research Council, Cambridge Stem Cell Institute, University of Cambridge, West Forvie Site, Robinson Way, Cambridge CB2 0SZ, UK. An emerging paradigm proposes that re-activation of the embryonic developmental program in injured adult epicardial tissues by ectopic signals can mediate epicardium differentiation towards cardiogenic fates or enhance the existing level of signalling activity within the epicardium (Smart et al, 2007). An in vitro model that recapitulates the key events regulating early lineage commitment to epicardium and its derivatives would facilitate efficient and reproducible generation of highly enriched vascular cells for potential applications in vascular disease modelling, drug screening and construction of bioengineered cardiac grafts
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