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312 Part IV Disorders of Hematopoietic Cell Development

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through the end of gestation. Fetal erythroid cells (produced in on their surface, whereas in adult cells, this structure, which bears
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the fetal liver and later in fetal bone marrow spaces) are smaller ABH blood group determinants, is highly branched (I antigen).
than embryonic cells (approximately 125 µm) but have a macrocytic The enzymatic activity of several enzymes in the glycolytic pathway
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appearance compared with adult normocytic red cells (approximately is greater in fetal than in adult red cells. In contrast, carbonic
80 µm). However, like adult cells, fetal erythroid cells eject their anhydrase levels are very low during intrauterine and early neonatal
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nuclei during maturation. life. Distinct isozyme patterns for several enzymes (i.e., phospho-
Apart from variations in size and morphologic characteristics, glycerate kinase, acetylcholinesterase) also distinguish fetal from adult
embryonic and fetal erythroid cells differ from each other and from red cells. 432,433
their adult counterparts in several other characteristics, including The most widely studied changes during red cell ontogeny are
hormonal or growth factor requirements, proliferative status, and the shifts or “switches” in globin types. Embryonic erythroblasts are
transplantation potential. For example, whereas fetal erythropoiesis characterized by their avid accumulation of iron, which is stored as
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is under the control of EPO, the extent of EPO’s influence on ferritin (0.3% to 1% of total protein) and by the synthesis of the
embryonic erythropoiesis is disputed. Most convincing are the results unique hemoglobins Gower I (ζ 2ε 2 ), Gower II (α 2ε 2 ), and hemo-
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of EPO/EPOR knockouts that showed only partial effects on globin Portland (ζ 2γ 2). The ζ- and ε-globin chains are embryonic
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embryonic erythropoiesis, in contrast to fetal erythropoiesis. Single- α-like and β-like chains, respectively. These three embryonic types
lineage transcriptosome analyses indicate that TGF-β may represent of hemoglobin are most likely synthesized in succession, because the
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a primary regulator of embryonic erythropoiesis. Evidence sug- concentration of Gower I is highest in smaller embryos. Thus a switch
gests that precursor cells from the extraembryonic mesoderm are from ζ- to α- and ε- to γ-globin gene production begins during the
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dependent on EPO for proliferation and erythroid differentiation. embryonic phase of erythropoiesis but is not complete until fetal
EPO levels increase between weeks 9 and 32 of gestation, and fetuses erythropoiesis is well established. During the transition from yolk
respond to hypoxia or anemia with increased EPO as early as 24 sac to fetal liver erythropoiesis (6 to 9 weeks), erythroid precursors
weeks. Fetal erythroid progenitors when studied in vitro appear within the fetal liver coexpress embryonic (ζ- or ε-) and fetal (α- or
more sensitive to EPO and KL than adult progenitors. In contrast, γ-) globin both in vivo and in vitro. 435,436 The predominant type
their in vitro response to lymphokines (e.g., IL-3 or GM-CSF) is of hemoglobin synthesized during fetal liver erythropoiesis is HbF
G
A
minimal compared to that of adult erythroid progenitors. 415,416 Of (α 2 γ 2 ), with a high proportion of γ :γ (7 : 3). Adult HbA (α 2 β 2 ),
note, in the early stages of fetal liver erythropoiesis, mainly erythroid which is detectable at the earliest stages of fetal liver erythropoiesis, is
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differentiation/maturation is promoted. Progenitors committed synthesized as a minor component throughout this period. However,
to other lineages are abundant in the fetal liver, but few mature HbA 2 (α 2 δ 2 ), which is a minor hemoglobin in the adult, is undetect-
cells (granulocytes, megakaryocytes) from other lineages are seen. able in these early stages. From about gestational week 30 onward,
In addition to their heightened sensitivity to EPO, fetal erythroid β-globin synthesis steadily increases so that, by term, 50% to 55%
progenitors and precursors are characterized by high proliferative of hemoglobin synthesized is HbA. By 4 to 5 weeks of postnatal age,
potential and shorter doubling times than adult cells when cultured 75% of the hemoglobin is HbA. This percentage increases to 95% by
in vitro. 415,417 The dependency of stem/progenitor cells on KL 4 months as the fetal-to-adult hemoglobin switch is completed. HbF
changes during ontogeny. Although generation of repopulating stem levels in circulating red cells are at a plateau for the first 2 to 3 weeks
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−
lo
cells (C-KIT /Sca1 /Thy1 /Lin ) and colony-forming unit–spleen (as a result of the decline in total erythropoiesis that follows birth),
is minimally affected during fetal life in mice that cannot produce but the HbF level gradually declines so that normal levels (<1%) are
