&p.1:Abstract The existence of the hemangioblast, a com- mon progenitor of the endothelial and hematopoietic cell lineages, was proposed at the beginning of the century. Although recent findings seem to confirm its existence, it is still unknown when and how the hemangioblasts dif- ferentiate. We propose a hypothesis about the origin of hemangioblasts from the embryonic splanchnic mesothe- lium. The model is based on observations collected from the literature and from our own studies. These observa- tions include: (1) the extensive population of the splanchnic mesoderm by mesothelial-derived cells coin- ciding with the emergence of the endothelial and hema- topoietic progenitors; (2) the transient localization of cytokeratin, the main mesothelial intermediate filament protein, in some embryonic vessels and endothelial pro- genitors; (3) the possible origin of cardiac vessels from epicardial-derived cells; (4) the origin of endocardial cells from the splanchnic mesoderm when this meso- derm is an epithelium; (5) the evidence that mesothelial cells migrate to the hemogenic areas of the dorsal aorta. (6) Biochemical and antigenic similarities between me- sothelial and endothelial cells. We suggest that the endo- thelium-lined vascular system arose as a specialization of the phylogenetically older coelomic cavities. The ori- gin of the hematopoietic cells might be related to the dif- ferentiation, reported in some invertebrates, of coelom- ocytes from the coelomic epithelium. Some types of coe- lomocytes react against microbial invasion and other types transport respiratory pigments. We propose that this phylogenetic origin is recapitulated in the vertebrate ontogeny and explains the differentiation of endothelial and blood cells from a common mesothelial-derived pro- genitor.&bdy: Introduction The early vascularization of the amniote embryo is a fast process. In only 48–72 h, the mouse embryo shifts from being completely avascular to a stage at which a well-de- veloped network of blood-containing vessels supplies al- most all the organism [51]. The endothelial cells and the blood cells are thought to originate from a hypothetical embryonic progenitor, the hemangioblast, whose exis- tence was postulated at the beginning of this century [31, 49]. The hemangioblast hypothesis is supported by the sharing of molecular markers in cells with endothelial or hemopoietic potential [18, 35, 44, 50, 64, 75, 76]. Poten- tial hemangioblastic cells have been isolated from em- bryonic stem cell-derived embryonic bodies [5]. After the hypothetical segregation of the angioblastic and hemogenic lineages, the endothelial progenitors (an- gioblasts) coalesce to form a capillary plexus in the splanchnic mesoderm (a process known as vasculogene- sis). Other parts of the embryo, namely the neuroectoder- mal and somatopleural areas, are basically vascularized through angiogenesis, i.e., sprouting and growth of pre- existing vessels [57]. The molecular mechanisms of blood vessel formation are being unveiled by some recent findings (reviewed in [1, 29, 61, 62]). However, a key question still exists: when and how is a mesodermal cell programmed to be- come an angioblast or, eventually, an hemangioblast? [13, 14, 16]. Some reports have suggested that commitment of cells to the hemangioblastic lineage occurs very early, during the formation of the mesoderm (primitive streak stage). This is based on experiments with quail blasto- disc cells treated with basic fibroblast growth factor. These cells express the early hemangioblastic marker vascular endothelial growth factor receptor-2 (VEGFR- 2) and form blood islands [22, 23]. These findings can be interpreted as differentiation of hemangioblasts from pluripotential epiblastic cells. R. Muñoz-Chápuli ( ✉ ) · J.M. Pérez-Pomares · D. Macías L. García-Garrido · R. Carmona · M. González Departamento de Biología Animal, Facultad de Ciencias - Instituto Andaluz de Biotecnología, Universidad de Málaga, E-29071 Málaga, Spain Tel.: +34-95-2131853 Fax: +34-95-2132000 e-mail: chapuli@uma.es&/fn-block: Differentiation (1999) 64:133–141 © Springer-Verlag 1999 MODELS & HYPOTHESES &roles:Ramón Muñoz-Chápuli · José María Pérez-Pomares David Macías · Lina García-Garrido · Rita Carmona Mauricio González Differentiation of hemangioblasts from embryonic mesothelial cells? A model on the origin of the vertebrate cardiovascular system &misc:Accepted in revised form: 26 October 1998