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64 Part II: The Organization of the Lymphohematopoietic Tissues Chapter 5: Structure of the Marrow and the Hematopoietic Microenvironment 65

apoptotic cells by neutrophils, macrophages, and dendritic cells. 349–351 CFU-Es through ProEBs, are identified by flow cytometric expres-
Vitronectin-deficient mice have normal blood cell counts, but throm- sion patterns of transferrin receptor (CD71) and the erythroid-spe-
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367
bogenesis, new microvessel formation and tissue repair capacity are cific membrane glycoprotein Ter119, or of CD44 and forward light
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impaired, most likely due to failure of inflammatory and thrombotic scatter. Likewise, expression patterns of glycophorin A, Band 3, and
mechanisms. Thus, in the marrow ECM, vitronectin functions mainly the α component of integrin permit identification of the same stages in
4
in the coordination of apoptotic cell clearance, cellular migration, bone human erythroid differentiation. 369
remodeling, and angiogenesis. In EBIs, CFU-Es lose SCF dependence that had been present
throughout their differentiation from HSCs, and CFU-Es, ProEBs,
Other Matrix Proteins and early basophilic erythroblasts develop a dependence upon EPO to
370
Osteopontin, a glycoprotein produced by osteoblasts and hematopoi- prevent apoptosis. The level of EPO, the principal regulator of ery-
etic cells in the marrow, binds to FN and collagen. 354,355 The predomi- thropoiesis, is regulated by tissue oxygen delivery in the kidney, and is
370
nant form of osteopontin in the marrow is thrombin-cleaved, and its dependent on both blood oxygen levels and red cell numbers. How-
N-terminal peptide is the active ligand for the α β and α β integrins ever, during hypoxic stress, CFU-Es and ProEBs can be increased without
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on HSCs and circulating hematopoietic progenitors that plays a role in differentiation in response to circulating glucocorticoid hormones 371,372
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their attraction to and binding in the marrow. Osteopontin can bind and BMP4 from central macrophages of EBIs. EPO prevents apopto-
356
numerous integrins and CD44, and its binding through β -integrin sis by decreasing expression of Fas, a membrane protein of the TNF-α
1
results in suppression of proliferation and maintenance of quiescence receptor family that is prominently expressed on CFU-E, ProEBs and
in HSCs. 354,355 Conversely, the same osteopontin–β -integrin pathway early basophilic stage erythroblasts. Fas activation triggers a series of
1
357
induces proliferation in erythroblasts. Osteopontin also plays a role in caspases, a family of intracellular proteases that cleave other caspase
374
the development of NK cells 358,359 and T lymphocytes. The fibulins are members in sequential fashion, ultimately inducing apoptosis. Fas-
355
proteins secreted by the stromal cells of marrow, including osteoblasts ligand, which binds and activates Fas, is produced mainly by immature
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and endothelial cells. 360,361 The metalloproteinase-resistant fibulin-1 erythroblasts in mice and by mature erythroblasts in humans. EPO
accumulates in the ECM where it binds to a specific site on FN, 360,361 also suppresses apoptosis in late-stage erythroblasts by inducing the
thereby disrupting HSC binding to FN with resultant decreases in HSC antiapoptotic protein Bcl-X , which stabilizes mitochondria, preventing
L
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361
proliferation and differentiation. Thus, fibulin-1 can act as a negative the activation of caspases other than those activated by Fas. As a result
regulator that can maintain the quiescence of HSCs in the marrow. of the Fas/Fas-ligand negative feedback within the EBI, differentiating
erythroblasts can modulate the rate of CFU-E/ProEB apoptosis and
HEMATOPOIETIC CELL ORGANIZATION provide regulated control rates of erythrocyte production commensu-
rate with erythropoietic demand.
