The fetal liver is a niche for maturation of primitive erythroid cells

Abstract

Primitive erythroid cells (EryP) are the earliest differentiated cell type of the mammalian embryo. They appear in the yolk sac by embryonic day 7.5, begin to enter the embryonic circulation 2 days later and continue to mature in a stepwise and synchronous fashion. Like their adult counterparts, EryP enucleate. However, EryP circulate throughout the embryo for several days before the first enucleated forms can be identified in the blood. We have used transgenic mouse lines in which GFP marks EryP to investigate this seemingly long lag and have identified a previously unrecognized developmental niche for EryP maturation. After exiting the yolk sac, EryP begin to express cell adhesion proteins, including ␣4, ␣5, and ␤1 integrins, on their surface and migrate into the fetal liver (FL), where they interact with macrophages within erythroblastic islands. Binding of EryP to FL macrophages in vitro is stage-specific and partly depends on VCAM-1. The ability to tag and track EryP nuclei using a transgenic mouse line expressing an H2B-EGFP fusion allowed us to identify and characterize extruded EryP nuclei and to demonstrate that molecules such as ␣4, ␣5, and ␤1 integrins are redistributed onto the plasma membrane surrounding the extruding nucleus. FL macrophages engulf extruded EryP nuclei in cocultures and in the native FL in vivo. We conclude that EryP home to, complete their maturation, and enucleate within the FL, a tissue that is just developing as EryP begin to circulate. Our observations suggest a simple solution for a puzzling aspect of the development of the primitive erythroid lineage.enucleation ͉ mouse embryo ͉ primitive erythropoiesis ͉ fetal liver ͉ macrophage P rimitive erythroid cells (EryP) are the first to differentiate in the postimplantation embryo and are detectable within the blood islands of the yolk sac by embryonic day 7.5 (E7.5) (1-3). EryP enter the circulation around E9.5 as a synchronous cohort and continue to mature in a stepwise, developmentally regulated fashion (4). Surprisingly, the terminal event in EryP differentiation, enucleation, is not detected for another 3 days (E12.5) (4, 5); it is largely completed by E15.5 (4).To tag and track EryP within the mouse embryo, particularly after midgestation, when large numbers of definitive erythroid cells (EryD) are present in the blood, we used a transgenic mouse line in which GFP is expressed in EryP (4, 6). We found that circulating EryP expressed a subset of cell adhesion molecules, including integrins, on their surface beginning around E12.5 and then appeared to redistribute some of these proteins, notably ␣4, ␣5, and ␤1 integrins, from the membrane of the nascent EryP reticulocyte to that surrounding the expelled nucleus (4). On the basis of these observations, we proposed that at least a subset of EryP may home to the fetal liver (FL) (4).The FL is a major site for the development of EryD (7), which mature within erythroblastic islands (EBIs). EBIs, first identified in bone marrow and later in FL and spleen, are morphologically distinct ...

Hematopoietic Microenvironment in the Fetal Liver: Roles of Different Cell Populations

“…The interaction of erythroid cells with macrophages mediated by the erythroblast macrophage protein (Emp) is necessary for their enucleation [14]. Moreover, macrophages express vascular cell adhesion molecule VCAM-1, which also mediates their adhesive interactions with erythroblasts [15], and jagged-1, a ligand for the Notch signal system involved in regulation of hematopoiesis [13]. The central macrophages of erythroblastic islands degenerate as hematopoiesis in the liver ceases [12].…”

Efeito da administração pré-natal da dexametasona em ratas sobre os perfis glicídicos e hematológicos materno e da prole

“…O restabelecimento no número de hemácias do grupo I para valores similares aos encontrados no grupo IV, aos 21 dias de gestação, mostra que a redução não perdura até o fim da gestação quando administrada apenas no terço inicial da gestação. Com relação à prole, sabe-se que a eritropoese fetal nos dois terços iniciais da gestação é realizada pelo tecido hepático (Isern et al, 2008) e que a regulação dessa função é realizada pelo nível de glicocorticoides circulantes (Bauer et al, 1999). A elevação significativa de eritrócitos verificada nos filhotes do grupo III no 10 o dia pós-natal sugere o estabelecimento de uma relação tempodependente devido à administração prolongada da dexametasona, mesmo tendo sido realizado o desmame.…”

Primitive erythropoiesis in the mammalian embryo

“…Primitive pyrenocytes that appear to have temporarily escaped this fate have been detected in the bloodstream of mouse embryos between E12.5-E16.5 of gestation, that is, during the time when primitive erythroid cells enucleate (McGrath, 2008). Interestingly, primitive erythroblasts are capable of physically interacting with macrophage cells in vitro and are thought to do so within the fetal liver in vivo (McGrath, 2008;Isern, 2008). These interactions are mediated in part through α4β1 integrins present on the surface of primitive erythroid cells and are presumed to involve VCAM1 expressed by macrophage cells in the fetal liver (McGrath, 2008;Isern, 2008).…”

“…Interestingly, primitive erythroblasts are capable of physically interacting with macrophage cells in vitro and are thought to do so within the fetal liver in vivo (McGrath, 2008;Isern, 2008). These interactions are mediated in part through α4β1 integrins present on the surface of primitive erythroid cells and are presumed to involve VCAM1 expressed by macrophage cells in the fetal liver (McGrath, 2008;Isern, 2008). These observations, taken together, indicate that terminal differentiation of mammalian primitive erythroid cells results in erythrocytes more similar to the enucleated red cells of mammals rather than the nucleated red cells of birds, fish and amphibians.…”