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Cell Fate Decisions in Early Blood Vessel Formation

https://doi.org/10.1016/S1050-1738(03)00105-1Get rights and content

Abstract

The close spatial relationship between endothelial and hematopoietic cells at different stages of development has led to the concept of a common progenitor, the hemangioblast. The vascular endothelial growth factor receptor, Flk1 or KDR, is a common marker of all cells—whether embryonic or adult—that have putative hemangioblast properties. In this article, a model is proposed in which Flk1 marks a common mesodermal precursor that segregates successive subsets of Flk1-expressing or Flk1-nonexpressing cells whose fate is determined by coexpression of lineage-specific transcription factors. Cells that retain Flk1 activity have endothelial potential, cells that also activate downstream transcription factors such as Tal1 and Runx1 gain primitive or definitive hematopoietic activity, and cells that lose Flk1 expression but gain expression of other transcription factors become smooth muscle or other cell types.

Section snippets

Anatomical Location of Vasculogenesis and Hematopoiesis in the Early Mouse Embryo

In the mouse, vascular precursors form in both the embryo and the extraembryonic yolk sac around E7.5 to E8. As judged by the expression of a number of different vascular markers, cells destined to become endothelial precursors or angioblasts are readily apparent in the head region by E8. At the same time, endocardial precursors are formed in the developing cardiac crescent. There is no evidence of association of these cells with any hematopoietic activity, however. In the extraembryonic

Evidence for the Existence of a Primitive Hemangioblast

Evidence for a morphologic region, like the BI region, where endothelial and hematopoietic cells are in close proximity, does not prove the existence of a common progenitor. However, a number of pieces of evidence suggest that the association is more than coincidental. Endothelial and hematopoietic progenitors share expression of many genes, such as Flk1, Flt1, Tie1, Tie2 (Dumont et al. 1995), Tal1 (Elefanty et al. 1998), and Runx1 (Lacaud et al. 2002). Disruption of Flk1 or Flt1, which encode

Evidence for a BL-CFC in Vivo

In the mouse embryo, Tal1 and Runx1 begin expression in mid- to late-streak stage embryos in the extraembryonic mesoderm and then become localized to the developing BIs Lacaud et al. 2002, Palis et al. 1999. GATA-1 and Lmo2 expression seem to be similar Manaia et al. 2000, Onodera et al. 1997, Silver and Palis 1997. Given the similarity of their gene expression profiles, BL-CFC derived from ES cells may be the in vitro equivalent of cells in the BI region of the yolk sac. Although morphology,

Hemangioblasts during Definitive Hematopoiesis

Initial yolk sac hematopoiesis is primitive, producing predominantly nucleated erythroid cells expressing embryonic globin. Only later in development do definitive hematopoietic stem cells (HSCs), capable of repopulating the neonate or adult blood system, arise. Definitive HSCs can arise from the yolk sac (Palis and Yoder 2001) and the intraembryonic aorta–gonad–mesonephros (AGM) region (Dzierzak et al. 1998). Within the broadly defined AGM region, hematopoietic precursors can be seen as clumps

Relative Adult Hemangioblasts

Adult hematopoiesis takes place largely in the bone marrow, where HSCs reside in a specialized stromal microenvironment or niche that promotes stem cell maintenance and differentiation. Here too there seems to be some relationship between endothelial cells and HSCs. In humans, it has been shown that the small subset of CD34+ bone marrow cells that coexpress KDR (the human orthologue of Flk1) are enriched for HSCs, whereas the CD34+KDR population produces only short-term hematopoietic

Multipotency of Hemangioblasts

Isolation of single cells that can give rise to both endothelial and hematopoietic cells in vitro is clear proof of a common origin of the two lineages. However, it does not distinguish whether this common origin is proximate—that is, the common precursor makes a simple choice between the two lineages—or whether the precursor isolated is a more primitive multipotent precursor, whose potency has not been revealed by the assays used. Originally, it was reported that the BL-CFC is a bipotent cell,

The Flk1/KDR Population Represents Multiple Types of Precursor

This survey of the literature on the putative hemangioblast has shown that the VEGF receptor, Flk1 or KDR, is a common marker of all cells—whether embryonic or adult—that have putative hemangioblast properties. It is more than just a marker, however, since VEGF signaling through the receptor is required for hematopoietic and endothelial development in vivo and for BL-CFC production in vitro. Flk1 may mark a common mesodermal precursor that also can give rise to non-Flk1-expressing cell types

Acknowledgements

M.E. was supported in part by Naito Foundation, Japan Society for the Promotion of Science, and Uehara Memorial Foundation for studying abroad. J.R. is a Canadian Institutes of Health Research (CIHR) Distinguished Investigator. This work was supported by a grant from the National Cancer Institute of Canada.

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