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a Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USAb INSERM U602, Hôpital Paul Brousse, Villejuif 94807, Francec Australian Stem Cell Centre, Clayton, Victoria 3800, Australiad Stem Cell Research Center at Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15213, USAe The University of Texas Health Science Center, Houston, Texas 77030, USA
Key Words: hematopoietic stem cell • embryonic stem cell • hemangioblast • embryo • blood vessel
Address for correspondence: Bruno Péault, Children's Hospital of Pittsburgh of UPMC, 3460 Fifth Avenue, 3302 Rangos Research Center, Pittsburgh, PA 15213. Voice: 412-692-6526; fax: 412-692-5837. bruno.peault{at}chp.edu
Human hematopoiesis proceeds transiently in the extraembryonic yolk sac and embryonic, then fetal liver before being stabilized in the bone marrow during the third month of gestation. In addition to this classic developmental sequence, we have previously shown that the aorta-gonad-mesonephros (AGM) embryonic territory produces stem cells for definitive hematopoiesis from 27 to 40 days of human development, through an intermediate blood-forming endothelium stage. These studies have relied on the use of traditional markers of human hematopoietic and endothelial cells. In addition, we have recently identified and characterized a novel surface molecule, BB9, which typifies the earliest founders of the human angiohematopoietic system. BB9, which was initially identified with a monoclonal antibody raised to Stro-1+ bone marrow stromal cells, recognizes in the adult the most primitive Thy-1+ CD133+ Lin–, non-obese diabetic—severe combined immunodeficiency disease (NOD–SCID) mouse engrating hematopoietic stem cells (HSCs). In the 3- to 4-week embryo, BB9 expression typifies a subset of splanchnopleural mesodermal cells that migrate dorsally and colonize the ventral aspect of the aorta where they establish a population of hemogenic endothelial cells. We have indeed confirmed that hematopoietic potential in the human embryo, as assessed by long-term culture-initiating cell (LTC-IC) and SCID mouse reconstituting cell (SRC) activities, is confined to BB9-expressing cells. We have further validated these results in the model of human embryonic stem cells (hESCs) in which we have modeled, through the development of hematopoietic embryoid bodies (EBs), primitive and definitive hematopoieses. In this setting, we have documented the emergence of BB9+ hemangioblast-like clonogenic angiohematopoietic progenitors that currently represent the earliest known founders of the human vascular and blood systems.
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