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C H A P T E R 26

BIOLOGY OF ERYTHROPOIESIS, ERYTHROID DIFFERENTIATION,

AND MATURATION

Thalia Papayannopoulou and Anna Rita Migliaccio

The production of erythroid cells is a dynamic and exquisitely regu- consists of the burst-forming unit-erythroid (BFU-E), named for the
lated process. The mature red cell is the final phase of a complex but ability of BFU-E to give rise to multiclustered colonies (erythroid
orderly series of genetic events that initiates when a multipotent stem bursts) of hemoglobin-containing cells. BFU-E represent the earliest
cell commits to the erythroid program. Expression of the erythroid progenitors committed exclusively to erythroid differentiation and
program occurs several divisions later in a greatly amplified popula- a quiescent reserve, with only 10% to 20% in cycle at any given
tion of erythroid cells, which have a characteristic form and structure, time. However, once stimulated to proliferate in the presence of
maturation sequence, and function. These maturing cells are termed appropriate cytokines, BFU-Es demonstrate a significant proliferative
erythroid precursor cells and reticulocytes. Terminally differentiated cells capacity in vitro, giving rise to colonies of 30,000 to 40,000 cells,
have a finite life span, and they are constantly replenished by influx which become fully hemoglobinized after 2 to 4 weeks, with a peak
from earlier compartments of progenitor cells that are irreversibly incidence at 14 to 16 days. They have a limited self-renewal capac-
committed to express the erythroid phenotype. During ontogeny, ity; at least a subset of BFU-E is capable of generating secondary
successive waves of erythropoiesis occur in distinct anatomic sites. Ery- bursts upon replating. In contrast to this class of progenitor cells,
throid cells developing in these sites have distinguishable phenotypes a second, more differentiated class of progenitors consists of the
and intrinsic programs that are dependent on gestational time and colony-forming unit–erythroid (CFU-E). Most (60–80%) of these
their microenvironment. At each site, erythroid cells are in intimate progenitors already are in cycle and thus proliferate immediately
contact with other cells (e.g., stromal cells, hematopoietic accessory after initiation of culture, forming erythroid colonies within 7 days.
cells, and extracellular matrix) comprising their microenvironment. Because CFU-E are more differentiated than BFU-E, they require
Within this microenvironment, erythroid development is influenced fewer divisions to generate colonies of hemoglobinized cells, and the
by cytokines, which are either elaborated by microenvironmental cells colonies are small (8–64 cells per colony).
or produced elsewhere and then entrapped in the extracellular matrix. Although the two classes of committed erythroid progenitors
Knowledge of the properties of erythroid progenitor and precursor (BFU-E and CFU-E) appear distinct from each other, in reality
cells and their complex interactions with the microenvironment is progenitor cells constitute a continuum, with graded changes in their
essential for understanding the pathophysiology of erythropoiesis. properties. Only progenitor cells at both ends of the differentiation
Aberrations in the generation and/or amplification of fully mature spectrum have distinct properties. Perhaps the earliest cell with the
and functional erythroid cells or in the regulatory influences of potential to generate hemoglobinized progeny is an oligopotent
microenvironmental cells or their cytokines/chemokines form the progenitor, which is capable of giving rise to mature cells of at
basis for various clinical disorders, including aplasias, dysplasias, and least one other lineage (granulocytic, macrophage, or megakaryo-
neoplasias of the erythroid tissue. cytic) 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
ERYTHROID PROGENITOR CELL COMPARTMENT myeloid progenitor, and the most primitive BFU-E have physical
and functional properties that are shared by both pluripotent stem
The erythroid progenitor cell compartment, situated functionally cells and progenitor cells committed to nonerythroid lineages. These
between the multipotent stem cell and the morphologically dis- properties include high proliferative potential, low cycling rate,
tinguishable erythroid precursor cells, contains a spectrum of cells response to a combination of cytokines, and presence of specific
with a parent-to-progeny relationship, all committed to erythroid surface antigens or surface receptors (see Table 26.1). In contrast,
differentiation. A complete understanding of how erythroid com- the latest CFU-E have many similarities with erythroid precursor
mitment is achieved at the biochemical or molecular level is lacking, cells and little in common with primitive BFU-E. Their proliferative
although some attempts at determining the molecular basis have potential is limited, they cannot self-renew, they lack the cell surface
1–4
been made. Evidence from in vitro cultures of single multipotent antigens common to all early progenitors, and they are exquisitely
progenitor cells allowed to differentiate in competent environments, sensitive to erythropoietin (EPO; see Table 26.1).
as well as evidence obtained by studying the phenotype of leukemic Although clonal erythroid cultures are indispensable for the study
cells, suggests that commitment to a specific hematopoietic lineage is of erythroid progenitors, they do not faithfully reproduce the in vivo
accomplished not by acquisition of new genetic information but by kinetics of red cell differentiation/maturation, and many maturing
restriction (probably on a stochastic basis) to specific programs from a cells have a megaloblastic appearance and lyse before they reach the
5,6
wider repertoire available to pluripotent progenitor cells. Molecular end stage of red cell development. In vivo, erythropoiesis probably
6–8
evidence supports this view. Although all erythroid progenitor occurs faster than predicted from culture data. For example, studies
cells share the irreversible commitment to express the erythroid in dogs with cyclic hematopoiesis, a genetic stem cell defect leading
phenotype, the properties of these cells progressively diverge as the to pulses of hematopoiesis, provide evidence that BFU-E mature to
cells become separated by several divisions. CFU-E over 2 to 3 days in vivo, although this process may require
Erythroid progenitor cells are sparse (Table 26.1) and difficult 5 to 6 days in canine marrow cultures. 14
to isolate in sufficient purity and numbers for study. For these Erythroid progenitors can be cultured in serum-depleted media, 15,16
reasons, the existence and characteristics of these cells were inferred as well as in serum-containing media. The effects of recombinant
from their ability to generate hemoglobinized progeny in vitro in growth factors can be studied in serum-depleted cultures without
clonal erythroid cultures (Fig. 26.1). Two classes of progenitors have the complicating influences of multiple or unknown factors present
9
been identified using this approach. The first, more primitive class in serum. Conditions that imitate lower oxygen pressures, found in
297