Although controversial fetal stem cells hog the limelight, hematopoietic stem cells (HSCs), which give rise to the entire adult blood system, quietly facilitate high-dose chemotherapy on a regular basis in hospitals worldwide. But HSCs have not been without intrigue--whence they come and how they arise in early development remains mysterious. Now, two collaborating labs have produced papers that place the camera's glare directly on the embryonic origins of adult HSCs.1,2
Professor Elaine Dzierzak, Department of Cell Biology and Genetics, Erasmus University, Rotterdam, first realized that embryonic HSCs have two different origins.3 "The work really started about 10 years ago when we were looking at where the first stem cells for the adult blood system come from," says Dzierzak. "We found this area within the body of the embryo, which we call the AGM region, [aorta-gonad-mesonephros] where the first hematopoietic stem cells are generated." Prior to this discovery, she says, scientists thought that the adult blood system originated in the yolk sac.
There are actually two waves of hematopoiesis, an embryonic wave that supports the embryo's growth, and a later wave that gives rise to the fetal and adult blood systems. Although the red blood cells that drive the embryonic wave of hematopoiesis originate in the yolk sac, the HSCs that drive the later wave begin in the AGM region. "People had described these clusters of cells in the aorta in the AGM region going back to the early 1900s," says Nancy Speck, professor of biochemistry, Dartmouth Medical School. "When it was shown that this region was the source of stem cells by Elaine's transplantation experiments, and other grafting experiments like those by Francoise Dieterlen-Lievre in the chick and James Turpen in the frog, the question was which of the cells coming out of this region actually were the stem cells." Speck recently completed a sabbatical in Dzierzak's lab where she learned to dissect embryos and transplant stem cells.4,5
Speck and graduate student Trista North had previously shown that a transcription factor called Runx1 marks endothelial cells in the few sites in the embryo where the stem cells emerge, and that Runx1 function is required to form aortic clusters.6 With the skills she learned in Dzierzak's lab, Speck and her team have now shown that all HSCs express Runx1, and indeed HSCs must express Runx1 to function.1
At the same time, Dzierzak's team was making lines of transgenic mice that express the green fluorescent protein (GFP) in the same pattern as the well- characterized HSC marker Sca-1. "We were hoping to find GFP expression in the midgestation embryo," says Dzierzak. "We found expression in the AGM region, and this expression was in some of the endothelial cells that line the ventral wall of the dorsal aorta. So what we did next was to sort for the GFP-expressing and nonexpressing cells from the ... aorta and transplanted them into irradiated mice to determine in which fraction the stem cell activity was located." The researchers found all the activity in the GFP-positive fraction.2
Speck's lab also discovered that the first HSCs in the murine fetus express endothelial-specific markers, supporting the hypothesis that they differentiate from endothelial cells. Previously, Shin-Ichi Nishikawa7 at Kyoto University had shown that cells expressing only endothelial markers could produce adult-type blood cells in vitro.
Genetics professor Roger Patient, University of Nottingham, and Faculty of 1000 member who reviewed the two papers, says he believes that the body of work reveals insights into HSC ontogeny. Much circumstantial evidence exists, he notes, showing "that blood and the endothelium it flows through share a common progenitor called the hemangioblast. ... It's quite a surprising idea, that the first adult blood stem cell is not in the yolk sac, but inside the embryo in close association with one of the major vessels."
Patient also notes that Bruno Péault's lab at France's INSERM (Institut National de la Santé et de la Recherche Médicale) showed similar findings in humans.8 "These papers now present evidence that the blood stem cells were actually part of the dorsal aorta, and [that] they undergo a transdifferentiation from an endothelial cell to becoming a blood stem cell. Evidence from mice, humans, and chicks are all pointing in the same direction."
Mignon Fogarty (email@example.com) is a freelance writer in Santa Cruz, Calif.
1. T.E. North et al., "Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo," Immunity, 16:661-72, May 2002.
2. M.F.T.R. de Bruijn et al., "Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta," Immunity, 16:673-83, May 2002.
3. A.M. Muller et al., "Development of hematopoietic stem cell activity in the mouse embryo," Immunity, 1:291-301, 1994.
4. L. Pardanaud et al., "Two distinct endothelial lineages in ontogeny, one of them related to hemopoiesis," Development, 122:1363-71, 1996.
5. J.B.Turpen et al., "Bipotential primitive-definitive hematopoietic progenitors in the vertebrate embryo, Immunity, 7:325, 1997.
6. T.E. North et al., "Cbfa2 is required for the formation of intra-aortic hematopoietic clusters," Development, 126:2563-75, 1999.
7. S.I. Nishikawa et al., "In vitro generation of lymphohematopoietic cells from endothelial cells purified from murine embryos," Immunity, 8:761-9, 1998.
8. E. Oberlin et al., "Blood-forming potential of vascular endothelium in the human embryo," Development, 129:4147-57, September 2002.