Identification of Myocardial and Vascular Precursor Cells in Human and Mouse Epicardium

Abstract

Abstract-During cardiac development, the epicardium is the source of multipotent mesenchymal cells, which give rise to endothelial and smooth muscle cells in coronary vessels and also, possibly, to cardiomyocytes. The aim of the present study was to determine whether stem cells are retained in the adult human and murine epicardium and to investigate the regenerative potential of these cells following acute myocardial infarction. We show that c-kit ϩ and CD34 ϩ cells can indeed be detected in human fetal and adult epicardium and that they represent 2 distinct populations. Both subsets of cells were negative for CD45, a cell surface marker that identifies the hematopoietic cell lineage. Immunofluorescence revealed that freshly isolated c-kit ϩ and CD34 ϩ cells expressed early and late cardiac transcription factors and could acquire an endothelial phenotype in vitro. In the murine model of myocardial infarction, there was an increase in the absolute number and proliferation of epicardial c-kit ϩ cells 3 days after coronary ligation; at this time point, epicardial c-kit ϩ cells were identified in the subepicardial space and expressed GATA4. Furthermore, 1 week after myocardial infarction, cells coexpressing c-kit ϩ , together with endothelial or smooth muscle cell markers, were identified in the wall of subepicardial blood vessels. In summary, the postnatal epicardium contains a cell population with stem cell characteristics that retains the ability to give rise to myocardial precursors and vascular cells. These cells may play a role in the regenerative response to cardiac damage. Key Words: epicardium Ⅲ infarction Ⅲ stem cells Ⅲ cardiovascular differentiation M yocardial infarction (MI) in the mammalian heart is associated with an acute inflammatory response, leading to the replacement of injured cardiomyocytes with granulation tissue and scar. 1 Recently it has been shown that the heart is a dynamic organ in which spontaneous myocyte regeneration together with myocyte death are major determinants of cardiac homeostasis in physiologic and pathologic conditions. 2 Myocardial regeneration appears to be mediated by multipotent cardiac stem cells (CSCs), resident in the heart, that give rise to new myocytes and vascular structures. A variety of studies document the presence of CSCs in the mouse, 3-10 rat, 11 dog, 12 and human adult heart. 7,13 The adult myocardium is enveloped by a layer of epithelial cells called epicardium that during embryogenesis, plays an important role in the formation of the coronary vasculature. The epicardium has an extracardiac origin: at approximately stage 18 in the avian heart and 10.5 days post coitum in the mouse, a cluster of cells derived from septum transversum in mammals and located close to the liver primordium in other vertebrates, populates the myocardial external surface of the heart. 14 Epicardial cells synthesize a dense layer of extracellular matrix that resides between them and the myocardium in the subepicardial space. A subset of these cells delaminate from the epicardium a...

Controlled delivery of fibroblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration

“…Thus, this finding suggests a potential role for NRG1 in cardiac progenitor recruitment. Moreover, it has been reported that c-Kit + progenitor cells can present a vascular phenotype, which might suggest that they participate in de novo vessel formation [40]. Nevertheless, we did not detect the recruitment of specific progenitors with a vascular phenotype.…”

The role of endothelial–mesenchymal transition in development and pathological process

“…Immunohistological analyses reveal that canonical Wnt activity is primarily confined to endothelial cells and a-SMA expressing in mesenchymal cells. The cell lineage tracing analysis demonstrates that at least half of the subepicardial SMA 1 cells within granulation tissue are endothelial origin, possibly through EndMT (20). Similar to epicardial cells, which undergo EMT and mainly adopt myofibroblast, fibroblast, and smooth muscle cell fates after MI, endothelial cells may be an additional significant source of repair cells after infarction.…”

Electrical competence of infarcted heart following stem cell based regenerative therapy, in a rat model

“…The heart contains several cohorts of resident cardiac progenitor cells (CPCs) which have been characterized by different groups (Beltrami AP et al 2003; Oh H et al 2003, Martin CM et al 2004, Messina E et al 2004, Laugwitz KL et al 2005, Limana F et al 2007, Davis DR et al 2010) and are considered to be responsible for tissue homeostasis (Quaini F et al 2002). Because CPCs are intrinsically programmed to generate myocardium, they appear best suited for the complex task of reconstituting tissue that is lost with a myocardial infarction (Chamuleau SA et al 2009) and restoring the blood supply in the damaged area (Dawn B et al 2005).…”