Bringing blood to life

Since ancient times, the heart and blood have been inextricably linked as fundamental elements to the process of life. William Harvey was the first to provide a plausible mechanism for blood circulation when in 1628 he defined the circulatory system to comprise a cardiac pump, intact vascular system, and recirculating blood. Harvey believed that blood was the fountain of life, the first (tissue) to live, and the last to die. His thesis has been supported in part by modern evidence that murine embryos mutant for genes necessary for blood, endothelial, and/or cardiac development who fail to establish or maintain circulation perish in utero. Harvey never articulated when he believed the blood comes to “life” (circulation commences) during mammalian development. Emergence of primitive erythroblasts (PEs) and nascent endothelial cells on embryonic day (E) 7.0 in the murine yolk sac may herald the beginnings of a circulatory system. But beating of the developing heart tube and linkage of the yolk sac and embryonic vascular systems on E8.25 is identified by some as evidence for the onset of systemic blood flow. But is blood flow equivalent to circulation? When does circulation (as defined by Harvey) begin in the murine embryo?

McGrath and colleagues (page 1669) provide compelling evidence that circulation is established in a graded series of maturational steps. Using simple tools and clever intuition, they examined murine embryos from E8.0 to E10.5 to determine the steady state density of PEs in the embryo proper and the distribution of PEs in the developing embryonic vessels. They report that the first PEs enter embryonic vessels at the 4 somite pair (sp) stage of development (E8.25) but that complete equilibration of PEs in the circulation is not accomplished until 35 sp (E10.5). What takes so long? The authors suggest that the process of cardiac maturation and/or vascular remodeling may regulate the dispersal of PEs throughout the vasculature. William Harvey would be intrigued.