These cells are functionally situated between the multipotent stem cell and the morphologically distinguishable erythroid precursor cells. This compartment contains a spectrum of cells with a parent-to-progeny relationship, all committed to erythroid differentiation. A complete understanding of how erythroid commitment is achieved at the biochemical or molecular level is finally starting to emerge in all its complexity (see intrinsic control of erythropoiesis) (most of the references published before 2016 are available in Papayannopoulou and Migliaccio[1]). Although all erythroid progenitor cells share the irreversible commitment to express the erythroid phenotype, the properties of these cells progressively diverge as the cells become separated by several divisions. Over time, increases in the sophistication of the technologies used to determine these properties have also increased the precision with which we define these cells.

Erythroid progenitor cells are sparse and difficult to isolate in sufficient purity and numbers for study. For these reasons, the existence and characteristics of these cells were first inferred by functional assays based on their ability to generate hemoglobinized progeny in vitro in clonal erythroid cultures. Two classes of progenitors have been identified using this approach. The first, more primitive class consists of the burst-forming unit-erythroid (BFU-E), named for the ability of BFU-E to give rise to multiclustered colonies (erythroid bursts) of hemoglobin-containing cells. BFU-E represent the earliest progenitors committed exclusively to erythroid differentiation and a quiescent reserve, with only 10% to 20% in cycle at any given time. However, once stimulated to proliferate in the presence of appropriate cytokines, BFU-Es demonstrate a significant proliferative capacity in vitro, giving rise to colonies of 30,000 to 40,000 cells, which become fully hemoglobinized after 2 to 4 weeks, with a peak incidence at 14 to 16 days. They have a limited self-renewal capacity; at least a subset of BFU-E is capable of generating secondary colonies upon replating. In contrast to this class of progenitor cells, a second, more differentiated class of progenitors consists of the colony-forming unit–erythroid (CFU-E). Most (60% to 80%) of these progenitors already are in cycle and thus proliferate immediately after initiation of culture, forming erythroid colonies within 7 days. Because CFU-E are more differentiated than BFU-E, they require fewer divisions to generate colonies of hemoglobinized cells, and the colonies are small (8 to 64 cells per colony).

Although BFU-E and CFU-E appear distinct from each other, in reality progenitor cells constitute a continuum, with graded changes in their properties. Only progenitor cells at both ends of the differentiation spectrum have distinct properties. Perhaps the earliest cell with the potential to generate hemoglobinized progeny is an oligopotent progenitor, which is capable of giving rise to mature cells of at least one other lineage (granulocytic, macrophage, or megakaryocytic) in addition to the erythroid. This progenitor, a multilineage colony-forming unit (CFU) called a colony-forming unit–granulocyte, erythrocyte, macrophage, megakaryocyte (CFU-GEMM) or common myeloid progenitor, and the most primitive BFU-E have physical and functional proper ties that are shared by both pluripotent stem cells and progenitor cells committed to non-erythroid lineages. These properties include high proliferative potential, low cycling rate, response to a combination of cytokines, and presence of specific surface antigens or surface receptors. In contrast, the most differentiated CFU-E have many similarities with erythroid precursor cells and have little in common with primitive BFU-E. Their proliferative potential is limited, they cannot self-renew, they lack the cell surface antigens common to all early pro genitors, and they are exquisitely sensitive to erythropoietin (EPO).

Although clonal erythroid cultures are indispensable for the study of erythroid progenitors, they do not faithfully reproduce the in vivo kinetics of red cell differentiation/maturation, and many maturing cells have a megaloblastic appearance and lyse before they reach the end stage of red cell development. In vivo, erythropoiesis probably occurs faster than predicted from culture data. For example, studies in dogs with cyclic hematopoiesis, a genetic stem cell defect leading to pulses of hematopoiesis, provide evidence that BFU-E mature to CFU-E over 2 to 3 days in vivo, although this process may require 5 to 6 days in canine marrow cultures.

