CHAPTER 4 STRUCTURE OF THE MARROW AND THE HEMATOPOIETIC MICROENVIRONMENT
CHAPTER 4 STRUCTURE OF THE MARROW AND THE HEMATOPOIETIC MICROENVIRONMENT
CAMILLE N. ABBOUD
MARSHALL A. LICHTMAN
Embryogenesis and Early Stem Cell Development
Sinus Architecture and Cellular Organization
Macrophages and Lymphocytes
Cell Adhesion and Homing
Other Adhesion Molecules
Cell Proliferation and Maturation
Stem Cell Circulation
The marrow, located in the medullary cavity of bone, is the sole site of effective hematopoiesis in human beings. It produces about 6 billion cells per kilogram of body weight per day. Hematopoietically active (red) marrow regresses after birth until late adolescence, after which time 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 comes to occupy about 50 percent of the space of red marrow in the adult, and 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, such as hemolytic anemia. Thus, hematopoiesis can be expanded by increasing the volume of red marrow 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 takes place in the intersinus spaces and is controlled by a complex array of stimulatory and inhibitory cytokines, cell-to-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 can also go into overdrive 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 pressures that led to hematopoiesis being confined to the medullary cavity of bone is unclear, but advances in knowledge of the chemical links between the two tissues may provide the answers.
Acronyms and abbreviations that appear in this chapter include: AGM, aorta-gonad-mesonephros; b-FGF, basic fibroblast growth factor; BMP, bone morphogenetic protein; ECMs, extracellular matrix proteins; ELAM-1, endothelial leukocyte adhesion molecule 1; GAGs, glycosaminoglycans; G-CSF, granulocyte colony stimulating factor; GCSFR, G-CSF receptor; GM-CSF, granulocyte-macrophage colony stimulating factor; HCA, hematopoietic cell antigen; HCAM, homing cell adhesion molecule; IAP, integrin-associated protein; ICAM-1, intercellular adhesion molecule 1; LIF, leukemia inhibitory factor; M-CSF, macrophage colony stimulating factor; MIP-1, macrophage inflammatory protein 1; MMP-9, matrix metalloproteinase 9; NK, natural killer; ODF, osteoclast differentiation and activation factor; OPG, osteoprotegrin; PCLP1, podocalyxin-1; PDGF, platelet-derived growth factor; PRR2, poliovirus receptor-related 2 protein; PSGL-1, P-selectin glycoprotein ligand; SDF-1, stroma-derived factor 1; SHP-1, Src homology 2 domain-bearing protein tyrosine phosphatase 1; TGF-b, transforming growth factor beta; TSP, thrombospondin; IIICS, type III connecting segment; VAP-1 vascular adhesion protein 1; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor; VLA-4, very late antigen 4.
The marrow, one of the largest organs in the human body, is the principal site for blood cell formation. In the normal adult its daily production amounts to about 2.5 billion red cells, 2.5 billion platelets, and 1.0 billion granulocytes per kilogram of body weight. The rate of production is adjusted to actual needs and can be varied from nearly zero to many times normal.1 Until the late nineteenth century, blood cell formation was thought to be the prerogative of the lymph nodes or the liver and spleen. In 1868 Neuman2 and Bizzozero3 independently observed nucleated blood cells in material squeezed from the ribs of human cadavers and proposed that the marrow is the major source of blood cells.4 The first in vivo marrow biopsy was probably done in 1876 by Mosler,5 who used a regular wood drill to obtain marrow particles from a patient with leukemia. Fifty years passed before Arinkin’s studies in 1929 established marrow aspiration as a safe, easy, and useful technique.6
Kinetic studies of marrow cells, using radioisotopes and in vitro cultures, have shown that cell lines consist of mature end cells with a finite functional life span, capable of limited proliferation before their full maturation but without the capacity for self-renewal. Sustained cellular production, on the other hand, depends on the presence of pools of primordial cells capable both of differentiation and of self-replication.7 The most primitive pool consists of pluripotential stem cells with the capacity for continuous self-renewal. The more mature pools consist of differentiated unipotential progenitor cells with their maturation restricted to single cell lines and with no capacity for self-renewal. The proliferative activity of these pools involves humoral feedback from peripheral target tissues8 as well as cell-to-cell interactions within the microenvironment of the marrow.9,10 The marrow stroma has evolved to provide a unique structural and chemical environment to support the survival, differentiation, and proliferation of pluripotential (lymphohematopoietic) stem cells. These stem cells can be identified and isolated using a unique array of surface antigen-receptor expression, especially CD34 and Thy-1, but lacking CD38 and CD33.11,12,13 and 14 Isolated cell populations enriched in stem cells can be quantified using in vitro progenitor assays15,16,17 and 18 and surrogate in vivo long-term repopulating assays in severely immunodeficient mice and xenogeneic animal models19,20,21 and 22 (see Chap. 14).
