The marrow, located in the medullary cavity of bone, is
the sole site of effective hematopoiesis in humans. The marrow produces
approximately six billion cells per kilogram of body weight per
day. Hematopoietically active (red) marrow regresses after birth
until late adolescence, after which it is focused in the lower skull,
vertebrae, shoulder and pelvic girdles, ribs, and sternum. Fat cells
replace hematopoietic cells in the bones of the hands, feet, legs,
and arms (yellow marrow). Fat occupies approximately 50 percent
of the space of red marrow in the adult. Further fatty metamorphosis
continues slowly with aging. In very old individuals, a gelatinous
transformation of fat to a mucoid material may occur (white marrow).
Yellow marrow can revert to hematopoietically active marrow if prolonged
demand is present, as in chronic hemolytic anemia. Hematopoiesis
can be expanded by increasing the volume of red marrow (expanding proliferating
populations) and decreasing the development (transit) time from
progenitor to mature cell.
The marrow stroma consists principally of a network of
sinuses that originate at the endosteum from cortical capillaries
and terminate in collecting vessels that enter the systemic venous
circulation. The trilaminar sinus wall is composed of endothelial
cells; an underdeveloped, thin basement membrane; and adventitial reticular
cells that are fibroblasts capable of transforming into adipocytes.
The endothelium and reticular cells are sources of hematopoietic
cytokines. Hematopoiesis occurs in the intersinus spaces and is controlled
by a complex array of stimulatory and inhibitory cytokines, cell–cell
contacts, and the effects of extracellular matrix components on
proximate cells. 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 system also can respond to meet increased demands for
additional cells as a result of blood loss, hemolysis, inflammation,
immune cytopenias, and other causes. Stem cells can leave and reenter
marrow as part of their normal circulation. Their extramedullary
circulation can be increased by exogenous cytokines and chemokines.
The evolutionary factors that led to confinement
of hematopoiesis to the medullary cavity of bone are not fully understood.
Two relationships that may underlie this requirement for proximity
are the biochemical and receptor contributions of osteoblasts to
hematopoiesis and the homing of hematopoietic stem cells to endosteum.
Acronyms and Abbreviations
Acronyms and abbreviations that appear in this chapter include: IIICS, type
III connecting segment; AGM, aorta-gonad-mesonephros; ALCAM, activated
leukocyte adhesion molecule; bFGF, basic fibroblast growth factor;
BFU-E, burst-forming unit–erythroid; BMP, bone morphogenetic
protein; CAR, CXCL 12-abundant reticular cells; CD, cluster of differentiation;
CFU-E, colony forming unit–erythroid; CFU-S, colony forming
unit–spleen; CLA, cutaneous lymphocyte antigen; EC, endothelial
cell; ECM, extracellular matrix protein; ELAM, endothelial leukocyte
adhesion molecule; FN, fibronectin; GAG, glycosaminoglycan; G-CSF,
granulocyte colony-stimulating factor; G-CSF-R, granulocyte colony-stimulating
factor receptor; GlyCAM, glycosylation-dependent cell adhesion molecule;
GM-CSF, granulocyte-macrophage colony-stimulating factor; HCA, hematopoietic
cell antigen; HCAM, homing cell adhesion molecule; HGF, hepatocyte
growth factor; HLA, human leukocyte antigen; HPP-CFC, ...