The First Trimester Human Placenta Is a Site of Primitive Red Blood Cell Maturation.
Authors: Van Handel Benjamin J. , Prashad Sacha , Huang Andy , Hamalainen Eija , Chen Angela , Mikkola Hanna K.A. 
Published: April 2020

Abstract
Embryonic hematopoiesis occurs in multiple anatomic sites and is generally divided into two waves, primitive and definitive. The primitive wave produces mostly red blood cells in the yolk sac, while the definitive wave generates hematopoietic stem cells (HSCs) that provide lifelong blood homeostasis. Definitive erythropoiesis, occurring first in the fetal liver and eventually the bone marrow, is an orchestrated process in which erythroblasts cluster around a central macrophage. These functional units, termed erythroblast islands, facilitate the maturation of nucleated erythroblasts to enucleated erythrocytes. It has long been thought that primitive red cells maintain their nucleus until undergoing apoptosis; however, the enucleation of primitive erythroblasts has been recently documented in mice, although the site at which this occurs is unknown. We have recently identified the placenta as a major hematopoietic organ that promotes the development of HSCs in mice; preliminary data suggests that the first trimester human placenta also supports definitive hematopoiesis. Surprisingly, our most recent findings indicate a novel, unexpected role for the human placenta in primitive hematopoiesis: the promotion of terminal maturation of primitive erythroblasts. Analysis of placental sections revealed a striking tendency of primitive red blood cells to extravasate from blood vessels in the villi and migrate out into the stroma. Furthermore, once out in the stroma, primitive erythroblasts mature: they lose expression of CD43 and enucleate. The finding that human primitive red blood cells enucleate is undocumented; interestingly, the developmental timing of erythroblast enucleation in humans parallels that in mice. At three weeks, nascent vessels in the placenta are empty, but starting at about 4 weeks, placental circulation begins and fills these vessels with large, nucleated primitive erythroblasts generated in the yolk sac. The migration of primitive erythroblasts into the stroma occurs between 4.5 and 7 weeks. Enucleation mirrors this process, with a large enrichment of enucleated cells in the stroma versus in the vessels at early developmental ages, suggesting that primitive erythroblasts enucleate in the placental stroma. This phenomenon is restricted to placental villi and does not occur in the chorionic plate. Strikingly, extravasated erythroblasts are often in close proximity to placental macrophages, reminiscent of the macrophage-erythroblast associations seen in fetal liver and bone marrow erythropoiesis at later developmental stages. Fetal liver-derived definitive erythrocytes enter circulation at around 8 weeks. After 9–10 weeks, most red blood cells can be observed in vessels, and almost all are enucleated. The concerted processes of extravasation and maturation of primitive erythroblasts in placental stroma nominate the placenta as an important site in primitive hematopoiesis. Furthermore, the association between placental macrophages and primitive erythroblasts suggests that primitive and definitive erythropoiesis share common mechanisms of terminal maturation.