d
KL, adult steel-Dickie (Sl/Sl ) mutant mice (which produce only achieved by 200 days after birth. 437
some soluble KL) display greatly impaired erythropoiesis and Several in vitro and in vivo approaches have been used to study the
hematopoiesis, suggesting that the KL/C-KIT pathway plays a role basis of globin switching through development. Beyond its biologic
in the recruitment and self-renewal behavior of adult stem cells in interest, rigorous research in this area was propelled by the possibil-
vivo. 418,419 The long-term transplantation potential is impaired in ity of manipulating globin switching to increase HbF production
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cells with mutations of C-KIT kinase activity. Transplantable stem in adults and ameliorate the clinical symptoms of disorders of the
cells from the yolk sac, in contrast to fetal liver cells, cannot engraft β-globin locus (e.g., sickle cell anemia, thalassemia). Transplantation
adult recipients, because of altered homing behavior or inability of experiments and ablative endocrine maneuvers in the sheep model
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bone marrow to support their development, as suggested by their have failed to provide convincing support for the effects of environ-
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engraftment in neonatal liver. The homing properties of fetal stem mental or humoral factors on the switching process, although some
cells transplanted into adult irradiated recipients were found to be modulation of the rate of switching was seen in these models. 438,439
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inferior to those of their adult counterparts. Whether this finding is Similar conclusions were reached with transplantation of human fetal
related to their increased cycling or other reasons is unclear. However, liver cells to adult recipients. 440,441 The most important determinant of
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fetal liver stem cells, despite their reduced homing potential, have fetal-to-adult hemoglobin switching seems to be postconceptual age,
higher engraftment levels, likely because of their proliferative prowess with the sharpest period for transition between 30 and 52 weeks. The
compared to adult stem cells. 422 fetal-to-adult switch appears to be unaffected by the time at which
The surface antigenic profiles of erythroid progenitors and precur- birth occurs or by changes in the kinetics of erythropoiesis induced
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sors are distinct at each ontogenic stage. For example, HLA class I and by perinatal hemolysis. A delay in switching usually is observed in
class II antigens are not detected in embryonic erythroid progenitor cases of general developmental retardation, in patients with certain
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cells but reach adult levels at approximately gestational week 9. chromosomal abnormalities (e.g., trisomy 13), and in diabetic infants
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CD34 hematopoietic progenitors present in yolk sac express Mac-1 because of increased circulating levels of α-aminobutyric acid, which
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but are negative for stem cell antigen 1 (Sca-1), which is expressed in directly affects HbF synthesis. Integration of data from studies
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fetal and adult CD34 murine progenitor cells. On the other hand, using in vitro and in vivo approaches indicates that developmental
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adult CD34 progenitors lack Mac-1 and AA4.1, which are expressed control of globin switching is intrinsic to erythroid cells. Stage-specific
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in fetal CD34 progenitor cells. Fetal BFU-E and CFU-E express transcriptional forces with negative or positive influences (or both) on
similar levels of HLA class II antigens, whereas adult CFU-E are specific globin genes may provide the molecular basis for differential
largely devoid of these antigens. 423,425 β 1 integrins, especially α 4β 1 and transcriptional activity during development. This view is favored by
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α 5, are expressed widely in all hemopoietic cells, including nucleated experiments in transgenic mice and in heterokaryons (produced
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erythroid cells. However, in the latter, they display a differentiation- by fusion of human with mouse cells), as well as by isolation of
dependent, developmentally segregated pattern of expression, because stage-specific transcription factors in other erythroid systems (e.g.,
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they are absent in embryonic murine erythroblasts, and among avian). Furthermore, because α-like and β-like globin genes are
adult cells, stem/progenitor cells express them in a constitutively activated sequentially in the order of their location in chromosome
active form in contrast to more mature cells. 427–429 Fetal red cells 11 or 16, respectively, it is possible that polarity of the transcriptional
display a straight, unbranched polylactosaminyl chain (i antigen) activity and globin promoter competition for the locus control region