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CHAPTER 5 The marrow stroma consists principally of a network of sinuses that orig-

STRUCTURE OF THE inate at the endosteum from cortical capillaries and terminate in collecting
vessels that enter the systemic venous circulation. The trilaminar sinus wall
MARROW AND THE is composed of endothelial cells; a thin basement membrane; and adventitial
reticular cells that are progenitors of chondrocytes, osteoblasts and adipocytes.
HEMATOPOIETIC Stem cells can leave and reenter marrow as part of their normal circulation.
Hematopoiesis, the proliferation and differentiation of stem cells and their
progeny in the intersinus spaces, is controlled by a complex array of stimu-
MICROENVIRONMENT latory and inhibitory cytokines, cell–cell contacts, and interactions with the
extracellular matrix. In this unique environment, lymphohematopoietic stem
cells differentiate into all the blood cell lineages. Mature cells are produced and
released to maintain steady-state blood cell levels. The hematopoietic system
Utpal P. Davé and Mark J. Koury*
also can respond to meet increased demands for additional cells as a result of
blood loss, hemolysis, inflammation, immune cytopenias, and other causes.
SUMMARY

The marrow, located in the medullary cavity of bone, is the site of hematopoie-
sis in humans. The marrow produces approximately 6 billion cells per kilogram HISTORY AND GENERAL
of body weight per day. Hematopoietically active (red) marrow regresses after CONSIDERATIONS
birth until late adolescence, after which it is focused in the lower skull, verte-
brae, shoulder and pelvic girdles, ribs, and sternum. Fat cells (yellow marrow) The marrow, one of the largest organs in the human body, is the prin-
replace hematopoietic cells in the bones of the hands, feet, legs, and arms. Fat cipal site for blood cell formation. In the normal adult, daily marrow
comprises approximately 50 percent of red marrow in the adult. Further fatty production amounts to approximately 2.5 billion red cells, 2.5 billion
replacement of the red marrow continues slowly with aging, but hematopoie- platelets, and 1 billion granulocytes per kilogram of body weight. The
sis can be expanded when demand for blood cells is increased. rate of production adjusts to actual needs and can vary from a basal
rate to several times normal. Until the late 19th century, blood cell
formation was thought to be the prerogative of the lymph nodes or
the liver and spleen. In 1868, Neuman and Bizzozero independently
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observed nucleated blood cells in material squeezed from the ribs of
Acronyms and Abbreviations: AGM, aorta-gonad-mesonephros; ALCAM, activated human cadavers and proposed that the marrow is the major source of
leukocyte adhesion molecule; bFGF, basic fibroblast growth factor; BFU-E, burst- blood cells. The first in vivo marrow biopsy probably was done in 1876
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forming unit–erythroid; BMP, bone morphogenetic protein; CAR, CXCL 12–abundant by Mosler, who used a wood drill to obtain marrow particles from a
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reticular cells; CD, cluster of differentiation; C/EBP, CCAAT/enhancer-binding protein; patient with leukemia. Studies by Arinkin in 1929 established marrow
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CFU-E, colony forming unit–erythroid; CFC-G, colony-forming cell-granulocyte; aspiration as a safe, easy, and useful technique (Chap. 3).
CXCL12/SDF1, stromal cell-derived factor; dpc, days postcoitum; EBI, erythroblastic Kinetic studies of marrow cells, using radioisotopes and in vitro
island; ECM, extracellular matrix; ELAM, endothelial leukocyte adhesion molecule; cultures, have shown that cell lineages consist mainly of maturing cells
EPO, erythropoietin; FN, fibronectin; GAG, glycosaminoglycan; G-CSF, granulocyte with a finite functional life span. On the other hand, sustained cellular
colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating production depends on pools of primordial cells capable of both dif-
factor; GMP, granulocyte-macrophage progenitor; HGF, hepatocyte growth factor; ferentiation and self-replication. The most primitive pool consists of
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HIF, hypoxia-inducible factor; HSC, pluripotent hematopoietic stem cell; ICAM, inter- pluripotential lymphohematopoietic stem cells with the capacity for
cellular adhesion molecule; IHH, Indian hedgehog family of proteins; IL, interleukin; continuous self-renewal, that is, hematopoietic stem cells (HSCs). The
LFA, lymphocyte function antigen; MAdCAM, mucosal addressin cell adhesion mole- more mature pools consist of differentiating progenitor cells, with their
cule; M-CSF, macrophage colony-stimulating factor; MEP, megakaryocytic-erythroid maturation restricted to single or limited numbers of cell lineages and
progenitor; MIP, macrophage inflammatory protein; MMP, matrix metalloproteinase; more restricted capacities for self-renewal (Chap. 18). The proliferative
MPP, multipotential pluripotential progenitor; MSC, mesenchymal stem cell; NFAT, activity of these pools involves humoral feedback from peripheral target
nuclear factor of activated T cells; NK, natural killer; OPG, osteoprotegerin; PDGF, tissues and cell–cell and cell–matrix interactions within the microen-
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platelet-derived growth factor; PECAM, platelet endothelial cell adhesion mole- vironment of the marrow. The marrow stroma and nearby hematopoi-
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cule; PPAR, peroxisome proliferator-activated receptor; ProEBs, proerythroblasts; etic cells provide unique structural and chemical environments (niches)
PSGL, P-selectin glycoprotein ligand; RANK, receptor activator of nuclear factor-κB; that support the survival, differentiation, and proliferation of pluripo-
Rb, retinoblastoma tumor-suppressor protein; SCF, stem cell factor; Siglecs, sialic tential HSCs. HSC interactive niches have been identified at the struc-
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acid-binding immunoglobulin (Ig)-like lectins; SP, side population; TGF-β, trans- tural and molecular levels and are dynamically controlled by bone
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forming growth factor-β; TLR, toll-like receptor; TNF-α, tumor necrosis factor-α; morphogenetic proteins (BMPs) and factors regulating intramedul-
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TPO, thrombopoietin; TRAP, tartrate-resistant acid phosphatase; TSP, thrombospon- lary osteoblastic cells and their progenitors. Early stem cells can be
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din; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor; identified and isolated using a unique array of surface antigen-receptor
VLA, very-late antigen.
lo
expressions (CD34+/−, Thy1, KIT+, CD38−, CD33−, vascular endo-
thelial [VE]-cadherin+, KDR/FLK1+, FLK2−/FLT3−, CD133+/−) 13–18
* Marshall A. Lichtman was an author of this chapter in the previous six editions, and have a unique molecular signature. 19,20 The ability to efflux specific
and some material from those editions, including all illustrations, has been chemical dyes has also been used to provide enriched populations of
retained. HSC. 21–24 Isolated cell populations enriched in HSC can be quantified

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