HEMATOPOIESIS AND STEM CELLS Aggf 1 acts at the top of the genetic regulatory hierarchy in speci fi cation of hemangioblasts in zebra fi sh

Hemangioblasts are the multipotent progenitors that can differentiate into both hematopoietic and endothelial cells (ECs). Defining the molecular mechanisms underlying specification of hemangioblasts may have great clinical potential for regenerativemedicine because it may lead to new strategies for treating a variety of hematologic and vascular disorders. The existence of hemangioblasts has been demonstrated in human and mouse embryos by the finding that single-cell–derived colonies can generate both hematopoietic and ECs in in vitro differentiation assays of mouse or human embryonic stem cells. Single-cell–resolution fate mapping of late zebrafish blastula and gastrula demonstrated the existence of hemangioblasts that produced both hematopoietic and ECs in vivo. Emerging evidence suggests that hemangioblasts may exist as circulating stem cells in the peripheral blood in the adult. The bipotential hemangioblasts are developed from the mesoderm in the early vertebrate embryo or the ventral mesoderm from zebrafish embryos. Hemangioblasts can then differentiate into either hematopoietic or EC lineages. For specification of the EC lineage, hemangioblasts first differentiate into angioblasts, which then give rise to vascular ECs, including arterial ECs and venous ECs. The hematopoietic lineage will generate blood cells, including erythroid cells, myeloid cells, and lymphoid cells. Early vertebrate embryonic hematopoiesis consisted of 2 stages or waves, the primitive hematopoiesis and definitive hematopoiesis, at different anatomical sites. The first stage of primitive hematopoiesis occurs in the intermediate cell mass in zebrafish. The second wave of definitive hematopoiesis produces adult-type hematopoietic stem cells (HSCs) in major vessels or highly vascularized structures, that is, the aorta-gonad-mesonephros region, umbilical/vitelline arteries, yolk sac, and placenta at the E10-11 stage. In zebrafish, the functionally equivalent structure of the aorta-gonad-mesonephros region is found in the ventral wall of the dorsal aorta marked by expression of c-myb and runx1. The differentiation of hemangioblasts from the mesoderm is regulated by a number of transcriptional factor genes, including several members of the E-twenty six family (etsrp, fli1), scl, and lmo2. Scl/tal1 encodes a basic helix-loop-helix transcription factor and plays an essential role in hematopoiesis and development of the dorsal aorta during zebrafish embryogenesis. Fli1was shown to act upstream of scl to drive blood and EC differentiation.Etsrpwas shown to act upstream of the full-length isoform of scl (scl-a) and fli1 to specify angioblasts or the N-terminal truncated isoform of scl-b to specify HSCs. Lmo2 encodes an LIM-containing protein that forms a complex with Scl/Tal1 to specify the development of hemangioblasts. A number of transcription factors are expressed in the anterior lateral mesoderm and/or the posterior lateral mesoderm and play a critical role in primitive and definitive hematopoiesis. Gata1 and pu.1 encode 2 early transcription factors regulating primitive hematopoiesis. Gata1 is a critical gene in dictating the erythroid