The first trimester human placenta is a site for terminal maturation of primitive erythroid cells

Abstract

IntroductionThe hematopoietic system during embryonic development provides two important functions: rapid generation of terminally differentiated blood cells for the survival and growth of the embryo and establishment of a pool of undifferentiated hematopoietic stem cells (HSCs) for postnatal life. To achieve these goals, embryonic hematopoiesis is segregated into multiple waves that occur in several anatomical sites, 1 a process that is broadly conserved in vertebrates. 2,3 The yolk sac is the site of the first wave of embryonic hematopoiesis that generates both primitive red blood cells (RBCs) that deliver oxygen to the embryo and macrophages that assist in tissue remodeling and immune defense. 4 The second wave of hematopoiesis also commences in the yolk sac with the production of a transient pool of erythromyeloid progenitors. Although they lack self-renewal ability and lymphoid potential, they have an important function in fetal hematopoiesis as they rapidly differentiate into mature definitive erythroid and myeloid cells after migration to the fetal liver. 5,6 The third wave of hematopoiesis emerges in the major intra-and extraembryonic arteries, generating HSCs that can both self-renew and differentiate into all blood cell types, including lymphoid cells. HSCs subsequently colonize the fetal liver where they expand before eventually seeding the bone marrow. HSCs emerge in the AGM (aorta-gonad-mesonephros region) and attached vitelline and umbilical arteries, 7-11 the yolk sac, and the placenta. The capacity of the placenta for generation 12 and expansion 13-15 of multipotential hematopoietic stem/progenitor cells has been described recently in both mouse and human, [16][17][18] whereas its potential function as a primitive hematopoietic organ has not been evaluated.The most important products of primitive hematopoiesis that are critical for the survival of the embryo are the primitive RBCs. Experimental evidence suggests that the yolk sac-derived primitive erythroid cells are specified directly from mesoderm with restricted hematopoietic potential, rather than from a multipotential HSC. [19][20][21][22] Primitive red cells differ from definitive red cells not only in their developmental origin, but also in their larger size and distinct globin expression pattern. 23 In mice, primitive RBCs can be identified by expression of ⑀y-globin, 24 which is absent from definitive red cells derived from the fetal liver and the adult bone marrow that express ␤-major globin. 25 In human, primitive red cells uniquely express the ␣-like -globin as well as the ␤-like ⑀-globin. 26 Furthermore, primitive red cells differ from definitive red cells in that they enter circulation as nucleated erythroblasts, whereas the definitive erythroid cells complete maturation and enucleation in their site of origin, the fetal liver 27 or bone marrow, before entering circulation (reviewed in Chasis 28 ). It has been documented that this process occurs in "erythroblast islands" in association with macrophages, which digest the ejected RBC ...

The embryonic origins of erythropoiesis in mammals

“…The free nuclei presumably are phagocytosed later, when they circulate through the fetal liver or other tissues, 42 possibly including the placenta, as reported for the human embryo. 57 Human primitive erythroblasts also enucleate, but the site is apparently the placental villi rather than the fetal liver. 57 Microscopic analysis suggests that the nuclei expelled by human EryP are engulfed by macrophages, although this finding remains to be confirmed more directly 57 (eg, using FACS).…”

“…57 Human primitive erythroblasts also enucleate, but the site is apparently the placental villi rather than the fetal liver. 57 Microscopic analysis suggests that the nuclei expelled by human EryP are engulfed by macrophages, although this finding remains to be confirmed more directly 57 (eg, using FACS). Interestingly, macrophage progenitors are present in the human placenta before the onset of circulation.…”

Human haematopoietic stem cell development: from the embryo to the dish

“…At least from week 5-6 of development, the human placenta contains high numbers of CD34 + cells, represented by immature CD34 ++ CD45 lo cells that lack CD38 and contain high colonyforming units-culture (CFU-C) numbers, and CD34 + CD45 lo cells committed to erythroid and myeloid differentiation containing fewer CFU-Cs (Barcena et al, 2009). At this stage, the placenta is also a site of extensive erythroid maturation: placental villi are enriched for primitive erythrocytes that express embryonic ζ-globin in association with macrophages, which may facilitate their enucleation (Van Handel et al, 2010). Although CD34 + cells appear in the human placenta as early as at week 5 of gestation, true HSCs can be detected there only after week 9 of gestation or even later, as determined by xenotransplantation into immunocompromised mice (Robin et al, 2009;Muench et al, 2017).…”

The placenta: the forgotten essential organ of iron transport

“…Research is needed to characterize the function of these heme-transport proteins in the placenta and to elucidate the placental heme metabolic pathway, especially in light of the recent recognition of placenta as a site for hematopoietic stem cell production and erythroid differentiation. 86,94,95 …”

“…The function of Hofbauer cells is not well defined but may include the support of trophoblast differentiation, stromal development, angiogenesis, and erythroid cell maturation. 85,86 Located in close vicinity to fetal capillaries, Hofbauer cells express most of the major heme and nonheme iron transporters and storage proteins, 25,49 suggesting a role in iron transport and/or regulation. 86,87 It is tempting to speculate that Hofbauer cells may function as the temporary iron storage site in villous stroma, storing iron when maternal supply exceeds fetal demands and releasing iron when supply is insufficient.…”