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

TPO concentrations are reciprocally related to the circulating platelet A group of hematopoietic growth factors, including SCF, GM-CSF,
mass, which is the major site of metabolism of the hormone. As the G-CSF, IL-6, and IL-5, support granulocytic progenitor/precursor via-
388
major regulator of megakaryocyte development, TPO acts in concert bility and proliferation. In some cases, these growth factors can mobi-
with several synergistic cytokines, including IL-11, IL-3, and IL-6. 386,387 lize of these progenitors/precursors and their mature progeny from the
TPO induces endomitosis in terminally differentiating megakaryo- marrow. These growth factors are produced in sites of inflammation in
cytes by inhibiting cytokinesis through reduced function of the con- peripheral tissues, although some such as SCF and M-CSF are normally
tractile ring of filamentous actin and suppression of nonmuscle myosin produced in the marrow stroma. Two hematopoietic growth factors
expression. 389,390 However, DNA replication and accumulation of cyto- have lineage-specific late-stage granulocytic cells as targets: IL-5 for
plasmic proteins continues during six to seven of these endomitotic cell eosinophil progenitors and G-CSF for neutrophilic progenitors. IL-5 is
cycles. The resultant polyploid nucleus and abundant cytoplasm char- produced mainly by the T-helper type 2 (Th2) lymphocytes in response
acterize the mature megakaryocyte which can account for 2 percent of to allergens (Chap. 62). 402,403 Eosinophilic progenitor cells display an
marrow hematopoietic cell volume. 93 IL-5α receptor protein that when associated with the common β recep-
402
Mature megakaryocytes lie directly outside the marrow vascular tor (CSF2RB), binds IL-5, leading to their survival and proliferation.
391
sinus wall because of their translocation during differentiation under Mature eosinophils have survival and chemotactic responses to IL-5,
the influence of platelet endothelial cell adhesion molecule (PECAM)-1 which mediates their entry into the circulation and accumulation in
(CD31) expressed on endothelial cells 392,393 and an autocrine pathway sites of allergic inflammation. GM-CSF, G-CSF, IL-3, and IL-6 all stim-
of VEGF-A and its receptor Flt-1 stimulating CXCR4 (receptor for ulate granulopoiesis in vivo, but only the deficiency of G-CSF results
CXCL12) expression on megakaryocytes. This migration of matur- in severe neutropenia, making it the likely regulator of normal circu-
394
404
ing megakaryocytes is associated with the development of podosomes, lating granulocyte numbers. Under normal steady-state conditions,
actin-based extensions that bind to and remodel the local ECM. The 1 to 2 percent of neutrophils circulate transiently in the blood, while the
395
podosomes not only direct the megakaryocytes through the marrow to majority remains in the marrow unless mobilized by inflammation in
the sinus wall, but they also extend through the sinus basement mem- other areas of the body.
brane into the circulation. Terminal differentiation of megakaryo- Models of G-CSF regulation of granulopoiesis and circulating neu-
395
cytes involves the development of branching cytoplasmic protrusions, trophils under normal conditions and during inflammatory states have
the proplatelets. Proplatelets are formed around a microtubular core been proposed. 405,406 Newly formed neutrophils have low expression of
that both provides a sliding mechanism that elongates and extends them CXCR4 and can exit the marrow by migration through sinusoidal endo-
into the vascular sinus lumen, but also provides a conduit for the redis- thelial cells. As they age in the circulation they express more CXCR4 and
tribution of cytoplasmic granules from the megakaryocytes to bulbous are attracted back to the marrow by stromal CXCL12, the CXCR4 lig-
405
formations at the distal ends of the proplatelets. 389 and. After reentering the marrow, the senescent neutrophils undergo
apoptosis and are phagocytosed by macrophages that, in turn, produce
G-CSF stimulating more granulopoiesis. Cells at sites of inflamma-
405
Granulocytes tion produce both G-CSF and chemokines, including KC chemokine
Granulocytes are mature myeloid cells comprised of neutrophils, eosin- (CXCL1), and macrophage inhibitory protein (MIP)-2 (CXCL2). The
ophils, and basophils originating from stem cells and myeloid progen- secreted G-CSF acts on the marrow mobilizing neutrophils by its ability
itor cells concentrated in the subcortical regions of the hematopoietic to reduce both marrow CXCL12 production and neutrophilic CXCR4
396
cords (Chap. 18). Granulocytes are terminally differentiated from expression. G-CSF, however, does not recruit the neutrophils to sites
common granulocyte-macrophage progenitor (GMP) cells which of inflammation from the blood. By their chemotactic properties,
405
arise from MPPs through the expression of multiple transcription fac- CXCL1 and CXCL2 also induce rapid mobilization from the marrow
405
tors (Chap. 61). The transcription factor PU.1 promotes the develop- into the blood and to sites of inflammation. Another model involves
ment of the GMP phenotype and antagonizes the activity of GATA-1, similar migration of neutrophils from the marrow that depends on
which promotes MEP differentiation. 397,398 The myeloid commitment of G-CSF downregulating CXCL12 production and neutrophilic CXCR4
GMPs is reinforced by C/EBPα, which promotes myeloid differentia- expression, but the feedback that decreases G-CSF occurs in the periph-
406
tion while suppressing the B-lymphoid transcription factor Pax5. 398,399 eral tissues. In this model, macrophages that phagocytose apoptotic
The further activity of C/EBPα is associated with granulocytic differ- neutrophils in the peripheral tissues decrease IL-23 production, which
entiation, whereas increased PU.1 activity is associated with monocytic decreases IL-17 production by a subset of T-lymphocytes that, in turn,
400
differentiation. The progression of myeloid differentiation beyond the results in decreased G-CSF in the marrow.
promyelocyte stage, including the formation of secondary and tertiary
granules, requires both C/EBP and the GFI-1 transcription factors. 400,401 CELL ADHESION AND HOMING
GFI-1 also antagonizes the activity of the Egr-1 and Egr-2 transcription
400
factors that are associated with monocytic differentiation. The timing After their initial migration from the yolk sac, AGM, or placenta to the
of expression and relative ratios of C/EBPα and GATA-2 transcription marrow, the HSCs are located in specific sites in the marrow through
factors regulate differentiation of the GMP into a mature neutrophil, interactions with other types of cells and with matrix proteins. HSCs
eosinophil, basophil, or mast cell. Increased C/EBPα activity at this do not remain permanently in the marrow because a small percent-
399
stage promotes a differentiation pathway toward neutrophils and eos- age of them are continuously entering the blood through the venous
inophils, whereas increased GATA-2 activity promotes differentiation sinusoids, circulating briefly, and then reentering the marrow. 407,408 In
toward basophils and mast cells. Cells differentiating along the neu- addition to the HSCs, the more differentiated progenitor cells, such
399
trophil and/or eosinophil pathway will follow a terminal neutrophil as the short-term repopulating cells and the primitive BFU-Es, can
path when only C/EBPα is expressed, and a terminal eosinophil path circulate in a similar manner. When circulating, the HSCs can either
when both C/EBPα and GATA-2 are expressed. Those cells differentiat- reenter the marrow or they can enter other organs. After entering the
ing along the basophil/mast cell pathway will follow a terminal mast cell interstitium of a peripheral organ, the HSCs can give rise to myeloid
path when only GATA-2 is active and a terminal basophil path when progeny and/or they enter the lymphatic drainage of the organ and cir-
both GATA-2 and C/EBPα are active. culate through lymphatic vessels and thoracic duct before reentering

Kaushansky_chapter 05_p0051-0084.indd 65 9/19/15 12:11 AM