BFU-E and their immediate progeny (but not CFU-E) are motile cells found in significant numbers in peripheral blood. As with BFU E, the ability of stem cells and progenitor cells to circulate is physi ologically important for the redistribution of marrow cells in cases of local damage to the microenvironment and for reconstitution of hematopoiesis after transplantation. The spectrum of BFU-E in cir culation probably is narrower (consisting mostly of early, quiescent BFU-E) than that of BFU-E in the bone marrow; otherwise, their properties are similar to those of marrow BFU-E. The number of circulating BFU-E (along with other progenitors and stem cells) can increase to significant levels after cytokine/chemokine treatments and after chemotherapy, a finding that has been exploited for transplantation purposes. At present, mononuclear cells contained in the blood from subjects mobilized with granulocyte colony-stimulating factor (G-CSF) are routinely used as a source of stem/progenitor cells for autologous and allergenic transplantation, alone or in combination with AMD3100, an inhibitor of CXCR4, the receptors expressed on the progenitor cells that by binding with SDF1 (also known as CXCL12) produced by stromal cells, retain the cells in the bone mar row . Apart from SDF1 another important pathway for retaining stem/progenitor cells in BM is represented by VLA-4 integrins (α4β1).[2] These pathways are independently regulated, but they work in concert.

In addition to forming colonies in semisolid medium, hematopoietic progenitors from different sources can generate erythroid cells in liquid culture. Liquid cultures do not allow progenitor cell enumeration but may generate more differentiated cells per progenitor cell than occurs in semisolid cultures. This culture system is often used for modeling erythroid disorders and in theory may generate numbers of erythroid cells equivalent to 1 unit of blood from discarded stem cell sources (cord blood and leukoreduced products of blood donations)[3] [4] ,which has led to the belief that red blood cells (RBCs) generated ex vivo may one day be used for transfusion therapies.

The hematopoietic compartments can also be defined on the basis of their antigenic profiling based on the expression on the plasma membrane of specific proteins recognized by monoclonal antibodies. These studies have first provided a robust definition of the progenitor cells present in bone marrow of normal mice where the prospectively isolated cells may be functionally tested not only in vitro but also in vivo.

The best representative antigen expressed by human BFU-E is the CD34 antigen, which has been successfully exploited for isolation of BFU-E and other progenitors. CD34 is a highly O-glycosylated cell surface glycoprotein expressed by all hematopoietic progenitors and vascular endothelial cells that may serve as a bumper that pre vents close contacts among these cells. Additional clinically important antigens expressed by human erythroid progenitors are the histocompatibility antigens. Like other hematopoietic progenitors, BFU-E display human leukocyte antigen (HLA) class I (A, B, C) and class II (DP, DQ, DR) antigens on their surface. Class II antigens (especially the products of the DR locus), in contrast to class I, are variably expressed by BFU-E. Furthermore, use of antibodies or conjugated ligands determined that, as most of the other immature hematopoietic progenitor cells, BFU-E display receptors for KIT ligand (KL, also known as stem cell factor, SCF), EPO, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-3 (the alpha and common beta subunit for both), gp130, the signaling subunit of the IL-6 receptor, and IL-11. They share with late colony-forming unit–megakaryocyte (CFU-Mk) progenitors the expression of the thrombopoietin (TPO) receptor (c-Mpl or TPO-R) and glycoprotein Iib/IIIa (CD41), an antigen previously thought to be restricted to megakaryocytes, which marks the divergence between definitive hematopoiesis and endothelial cells during development. However, the majority of BFU-E, in contrast to myeloid progenitors, do not express the restricted hematopoietic phosphatase CD45R and aldehyde dehydrogenase activity, an enzyme lost in humans during the transition from CMP to MEP.

As BFU-E mature to the CFU-E stage, they begin to express sur face proteins characteristic of erythroblasts, the morphologically recognizable erythroid cells. For example, CFU-E expresses Rh antigens and the erythroid-specific sialoglycoprotein glycophorin A. Blood group antigens of the ABH Ii type are detectable in a subset of CFU E. In contrast, CD34 molecules, class II antigens, and certain growth factor receptors (i.e., IL-3R, KIT) are greatly diminished or virtually absent at the CFU-E stage. Conversely, the EPO-receptor is greatly expressed at the CFU-E stage but barely detectable on BFU-E. Thus, CFU-E, in contrast to BFU-E, cannot survive in vitro even for a few hours in the absence of EPO.

In conclusion, the Weissman laboratory has defined the phenotype of human erythroid progenitors as lineage−, CD34+, CD38+, IL-3 receptor α−, and CD34RA− for MEP and Lineage−, CD34+, CD38+, IL-3 receptor α−, CD34RA−, CD71intermediate, and CD105+ for erythroid restricted progenitor cells [5] while other investigators have defined the phenotype for human BFU-E as CD45+, GPA−, IL-3 receptor−, CD34+, CD36−, and CD71low and that for CFU-E as CD45+,GPA−, IL-3R−, CD36+, and CD71high.[6]

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