Erythropoiesis: development and differentiation

Abstract

Through their oxygen delivery function, red blood cells are pivotal to the healthy existence of all vertebrate organisms. These cells are required during all stages of life--embryonic, fetal, neonatal, adolescent, and adult. In the adult, red blood cells are the terminally differentiated end-product cells of a complex hierarchy of hematopoietic progenitors that become progressively restricted to the erythroid lineage. During this stepwise differentiation process, erythroid progenitors undergo enormous expansion, so as to fulfill the daily requirement of ~2 × 10(11) new erythrocytes. How the erythroid lineage is made has been a topic of intense research over the last decades. Developmental studies show that there are two types of red blood cells--embryonic and adult. They develop from distinct hemogenic/hematopoietic progenitors in different anatomical sites and show distinct genetic programs. This article highlights the developmental and differentiation events necessary in the production of hemoglobin-producing red blood cells.

Figure 1.

Ontogeny of the mouse hematopoietic system. (A) During gastrulation of the mouse conceptus, emerging mesodermal cells (brown arrows) migrate to the extraembryonic compartments (yolk sac and allantois). Blood islands begin to form in the yolk sac upon interactions of the mesoderm (orange) with the endoderm (gray). (Red arrows) Mesoderm migrating into the embryo proper. (B) Embryonic day 10.5 (E10.5) mouse embryo. Hematopoietic sites include the aorta (AGM region), yolk sac, umbilical and vitelline arteries, placenta, and liver. (Dotted line) The transverse section in panel C. (C) Transverse section showing the AGM region of an E10.5 mouse embryo. Urogenital ridges are lateral to the aorta. A hematopoietic cluster on the ventral wall of the aorta is shown. (D) Close-up of the aorta showing a hemogenic endothelial cell transitioning to a hematopoietic cluster cell. Nonhemogenic endothelial cells (blue) and mesenchymal cell (yellow) are shown.

Figure 2.

Ontogeny of erythroid lineage cells in the circulation. Embryonic erythrocytes (primitive red blood cells [RBCs]) are made by the yolk sac at E7.5 and are found in the circulation until ∼E11/12. At E9, the yolk sac and placenta generate definitive progenitors that migrate to the fetal liver, where they differentiate to definitive RBCs (expressing fetal/adult globin) and enter the circulation. At E10.5, the AGM generates the first HSCs that migrate to the fetal liver and differentiate to the erythroid lineage (among other lineages), and these definitive RBCs enter the circulation. Fetal liver HSCs migrate and colonize the bone marrow at birth, where they provide lifelong production of definitive RBCs for the circulation. The spleen also is a site of differentiation for erythroid cells (not shown).

Figure 3.

Proposed models for the hematopoietic hierarchy. In the model proposed by the Weissman group (Kondo et al. 1997; Akashi et al. 2000; Manz et al. 2002) (solid arrows), multipotential progenitors (MPPs or short-term HSCs [ST-HSCs]) give rise to either a common lymphocyte progenitor (CLP) or a common myeloid progenitor (CMP), which, in turn, gives rise to either a granulocyte-macrophage progenitor (GMP, equivalent to CFU-GM) or a megakaryocyte-erythroid progenitor (MEP). The alternate model suggested by the Jacobson group (Adolfsson et al. 2005) (dotted arrows) involves the generation of MEPs directly from the MPPs/ST-HSCs, whereas a lymphoid-primed multipotential progenitor (LMPP) has the potential to generate both CLPs and GMPs. LT-HSC, Long-term hematopoietic stem cell; NK cell, natural killer cell. (This figure is modified from data by Ferreira et al. 2005; reprinted, with permission, from the author as defined by the American Society for Microbiology.)

Figure 4.

Erythroid differentiation in the mouse. The expression of the most commonly used cell surface markers to identify the various stages is indicated by the bars. Cells at the CFU-e and pro-erythroblast stage are the most sensitive to, and dependent on, the presence of EPO. Gray, low expression; black, high expression; HSC, hematopoietic stem cell; CMP, common myeloid progenitor; MEP, megakaryocyte-erythroid progenitor; BFU-e, burst-forming unit, erythroid; CFU-e, colony-forming unit, erythroid.

Figure 5.

The erythroblastic island. (A) Erythroblastic island in E13.5 fetal liver. The cytoplasmic extensions of the central macrophage (stained with the F4/80 antibody) (brown) are surrounding erythroid cells at various stages of differentiation. (B) Schematic drawing of an erythroblastic island.