Submitted to: Blood
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/19/2008
Publication Date: 10/15/2008
Citation: Goldie, L.C., Lucitti, J.L., Dickinson, M.E., Hirschi, K.K. 2008. Cell signaling directing the formation and function of hemogenic endothelium during murine embryogenesis. Blood. 112(8):3194-3204. Interpretive Summary: During fetal embryonic development, blood stem cells are thought to derive from a specialized type of vascular endothelial cell (cells that line the interior surface of blood vessels), known as hemogenic (blood-forming) endothelium. However until recently, these cells had yet to be isolated and characterized, and it was not known where these cells physically reside in the developing embryo. In this study, we sought to isolate and define the molecular characteristics of hemogenic endothelium in early mouse embryos, and demonstrate their ability to function as blood stem cells, i.e., to generate all types of adult blood cells. We also sought to identify molecular signals that regulate the development of hemogenic endothelial cells, and subsequent development of mature blood cells. We found that hemogenic endothelial cells first develop in the mouse embryonic yolk sac, in a process which is critically dependent upon signaling by vitamin A (retinoic acid). Formation of hemogenic endothelial cells, and subsequent development of blood stem cells, was significantly impaired in the absence of vitamin A, and could be restored in vitamin A-deficient mouse embryos by dietary provision of retinoic acid to pregnant mothers. Thus, we identified a novel, critical role for vitamin A in the development of hemogenic endothelium, blood stem cells, and the mature blood system.
Technical Abstract: During developmental hematopoiesis, multilineage hematopoietic progenitors are thought to derive from a subset of vascular endothelium. Herein, we define the phenotype of such hemogenic endothelial cells and demonstrate, on a clonal level, that they exhibit multilineage hematopoietic potential. Furthermore, we have begun to define the molecular signals that regulate their development. We found that the formation of yolk sac hemogenic endothelium and its hematopoietic potential were significantly impaired in the absence of retinoic acid (RA) signaling, and could be restored in RA-deficient (Raldh2(-/-)) embryos by provision of exogenous RA in utero. Thus, we identify a novel, critical role for RA signaling in the development of hemogenic endothelium that contributes to definitive hematopoiesis.