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hematopoietic development

Wednesday 25 June 2008

The first hematopoietic and endothelial precursors arise from extra-embryonic mesoderm and differentiate to form the blood islands in the yolk sac of the early embryo.

The close spatial and temporal development of these lineages within the blood islands provided the basis for the hypothesis that they arise from a common progenitor, the hemangioblast.

Indirect evidence supporting the hemangioblast concept came from studies demonstrating that a large number of genes are expressed by both hematopoietic and endothelial lineages and that some of these genes are essential for both blood cell and vascular development.

Direct demonstration for the existence of a progenitor with hemangioblast properties has been provided by experiments using a model system based on the in vitro differentiation potential of embryonic stem (ES) cells.

When allowed to differentiate in culture, ES cells generate colonies known as embryoid bodies (EBs) that contain a broad spectrum of cell types representing derivatives the three primary germ layers.

Support for the ES differentiation system as a valid model of embryonic development has come from studies demonstrating that the molecular and cellular events associated with the establishment of lineages such as the hematopoietic, endothelial, neural and skeletal muscle show striking similarities in the EBs and the early embryo.

The ES/EB model has been particularly useful in elucidating the early events involved in the development of the hematopoietic system and has enabled the identification of a progenitor with characteristics of the hemangioblast, the putative precursor of the hematopoietic and endothelial lineages.

These progenitors, known as blast colony forming cells (BL-CFC), arise within two to four days of EB differentiation and express the tyrosine kinase receptor Flk1.

They generate colonies with hematopoietic, endothelial and vascular smooth muscle in methylcellulose cultures in response to vascular endothelial growth factor (VEGF).

These characteristics suggest that the BL-CFC could represent the in vitro equivalent of the yolk sac hemangioblast and as such, the earliest commitment step in the differentiation of mesoderm to the hematopoietic and endothelial lineages.

EBs generated from this ES line expressed readily detectable levels of GFP when observed under a fluorescence microscope. The hematopoietic potential of the heterozygous GFP-Bry ES cells was normal, indicating that this aspect of mesoderm development was intact.

Importantly, GFP expression faithfully recapitulated brachyury expression in differentiating EBs and as such, provides a unique marker for the identification and isolation of cells expressing this gene.

Co-expression of GFP with Flk1 revealed the emergence of 3 distinct cell populations, GFP-Flk1-, GFP+Flk1- and GFP+Flk1+ cells, which represent a developmental progression ranging from pre-mesoderm to pre-hemangioblast mesoderm to the hemangioblast.