Background-Proper development of compact myocardium, coronary vessels, and Purkinje fibers depends on the presence of epicardium-derived cells (EPDCs) in embryonic myocardium. We hypothesized that adult human EPDCs might partly reactivate their embryonic program when transplanted into ischemic myocardium and improve cardiac performance after myocardial infarction. Methods and Results-EPDCs were isolated from human adult atrial tissue. Myocardial infarction was created in immunodeficient mice, followed by intramyocardial injection of 4ϫ10 5 enhanced green fluorescent protein-labeled EPDCs (2-week survival, nϭ22; 6-week survival, nϭ15) or culture medium (nϭ24 and nϭ18, respectively). Left ventricular function was assessed with a 9.4T animal MRI unit. Ejection fraction was similar between groups on day 2 but was significantly higher in the EPDC-injected group at 2 weeks (short term), as well as after long-term survival at 6 weeks. End-systolic and end-diastolic volumes were significantly smaller in the EPDC-injected group than in the medium-injected group at all ages evaluated. At 2 weeks, vascularization was significantly increased in the EPDC-treated group, as was wall thickness, a development that might be explained by augmented DNA-damage repair activity in the infarcted area. Immunohistochemical analysis showed massive engraftment of injected EPDCs at 2 weeks, with expression of ␣-smooth muscle actin, von Willebrand factor, sarcoplasmic reticulum Ca 2ϩ -ATPase, and voltage-gated sodium channel (␣-subunit; SCN5a). EPDCs were negative for cardiomyocyte markers. At 6-weeks survival, wall thickness was still increased, but only a few EPDCs could be detected. Key Words: myocardial infarction Ⅲ stem cells Ⅲ remodeling Ⅲ magnetic resonance imaging Ⅲ angiogenesis C urrent therapy aimed at alleviating the sequelae of sustained myocardial infarction (MI) is not able to restore the function of the scarred area. Stem cell therapy poses a promising alternative therapy. Because therapeutic use of embryonic stem cells is an ethically intricate issue and is technically difficult in relation to the possible rejection of the cells and tumor formation, use of adult stem cells appears to be a more feasible option. Many different types of adult cells have been demonstrated to improve cardiac function after a MI, although the underlying mechanism has only been partially unraveled (for review, see Murry et al 1 ). Most of the cell types used are not known to be of importance during normal cardiogenesis. We chose to transplant epicardiumderived cells (EPDCs) because these cells are known to be crucial for cardiac development, because of both their physical contribution 2 and their modulatory role. 3,4 Conclusions-After Clinical Perspective p 927During embryogenesis, epicardium migrates from the extracardiac proepicardium to cover the premature heart, which by that time consists of only myocardium and endocardium, with cardiac jelly in between. 5 A subset of the epicardial cells undergoes epithelial-mesenchymal transformation (EMT...

Mesenchymal stem cells (MSCs) from healthy donors improve cardiac function in experimental acute myocardial infarction (AMI) models. However, little is known about the therapeutic capacity of human MSCs (hMSCs) from patients with ischemic heart disease (IHD). Therefore, the behavior of hMSCs from IHD patients in an immune-compromised mouse AMI model was studied. Enhanced green fluorescent protein-labeled hMSCs from IHD patients (hMSC group: 2 x 10(5) cells in 20 microl, n = 12) or vehicle only (medium group: n = 14) were injected into infarcted myocardium of NOD/scid mice. Sham-operated mice were used as the control (n = 10). Cardiac anatomy and function were serially assessed using 9.4-T magnetic resonance imaging (MRI); 2 wk after cell transplantation, immunohistological analysis was performed. At day 2, delayed-enhancement MRI showed no difference in myocardial infarction (MI) size between the hMSC and medium groups (33 +/- 2% vs. 36 +/- 2%; P = not significant). A comparable increase in left ventricular (LV) volume and decrease in ejection fraction (EF) was observed in both MI groups. However, at day 14, EF was higher in the hMSC than in the medium group (24 +/- 3% vs. 16 +/- 2%; P < 0.05). This was accompanied by increased vascularity and reduced thinning of the infarct scar. Engrafted hMSCs (4.1 +/- 0.3% of injected cells) expressed von Willebrand factor (16.9 +/- 2.7%) but no stringent cardiac or smooth muscle markers. hMSCs from patients with IHD engraft in infarcted mouse myocardium and preserve LV function 2 wk after AMI, potentially through an enhancement of scar vascularity and a reduction of wall thinning.

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Apoptosis in the atrioventricular canal myocardium and controlled replacement of this myocardium by epicardially derived HCN4-/Trop1- sulcus tissue are essential determinants of mature ventricular activation pattern. Disruption can lead to persistence of accessory atrioventricular connections, forming a morphological substrate for ventricular pre-excitation. Developmental Dynamics 247:1033-1042, 2018. © 2018 Wiley Periodicals, Inc.

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