Fuelled by the obesity epidemic, there is considerable interest in the developmental origins of white adipose tissue (WAT) and the stem/progenitor cells from which it arises. While increased visceral fat mass is associated with metabolic dysfunction, increased subcutaneous WAT is protective. There are 6 visceral fat depots: perirenal, gonadal, epicardial, retroperitoneal, omental and mesenteric and it is a subject of much debate whether these have common developmental origins and whether this differs from subcutaneous WAT. Here we show that all 6 visceral WAT depots receive a significant contribution from cells expressing Wt1 late in gestation. Conversely, no subcutaneous WAT or brown adipose tissue (BAT) arises from Wt1 expressing cells. Postnatally, a subset of visceral WAT continues to arise from Wt1 expressing cells, consistent with the finding that Wt1 marks a proportion of cell populations enriched in WAT progenitors. We show all visceral fat depots have a mesothelial layer like the visceral organs with which they are associated and provide several lines of evidence that Wt1 expressing mesothelium can produce adipocytes. These results: reveal a major ontogenetic difference between visceral and subcutaneous WAT; pinpoint the lateral plate mesoderm as a major source of visceral WAT; support the notion that visceral WAT progenitors are heterogeneous; and suggest that mesothelium is a source of adipocytes.

Recent reports suggest that mammalian embryonic coronary endothelium (CoE) originates from the sinus venosus and ventricular endocardium. However, the contribution of extracardiac cells to CoE is thought to be minor and nonsignificant for coronary formation. Using classic (Wt1 Cre ) and previously undescribed (G2-Gata4 Cre ) transgenic mouse models for the study of coronary vascular development, we show that extracardiac septum transversum/ proepicardium (ST/PE)-derived endothelial cells are required for the formation of ventricular coronary arterio-venous vascular connections. Our results indicate that at least 20% of embryonic coronary arterial and capillary endothelial cells derive from the ST/PE compartment. Moreover, we show that conditional deletion of the ST/PE lineage-specific Wilms' tumor suppressor gene (Wt1) in the ST/PE ofG2-Gata4 Cre mice and in the endothelium of Tie2 Cre mice disrupts embryonic coronary transmural patterning, leading to embryonic death. Taken together, our results demonstrate that ST/PE-derived endothelial cells contribute significantly to and are required for proper coronary vascular morphogenesis.T he coronary vascular system, whose function is necessary to sustain late embryonic and postnatal cardiac function, is formed by a complex network of blood vessels, including arteries, arterioles, capillaries, venules, and veins (1). Recent reports indicate that various sources of endothelial cells contribute to the mammalian embryonic coronary system (2-4). However, the specific fate and function of these different endothelial cell pools during coronary vascular morphogenesis is the subject of intense controversy (5).Two endocardial populations have been reported to participate in the building of the embryonic coronary vascular system. The first derives from the sinus venosus endocardium, which sprouts to give rise to the nascent Apelin + coronary vasculature (2). A careful analysis of this study suggests that the sinus venosus endocardium, which is able to vascularize subepicardial and myocardial heart layers, mainly provides a cellular scaffold for the development of coronary veins (CoV). Accordingly, a second source of coronary endothelium (CoE) has been identified in the ventricular endocardium (Nfatc1 + lineage), which contributes massively to coronary arterial (CoA) endothelium (3, 6).A third disputed source of CoE is the proepicardium (PE), a structure that comprises epicardial progenitor cells. The PE protrudes from the septum transversum (ST), a folding of the lateral mesoderm that initiates the separation of thoracic and abdominal cavities in mammals (7). Although in vivo cell tracing and in vitro culture of avian PE cells clearly shows that PE cells can differentiate into CoE (8, 9), data from studies in mammals claimed the contribution of PE to CoE is minor (10-12). The so-called "epicardial" Cre constructs used in these studies are based on the expression of genes such as Gata5, Tbx18, or Wilms' tumor suppressor (Wt1) ( Table S1), all of which are expressed by both PE and...