Erythroblasts In EBIs, differentiation events include: (1) hemoglobin produc-
Erythroid progenitor cells arise from MPPs via the activity of the tion in differentiating erythroblasts, (2) formation of the erythrocyte
transcription factor GATA-1, which promotes differentiation toward plasma membrane and underlying membrane skeleton, (3) cell size
the bipotent MEP that can subsequently differentiate into either ery- decrease associated with the terminal 4 to 5 cell divisions being a result
throblasts or megakaryocytes (Chap. 32). MEP fate is determined by of decreased duration of the G phase of erythroblasts attached to
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the relative activities of two competing transcription factors, KLF-1, central macrophages, and (4) nuclear condensation, stiffening,
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which directs differentiation toward the erythroid lineage, and Fli-1, and extrusion. Erythroblast enucleation requires nonmuscle myo-
381
which directs differentiation toward the megakaryocytic lineage. 362,363 sin IIB and filamentous actin to produce a membrane-enveloped
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381
The earliest progenitor cells committed solely to erythroid differenti- nucleus and a nascent reticulocyte. The central macrophage sends out
ation, BFU-Es, which are defined by production of large colonies or extensive slender membranous processes that envelop each erythrob-
364
bursts of erythroblasts after weeks in tissue culture, can circulate in the last and phagocytize defective erythroblasts and extruded nuclei.
383
blood and reenter the marrow. When a BFU-E or one of its progeny, The extruded nuclei display phosphatidylserine on their plasma mem-
the colony-forming units–erythroid (CFU-Es), associates with a mar- branes that leads to rapid phagocytosis by the central macrophage.
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364
row macrophage, they form the precursor of the basic unit of terminal Phagocytosis of extruded nuclei with recycling of the DNA compo-
erythropoiesis, the erythroblastic island (EBI). Under the influence of nents is essential in that deoxyribonuclease II–deficient mice die from
94
the KLF-1 in both the macrophage and the erythroid cells, 365,366 an EBI an underproduction anemia with fetal liver macrophages filled with
develops as a central macrophage surrounded by as many as 30 adherent extruded erythroid nuclei. The irregularly shaped, maturing reticulo-
385
erythroblasts at various stages of differentiation from CFU-E through cytes can interact directly with the central macrophages before entering
enucleating orthochromatic erythroblast. At least five cell-surface pro- the blood through the venous sinuses. 94
tein pairs contribute to adherence between macrophages and erythrob-
lasts in EBIs : (1) VCAM-1 on macrophages and α β integrin (VLA-4) Megakaryocytes
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on erythroblasts; (2) α component of integrins on macrophages and During thrombopoiesis, HSC in the subcortical regions of the hemato-
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ICAM-4 on erythroblasts; (3) erythroblast-macrophage protein (EMP), poietic cords generate megakaryocytes by sequential, overlapping
on both erythroblasts and macrophages via a homophilic reaction; (4) expressions of specific transcription factors. First HSCs differentiate
CD169/Siglec-1 on macrophages and sialylated glycoproteins on ery- to common myeloid progenitors (CMPs) via the influence of PU.1 and
throblasts; and (5) hemoglobin-haptoglobin receptor (CD163) on mac- GATA-1, next to MEPs via GATA-1/FOG, then to megakaryocytic
rophages and an unknown binding partner on erythroblasts. progenitors via Fli-1, and finally to megakaryocytes via NF-E2 (Chap.
Differentiating erythroblasts are defined as basophilic, polychro- 111). 362,386 The microenvironmental factors that control survival and dif-
matophilic, and orthochromatic erythroblasts by their morphologic ferentiation of megakaryocytes and their progenitors include a similar
appearances in Giemsa-stained films of aspirated marrows. However, pattern of dependence to that of erythroid progenitors, with an over-
CFU-Es and their immediate progeny, the proerythroblasts (ProEBs), lapping decrease in dependence on SCF and an increasing dependence
as well as the morphologically defined, later erythroblast stages can be upon a physiologically regulated cytokine, TPO in the case of megakary-
purified and defined by flow cytometry. Murine erythroid cells from ocytes, which ceases before the completion of differentiation. 386,387
Kaushansky_chapter 05_p0051-0084.indd 64 9/19/15 12:10 AM