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310 Part IV Disorders of Hematopoietic Cell Development

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cells, suggesting that soluble KL initiates the response to stress by several other molecules. These molecular interactions have been
priming erythroid cells to respond to glucocorticoids. identified as being critical for erythroblastic island integrity (see also
The pathway(s) that regulate erythropoiesis under conditions of Erythroid Morphologically Recognizable Precursors). EMP expressed
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acute or chronic anemia are starting to emerge. In mice, stress on both erythroblasts and macrophages mediates cell–cell attachment
induces the formation of an erythroid permissive microenviron- through homophilic binding, and erythroblast intercellular adhesion
ment in the spleen and other extramedullary sites. In fact, recent molecule-4 (ICAM-4) links erythroblasts to macrophages by inter-
evidence suggests that, in addition to increasing EPO production acting with α v integrin expressed in macrophages. 397–399 Mice with
by the kidney, to raise the levels of soluble KL in the serum and to targeted deletion of EMP are severely anemic and die at an embryonic
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activate GR response, this pathway activates spleen-specific microen- stage, and ICAM-4 mice have markedly reduced erythroblas-
vironmental cues (BMP4/Hedgehog), which generate stress-specific tic islands. Of interest, retinoblastoma (RB)-deficient macrophages
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hematopoietic compartments. 82,369 The identity of the hematopoietic do not bind RB erythroblasts, and failure of this interaction
stem cell niche in the spleen and the human equivalent of this cell may mediate the defect in fetal liver erythropoiesis observed in
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are yet to be determined. RB mice. RB normally stimulates macrophage differentiation
Besides cell–cytokine interactions, (paracrine) cell–cell adhesion by counteracting inhibition of Id2 (a helix-loop-helix protein) on
and adhesion of cells to the extracellular matrix are important PU.1, a transcription factor crucial in macrophage differentiation.
functions of the microenvironment. 370,371 Perhaps most studied In addition to the aforementioned pathways, macrophage CD163
are the β 1 integrins VLA4 and VLA5, which mediate the adher- can serve as an erythroblast adhesion receptor in erythroblastic
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ence of hematopoietic cells to stromal cells, fibronectin, or other islands, promoting erythroid proliferation and/or survival. More
components of the extracellular matrix. 371,372 In mice lacking β 1 studies addressing the specific interactions between macrophages and
integrins, hematopoietic stem cells fail to colonize the fetal liver erythroid cells that promote erythroid differentiation are needed for
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during embryonic development, and cells lacking α 4 integrin fail definite conclusions regarding specialized “erythroid niches” and
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to contribute to normal hematopoiesis postnatally. Conditional their complex function. Of note, tissue macrophages express RNA
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deletions of β 1 integrin or α 4 integrin during adult stage lead to mild for EPO and may also influence erythropoiesis through this
anemia with increased ROS formation and decreased RBC survival mechanism.
in β 1 -deficient mice and in impairment in erythroid stress response The microenvironment is not only a passive surface for the
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in both β 1 - and α 4 -deficient mice. In addition to intrinsic effects adherence of progenitor cells; it exerts a crucial and interactive role
on erythropoiesis, antibodies to VLA4 or to the vascular cellular in development and maturation. Some interactions are lineage (red
adhesion molecule-1 (VCAM-1, a VLA4 ligand on endothelial cells) cell) specific, whereas other interactions affect hematopoiesis more
influence the retention of stem/progenitor cells in bone marrow and broadly. Stromal and accessory cells secrete cytokines and/or express
thereby impair their homing and lead to their mobilization in adult them in a transmembrane form on their cell surface. Cytokines
mice, in primates, and in MS patients. 376–380 In in vitro studies, are retained via binding to components of the extracellular matrix.
