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.

STEM CELLS 2007;25:271-278

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training.

SUMMARY Efforts to prevent human immunodeficiency virus (HIV-1) infection would benefit from understanding the factors that govern virus neutralization by antibodies. We present a mechanistic model for HIV-1 neutralization that includes both virus and antibody parameters. Variations in epitope integrity on the viral envelope glycoprotein (Env) trimer and Env reactivity to bound antibody influence neutralization susceptibility. In addition, we define an antibody-specific parameter, the perturbation factor (PF), that describes the degree of conformational change in the Env trimer required for a given antibody to bind. Minimally perturbing (low-PF) antibodies can efficiently neutralize viruses with a broad range of Env reactivities due to fast on-rates and high affinity for Env. Highly perturbing (high-PF) antibodies inhibit only viruses with reactive (perturbation-sensitive) Envs, often through irreversible mechanisms. Accounting for these quantifiable viral and antibody-associated parameters helps to predict the observed profiles of HIV-1 neutralization by antibodies with a wide range of potencies.

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...

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Recently, debate has arisen about the usefulness of cell tracking using iron oxide-labeled cells. Two important issues in determining the usefulness of cell tracking with MRI are generally overlooked; first, the effect of graft rejection in immunocompetent models, and second, the necessity for careful histological confirmation of the fate of the labeled cells in the presence of iron oxide. Therefore, both iron oxide-labeled living as well as dead epicardium-derived cells (EPDCs) were investigated in ischemic myocardium of immunodeficient non-obese diabetic (NOD)/acid: non-obese diabetic severe combined immunodeficient (NOD/scid) mice with 9.4T MRI until 6 weeks after surgery, at which time immunohistochemical analysis was performed. In both groups, voids on MRI scans were observed that did not change in number, size, or localization over time. Several studies demonstrated that iron-labeled cellular transplants were visible with MRI and could be followed over time (3,4,6,7), even when a magnet of clinical field strength was used (4,8), although the detection limit was low and only high numbers of iron-loaded cells were visible (9). It was only assumed that these hypointense spots on the MRI images actually represented the transplanted living iron-loaded cells. It was not verified whether the transplanted cells were indeed present in histological sections, and whether MRI signal was really generated by the original transplant and not by, e.g., macrophages that had phagocytosed the iron-containing cells. The first study (5) that addressed this issue reported that the MRI signal originally generated by iron in transplanted MSCs appeared to be present regardless of the existence of these cells, which was later confirmed by Terrovitis et al. (10), who demonstrated, like Amsalem et al. (5) had done before, that iron-loaded macrophages created the signal rather than the iron-loaded living transplanted cells.As suggested by Sadek and Garry (11) in a comment on the study of Amsalem et al. (5), the results should be extended by studies in immunocompromised animals. In the previous studies, cardiac-derived stem cells (CDCs) or MSCs, which are not immunoprivileged, were harvested from "syngeneic" rats and transplanted into other inbred immunocompetent rats (5,10). However, rats cannot, unlike mouse donors from same inbred strain, be considered really syngeneic but rather allogeneic (5), implying that the cells could simply be rejected by the host, and thus that the concern regarding the utility of SPIOs in cardiac cell therapy applies only to comparable studies with nonautologous cells and immunocompetent animals. Sadek and Garry (11), therefore, pleaded for similar experiments with either autologous cell transplantation in normal animals, or with allogeneic stem cell transplantation into immunodeficient animals (11). It could very well be that iron-loaded transplanted cells are not rejected in those settings or that the clearance pattern is altered in such a way that the hypointense signals from iron-oxide largely correspon...