A long way to stemness

Hematopoiesis starts with generation of “primitive” erythroblasts and macrophage progenitors in the visceral yolk sac. The earliest strictly defined adulttype or definitive HSCs can be detected in the AGM region at around E11. Accumulation of stem cells activity in the explant cultures of the AGM region strengthened a growing perception that HSCs originate intraembryonically and mammalian hematopoiesis as a whole has multiple origins. Several lines of evidence suggest that dHSCs derive from a transitory subset of endothelial cells called hemogenic endothelium. HSC precursors were directly traced to conceptus cells that express VE-cadherin, a specific marker of endothelial lineage. Selective deletion of Runx1 in VE-cadherin+ cells resulted in the ablation of all hematopoietic progenitors including HSCs and development of the characteristic Runx1-null phenotype. Emergence of HIACs during midgestation has also been regarded as evidence in support of dHSC generation by dorsal aorta endothelium. A strong lymphoid potential of the pre-circulation embryo proper suggests that dHSC precursors segregate in situ from the P-Sp mesoderm that precedes the appearance of the aorta hemogenic endothelium. This theory, however, has some important caveats. First, endothelial cells of midgestation dorsal aorta do not proliferate, leaving HIACs to be generated either through vascular remodeling or blood cell clustering. Robust dHSC expansion in reaggregation AGM explant cultures indicates that dHSC maturation in the AGM region is largely structure-independent and dHSCs are unlikely to arise through the remodeling mechanism. Second, the A long way to stemness