The Hemangioblast

Although the blood islands were identified as the earliest site of haematopoietic and endothelial development almost 100 years ago, attempts to identify, isolate and characterize the precursors representing these initial stages of lineage development, including the elusive haemangioblast, have been largely hampered by the inaccessibility of the early mammalian embryo.  The differentiation of embryonic stem (ES) cells in culture offers a powerful alternative approach to study the development of such lineages that are established very early in embryonic life.  When removed from conditions that maintain them in vitro in an undifferentiated state, ES cells will spontaneously differentiate and form colonies or embryoid bodies (EBs) that contain precursors for multiple lineages including those of the hematopoietic and endothelial systems.  Several studies have established that the early events of haematopoietic and endothelial commitment in the ES/EB model are comparable, if not identical, to that of the early yolk sac embryo.  Using this model system, a precursor was recently identified that generates blast colonies containing precursors of endothelial and haematopoietic lineages.  The blast colony-forming cells (BL-CFC) that generate these colonies represent a transient population that appears in the EBs prior to the emergence of any other haematopoietic lineage precursors.  The characteristics of the BL-CFC suggest that it represents the in vitro equivalent of the haemangioblast and as such the earliest stage of haematopoietic development described to date. Recent studies have now provided evidence for the presence of this bipotential precursorin vivo.


 

In vitro differentiation of ES cells

When removed from conditions that maintain them in vitro in an undifferentiated state, ES cells will spontaneously differentiate and form colonies or embryoid bodies (EBs) that contain precursors for multiple lineages including those of the hematopoietic and endothelial systems. Several studies have established that the early events of hematopoietic and endothelial commitment in the ES/EB model are comparable, if not identical, to that of the early embryo. Using this model system, a precursor was recently identified that generates blast colonies containing precursors of endothelial and hematopoietic lineages. The blast colony-forming cells (BL-CFC) that generate these colonies represent a transient population that appears in the EBs prior to the emergence of any other hematopoietic lineage precursors. The characteristics of the BL-CFC suggest that it represents the in vitro equivalent of the hemangioblast and as such the earliest stage of hematopoietic development described to date.

 

Hemangioblast FLK-1 Assay

 

A new model of haematopoietic development

We performed a series of studies to determine the cellular and molecular events leading to the generation of blast colony from BL-CFC.  Our data demonstrate that the haemangioblast generates haematopoietic cells through the formation of a haemogenic endothelium intermediate, providing the first direct link between these two precursor populations.  This haemogenic endothelial cell population is transiently generated during blast development and is also detected in gastrulating embryos.  At the molecular level, we have demonstrated that the transcription factor SCL/TAL1 is indispensable for the establishment of this haemogenic endothelium cell population from the haemangioblast whereas RUNX1/AML1 is critical for generation of haematopoietic cells from this haemogenic endothelium.  These results indicate that the two a priori conflicting theories on the origin of haematopoietic development, haemangioblast and haemogenic endothelium, can be merged into a single linear developmental process leading to the formation of the first committed haematopoietic precursors.