Lie-Venema Heleen, van den Akker Nynke M S, Bax Noortje A M, Winter Elizabeth M, Maas Saskia, Kekarainen Tuija, Hoeben Rob C, deRuiter Marco C, Poelmann Robert E, Gittenberger-de Groot Adriana C
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, The Netherlands.
ScientificWorldJournal. 2007 Nov 12;7:1777-98. doi: 10.1100/tsw.2007.294.
During heart development, cells of the primary and secondary heart field give rise to the myocardial component of the heart. The neural crest and epicardium provide the heart with a considerable amount of nonmyocardial cells that are indispensable for correct heart development. During the past 2 decades, the importance of epicardium-derived cells (EPDCs) in heart formation became increasingly clear. The epicardium is embryologically formed by the outgrowth of proepicardial cells over the naked heart tube. Following epithelial-mesenchymal transformation, EPDCs form the subepicardial mesenchyme and subsequently migrate into the myocardium, and differentiate into smooth muscle cells and fibroblasts. They contribute to the media of the coronary arteries, to the atrioventricular valves, and the fibrous heart skeleton. Furthermore, they are important for the myocardial architecture of the ventricular walls and for the induction of Purkinje fiber formation. Whereas the exact signaling cascades in EPDC migration and function still need to be elucidated, recent research has revealed several factors that are involved in EPDC migration and specialization, and in the cross-talk between EPDCs and other cells during heart development. Among these factors are the Ets transcription factors Ets-1 and Ets-2. New data obtained with lentiviral antisense constructs targeting Ets-1 and Ets-2 specifically in the epicardium indicate that both factors are independently involved in the migratory behavior of EPDCs. Ets-2 seems to be especially important for the migration of EPDCs into the myocardial wall, and to subendocardial positions in the atrioventricular cushions and the trabeculae. With respect to the clinical importance of correct EPDC development, the relation with coronary arteriogenesis has been noted well before. In this review, we also propose a role for EPDCs in cardiac looping, and emphasize their contribution to the development of the valves and myocardial architecture. Lastly, we focus on the congenital heart anomalies that might be caused primarily by an epicardial developmental defect.
在心脏发育过程中，第一和第二心脏场的细胞产生心脏的心肌成分。神经嵴和心外膜为心脏提供了大量对心脏正常发育不可或缺的非心肌细胞。在过去20年中，心外膜衍生细胞（EPDC）在心脏形成中的重要性日益明显。心外膜在胚胎学上由心外膜前体细胞在裸露的心管上生长形成。经过上皮-间充质转化后，EPDC形成心外膜下间充质，随后迁移到心肌中，并分化为平滑肌细胞和成纤维细胞。它们对冠状动脉的中膜、房室瓣和心脏纤维骨架有贡献。此外，它们对心室壁的心肌结构以及浦肯野纤维形成的诱导也很重要。虽然EPDC迁移和功能的确切信号级联仍有待阐明，但最近的研究揭示了一些参与EPDC迁移和特化以及心脏发育过程中EPDC与其他细胞之间相互作用的因素。这些因素包括Ets转录因子Ets-1和Ets-2。用慢病毒反义构建体在心脏外膜中特异性靶向Ets-1和Ets-2获得的新数据表明，这两个因子独立参与EPDC的迁移行为。Ets-2似乎对EPDC迁移到心肌壁以及房室垫和小梁的心内膜下位置尤为重要。关于EPDC正确发育的临床重要性，与冠状动脉生成的关系早就被注意到了。在这篇综述中，我们还提出了EPDC在心脏成环中的作用，并强调它们对瓣膜和心肌结构发育的贡献。最后，我们关注可能主要由心外膜发育缺陷引起的先天性心脏异常。
