Hematopoietic stem cells (HSC), the self-renewing cells of the adult blood differentiation hierarchy are generated during embryonic stages. The first adult-repopulating HSCs are produced in the aorta-gonad-mesonephros (AGM) region of the embryo through the transition of a specialized set of endothelial cells to hematopoietic fate. The developmental regulators BMP4 and Hedgehog affect their production/expansion, but it is unknown whether they act to affect the same HSCs. In this study using the BRE GFP reporter mouse strain that identifies BMP/Smadactivated cells, we find that the AGM harbors two types of adult-repopulating HSCs upon explant culture: One type of HSC is BMP-activated. The other is a non-BMP-activated HSC type that is indirectly controlled by Hedgehog signalling through the VEGF pathway. Our results, obtained under defined conditions in which the responsiveness to distinct developmental signalling pathways discriminates two HSC types, are the first to demonstrate that HSC heterogeneity begins already early during development and suggest that the basis of HSC heterogeneity is microenvironment dependent.
- HEMATOPOIETIC STEM
- PROGENITOR CELLS