hematopoietic progenitors bind to specific domains of fibronectin All components of the microenvironment are involved in adhesive
in a differentiation-dependent manner (long-term culture-initiating interactions, some of which maintain quiescence (i.e., interactions
cell and day 12 colony-forming unit-spleen in mice adhere mainly of stem cells with endosteal surfaces 403,404 ), whereas other cell–cell
through the heparin-binding domain and CS-1). BFU-E and other interactions or interactions of cells with matrix components induce
progenitor cells adhere to both the cell-binding (Arg-Gly-Asp-Ser proliferation and/or differentiation. 405–407 An individual progenitor
[RGDS]) and heparin-binding domains, whereas CFU-E preferen- cell, in an anatomic niche adjacent to certain stromal cells, accessory
tially bind the RGDS sequence, and reticulocytes fail to adhere to cells, and extracellular matrix molecules, likely responds to the sum
fibronectin. 353,381–384 This differential binding could influence the of the signals that it uniquely receives. In this way, erythropoiesis, or
proliferation and especially the maturation and survival of developing the entire hematopoiesis, is influenced by the complexity of the ME
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erythroid cells, particularly under stress, as well as the migration of interaction network.
progenitor cells in and out of the bone marrow cavity. 374,376 Hemato-
poietic cytokines/chemokines present in the microenvironment can
also modulate the affinity of β1 integrins for ligand, 386,387 adding ONTOGENY OF ERYTHROPOIESIS
complexity to the regulation of erythropoiesis within the marrow
microenvironment. During human development, distinct anatomic areas for production
Many observations suggest that hematopoietic progenitor cells at of erythroid cells are recruited sequentially, in a temporal succession
one stage of fetal development may not be supported by a hematopoi- that allows overlap (Fig. 26.3). In addition, parallel changes occur
etic microenvironment of a different ontogenetic stage. For example, in the morphologic and functional properties of the erythroid cells
cells present in the murine yolk sac are not able to repopulate adult themselves.
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recipients, although they can repopulate newborn recipients with During the phase of embryonic erythropoiesis in the blood islands
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active fetal liver hematopoiesis. Targeted disruption of CXCL12/ of yolk sac, aggregates of immature erythroid cells undergo matura-
SDF1, a member of the CXC chemokine family that is constitutively tion synchronously as a single cohort. Before their maturation is
expressed by bone marrow stromal cells (i.e., reticular/endothelial completed, they begin to circulate, and by gestational week 5 they
cells or osteoblasts), leads to inhibition of marrow hematopoiesis, are found in the vascular spaces of the rudimentary liver (Fig. 26.4).
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although fetal liver hematopoiesis is unaffected, suggesting that At about the same time, foci of immature erythroid cells emerge
this chemokine is important in maintaining normal bone marrow within the fetal liver as the fetal (or hepatic) phase of erythropoi-
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hematopoiesis. Other factors with distinct function on fetal versus esis commences. From week 7 onward, the liver is progressively
adult hematopoiesis have also been described: Sox17 for fetal hemato- filled with erythroid precursors and becomes the dominant site of
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poiesis or TEL (translocation-ETS [E26 transformation-specific]- erythroid cell production until approximately gestational week 30.
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leukemia) and Bmi-1 for adult hematopoiesis. Accessory cells, Although some red cell production can be found in the thymus,
such as stromal cells, in addition to secreting cytokines, express the spleen, or occasionally in the lymph nodes, these other sites are
adhesion molecules, and they may influence marrow hematopoiesis never dominant. However, recently placenta has been recognized as
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by their nonrandom distribution in the marrow cavity. T cells (along an important local erythropoietic site. From month 6 onward, the
with mast cells) are the only source of IL-3 and, through secretion of cavities of long bones are invaded by vascular sprouts and become
TNF-α and IFN-γ, may negatively affect erythropoiesis. In histologic competent to support red cell development. Shortly after birth, all
sections of normal marrow, islands of maturing erythroblasts (eryth- bone cavities are actively engaged in erythroid production, and the
roblastic islands) often surround a central macrophage, termed a nurse hepatic (fetal) phase of erythropoiesis comes to an end, as the final
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cell. Adhesion may be mediated through the binding of VLA4 (on (adult) phase of erythropoiesis unfolds exclusively within the bone
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erythroid cells) to VCAM-1 (on central macrophages), or through marrow.