We have isolated c-Kit
IntroductionDefining the embryonic origin of mammalian hematopoietic stem cells (HSCs) is important for several reasons: understanding how specific adult cell lineages develop, uncovering the pathophysiology of inherited diseases of the hematopoietic system, and developing new, HSC-based therapeutic strategies. The process of blood cell development in the mammalian conceptus is particularly complex, as it occurs at least in 3 sites separated in both space and time: the yolk sac (YS), the para-aortic splanchnopleure and aorta-gonad-mesonephros (AGM) region, and the chorioallantoic placenta. 1,2 Cells with hematopoietic activity can be further distinguished on the basis of their functional properties, as defined by their ability to give rise to all the blood cell lineages in vitro and/or in vivo in either newborn or adult mice.In the mouse, the first definitive repopulating HSCs are found at approximately embryonic day (E) 9.0 in the dorsal aorta and in the YS and at approximately E10 in the vitelline, the umbilical arteries, and the placenta. [3][4][5][6][7][8][9][10] Given that the circulatory system is already established at E8.0 to E8.25, 11 even though not fully functional until E10, 12 the question of whether regions other than the dorsal aorta 4 represent sites of de novo generation of HSC has, until very recently, been subject to much debate. The work performed by Rhodes et al in embryos lacking a circulatory system now suggests that the placenta may correspond to a true site of HSC generation and expansion. 10 These recently published findings still require further investigation to fully define the in vivo functional activity of this hematopoietic site in the absence of circulation because it is well known that prospective hematopoietic cells are influenced by morphogens and factors produced by the immediate environment. 1 Strikingly, there are close interactions between the mesoderm of each known hematopoietic site and the endoderm (in the bilaminar YS), trophectoderm (in the placenta), and the dorsal ectoderm and ventral endoderm (in the AGM region). 1 These close layers probably provide signaling molecules, including vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor-1, which are essential for the hematopoietic specification of the mesoderm 13 via the controlled expression of key hematopoietic transcriptions factors such as Gata2 and Runx1. Indeed, both Gata2-and Runx1/Aml1-deficient mice present a complete absence of definitive HSCs in the AGM, whereas YS hematopoietic progenitors are still present (albeit in low numbers, in the case of the GATA2 deficiency 1 ). Indeed, LMO2, GATA2, and SCL were shown to bind to the conserved E regions of the Runx1 locus, inducing its transactivation and the expression of Runx1 14 transcription factor that marks the onset of definitive hematopoiesis. 15,16 Whether human and murine hematopoietic systems have the same extra-and intraembryonic sites is still unknown. In humans, cells with hemogenic p...
