Figure 1.
Comparative view of multilayered hematopoiesis during human and mouse development. Hematopoiesis is a conserved developmental process in mammals, but the anatomy of the hematopoietic sites, duration of the hematopoietic waves, and output of the progenitors differ between human and mouse. (Left) Human and mouse embryos are depicted at the stage when HSC emergence peaks (CS15; 5 weeks; E11). Although embryonic structures and the main vascular circuitry are similar, the anatomy of extraembryonic tissues is different. The human placenta is villous type and surrounds the embryo and amniotic membrane, whereas the yolk sac is a balloon-like appendage inside the amnion. The mouse placenta is labyrinthine-type, and the yolk sac surrounds the embryo and amnion. In both species, blood flows from the aorta through the vitelline and umbilical arteries to the yolk sac and the placenta and returns to the embryo through the liver via vitelline and umbilical veins. Human hematopoiesis starts by 2.5 weeks (CS7) in the yolk sac, with the first, primitive progenitor wave, during which the main products are nucleated primitive erythroblasts that enter circulation. In addition, the precirculation placenta generates macrophages (Hofbauer cells) that assist in primitive erythroblast enucleation in the placental villi. At 3.25 weeks (CS8-CS9) the second, transient- (or pro) definitive wave of human hematopoiesis is initiated in the yolk sac and possibly in the embryo proper as well. In human, the second wave starts with YSMPs, followed by LMPs of yet unknown origin. HSC-independent progenitors give rise to tissue-resident macrophages, such as microglia, Langerhans cells, and Kupffer cells that can last into adulthood and HSC-independent lymphoid populations. HSC-independent macrophages may have diverse origins, and most brain microglia generation in mice is linked to primitive rather than second wave progenitors. Many of second wave progenitors colonize the liver where they differentiate to blood and immune cells to support development. Between 4 and 6 weeks (CS14-CS16) a third, HSC-forming, definitive hematopoietic wave arises in the AGM region and produces nascent HSCs. HSCs first migrate through the placenta and yolk sac before they seed the liver (CS17). During these transitions HSCs undergo maturation, limited expansion, and some give rise to terminally differentiated progeny. HSCs start generating multilineage progeny already in the first trimester liver and move to the BM during the second trimester to sustain postnatal hematopoiesis. Mouse hematopoiesis is aligned according to comparable developmental stages as in human. Because mouse embryogenesis is compressed into a much shorter timeframe, a greater overlap of developmental events and hematopoietic populations is apparent. The end of mouse gestation (3 weeks) compares to the early fetal period (9 weeks) of human development. Some progenitor populations differ in their lineage output, such as mouse yolk sac transient definitive progenitors are highly primed for erythromyeloid differentiation (EMPs), whereas the corresponding yolk sac progenitors in human show myeloid skewing (YSMPs), and the first signs of liver erythropoiesis link to HSCs. Weeks are referred to as developmental age, (ie, weeks after fertilization, which is 2 weeks less than gestational weeks or weeks from the last menstrual cycle). Dotted lines depict developmental milestones, such as the onset of heartbeat, transition from embryonic to fetal period during human development, and birth, which occurs at very different developmental stages in mouse and human. The main hematopoietic cell types are described (bottom right). EMPs, erythromyeloid progenitors; Ery, erythroid cell; Mono/Mφ, monocyte/macrophage.

Comparative view of multilayered hematopoiesis during human and mouse development. Hematopoiesis is a conserved developmental process in mammals, but the anatomy of the hematopoietic sites, duration of the hematopoietic waves, and output of the progenitors differ between human and mouse. (Left) Human and mouse embryos are depicted at the stage when HSC emergence peaks (CS15; 5 weeks; E11). Although embryonic structures and the main vascular circuitry are similar, the anatomy of extraembryonic tissues is different. The human placenta is villous type and surrounds the embryo and amniotic membrane, whereas the yolk sac is a balloon-like appendage inside the amnion. The mouse placenta is labyrinthine-type, and the yolk sac surrounds the embryo and amnion. In both species, blood flows from the aorta through the vitelline and umbilical arteries to the yolk sac and the placenta and returns to the embryo through the liver via vitelline and umbilical veins. Human hematopoiesis starts by 2.5 weeks (CS7) in the yolk sac, with the first, primitive progenitor wave, during which the main products are nucleated primitive erythroblasts that enter circulation. In addition, the precirculation placenta generates macrophages (Hofbauer cells) that assist in primitive erythroblast enucleation in the placental villi. At 3.25 weeks (CS8-CS9) the second, transient- (or pro) definitive wave of human hematopoiesis is initiated in the yolk sac and possibly in the embryo proper as well. In human, the second wave starts with YSMPs, followed by LMPs of yet unknown origin. HSC-independent progenitors give rise to tissue-resident macrophages, such as microglia, Langerhans cells, and Kupffer cells that can last into adulthood and HSC-independent lymphoid populations. HSC-independent macrophages may have diverse origins, and most brain microglia generation in mice is linked to primitive rather than second wave progenitors. Many of second wave progenitors colonize the liver where they differentiate to blood and immune cells to support development. Between 4 and 6 weeks (CS14-CS16) a third, HSC-forming, definitive hematopoietic wave arises in the AGM region and produces nascent HSCs. HSCs first migrate through the placenta and yolk sac before they seed the liver (CS17). During these transitions HSCs undergo maturation, limited expansion, and some give rise to terminally differentiated progeny. HSCs start generating multilineage progeny already in the first trimester liver and move to the BM during the second trimester to sustain postnatal hematopoiesis. Mouse hematopoiesis is aligned according to comparable developmental stages as in human. Because mouse embryogenesis is compressed into a much shorter timeframe, a greater overlap of developmental events and hematopoietic populations is apparent. The end of mouse gestation (3 weeks) compares to the early fetal period (9 weeks) of human development. Some progenitor populations differ in their lineage output, such as mouse yolk sac transient definitive progenitors are highly primed for erythromyeloid differentiation (EMPs), whereas the corresponding yolk sac progenitors in human show myeloid skewing (YSMPs), and the first signs of liver erythropoiesis link to HSCs. Weeks are referred to as developmental age, (ie, weeks after fertilization, which is 2 weeks less than gestational weeks or weeks from the last menstrual cycle). Dotted lines depict developmental milestones, such as the onset of heartbeat, transition from embryonic to fetal period during human development, and birth, which occurs at very different developmental stages in mouse and human. The main hematopoietic cell types are described (bottom right). EMPs, erythromyeloid progenitors; Ery, erythroid cell; Mono/Mφ, monocyte/macrophage.

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