EMBRYOGENESIS AND EARLY STEM CELL DEVELOPMENT
The yolk sac and later the fetal liver are sites of early erythropoiesis and contain cells with multilineage differentiation capabilities beginning at day 8 of gestation (yolk sac).23 Non-yolk-sac regions such as the paraaortic splanchnopleura give rise to B-cell progenitors when transplanted into mice with severe combined immunodeficiency.24 The aorta-gonad-mesonephros region (AGM) contains pluripotential stem cells during embryogenesis.25 Stem cells in the AGM region appear before the fetal liver, indicating the importance of this mesodermal region of the embryo in stem cell migration. Early lymphoid precursors have been identified in the day 8 yolk sac26 and the body of embryos beginning at the 10- to 12-somite stage.27 The earliest repopulating lymphohematopoietic stem cells in the day 9 yolk sac have been detected in vivo, using primary conditioned newborn mice,28 and in vitro.29
The early inductive microenvironment for pluripotential stem cells elaborates KIT ligand, encoded by the Sl locus; a later transition from early independent to the late KIT-ligand-dependent fetal hematopoiesis in the embryo occurs.30 Similarly, KIT-negative stem cells have been shown to give rise to KIT-positive cells with pluripotential stem cell activity.31 Murine embryonic stem cells require multiple growth factors such as leukemia inhibitory factor (LIF), KIT ligand, and basic fibroblast growth factor (b-FGF) acting in concert.32,33 Direct interactions and soluble growth factors from AGM stromal34 or endothelial cells35 and marrow-derived stromal cells improve the survival of primitive hematopoiesis.34,35 and 36 This action is exerted via intimate cell-cell interactions of CD34-positive stem cells, which are HLA-DR-negative and uncommitted, with adventitial reticular cells.36
Locally expressed cytokines may lead to differences in the functions of the stromal cells of early blood islands27,32 and those of marrow or spleen.37 Morphologic studies of marrow recovering from aplasia show that early hematopoiesis is localized to the endosteum and vascular endothelium.38 The intimate relationship of angiogenesis and early hematopoiesis is validated by the demonstration that AGM-derived single cells at day 10.5 postcoitum express the receptor tyrosine kinase, TEK, and give rise to hematopoietic cells in the presence of IL-3 and endothelial cells when exposed to angiopoietin-1, defining them as hemangioblasts.39 Podocalyxin-1 (PCLP1), a highly glycosylated protein with similarity to CD34, a high-endothelial venule ligand for L-selectin, has been found on AGM-derived hemangioblasts.40 These PCLP1-positive, CD45-negative cells give rise to hematopoietic cells and endothelial cells when cultured over stromal cells.40 Expression of the alpha4-integrin, in CD45-negative vascular E (VE)-cadherin-positive or -negative cells, defines the earliest precursor of hematopoietic cell lineage diverged from endothelial cells.41 Primitive stem cells obtained from human fetal liver or marrow reconstitute all lymphohe-matopoietic-derived cells and part of the stromal microenvironment in in vivo repopulation assays.42 These observations are consistent with the early derivation of hematopoietic, vascular, and stromal cells from a CD34-negative, vascular-endothelial cell growth factor 2 receptor (known as KDR) -positive, multipotential mesenchymal stem cell.43,44,45,46 and 47 These findings are also underscored by the identification of AC133-positive, CD34-negative, CD7-negative hematopoietic stem cells685 and by the presence of endothelial precursors in AC133-positive progenitor cells.686 The presence of long-term reconstituting hematopoietic stem cells in murine skeletal tissue,48 and in brain-derived neural cells,49 emphasizes the plasticity of these totipotential cells. (See Chap. 14.)
Cavities within bone occur in the human being at about the fifth fetal month and soon become the exclusive site for granulocytic and megakaryocytic proliferation. Erythropoietic activity at the time is confined to the liver, and it is not until the end of the last trimester that the microenvironment in the marrow becomes supportive of erythroblasts (Fig. 4-1). At birth, the bone cavities are the only sites of significant hematopoietic activity and are completely engorged with hematopoietic cells.50,51 The sequential appearance and disappearance of hematopoietic activity is governed by signaling via chemokine receptors (CXCR4) for stroma-derived factor 1 (SDF-1)52,53 and cellular adhesion molecule-ligand pair interactions, such as, alpha4-integrin with vascular cell adhesion molecule 1 (VCAM-1) or alpha4-integrin with fibronectin.54,55
FIGURE 4-1 Expansion and recession of hematopoietic activity in extramedullary and medullary sites.
By the fourth year of life, a significant number of fat cells have appeared in the diaphysis of the human long bones.56 These cells slowly replace hematopoietic elements and expand centripetally until, at about the age of 18 years, hematopoietic marrow is found only in the vertebrae, ribs, skull, pelvis, and proximal epiphyses of the femora and humeri. Direct measurements of the volume of bone cavities reveal that the bone cavity volume increases from 1.4 percent of body weight at birth to 4.8 percent in the adult,50,57 while the blood volume decreases from 8 percent of body weight in the newborn to about 7 percent in the adult.58 The expansion of marrow space continues throughout life, resulting in a further gradual increase in the amount of fatty tissue in all bone cavities, especially in the long bones.59,60 The preference of hematopoietic tissue for centrally located bones has been ascribed to higher central tissue temperature with greater vascularity.61 However, since complete reactivation of fatty marrow can occur in experimental animals in which hematopoietic expansion is induced, other factors must be involved.62,63
The blood supply comes from two major sources.64 The nutrient artery, the principal source, penetrates the cortex through the nutrient canal. In the marrow cavity, it bifurcates into ascending and descending medullary arteries from which radial branches travel to the inner face of the cortex. After repenetrating the endosteum, the radial vessels diminish in caliber to structures of capillary size that course within the canalicular system of the cortex. Here arterial blood from the nutrient artery mixes with blood that enters the cortical capillary system from the periosteal capillaries derived from muscular arteries. After reentering the marrow cavity, the cortical capillaries form a sinusoidal network. Hematopoietic cells are located in the intersinusoidal tissue spaces (Fig. 4-2). Some arteries have specialized, thin-walled segments that arise abruptly as continuations of arteries with walls of normal thickness.65 These vessels give off nearly perpendicular branches analogous to the arterial branching observed in the spleen and kidney, permitting volume compensation for changes in intramedullary pressure. In the marrow cavity, blood flows through a highly branching network of medullary sinuses. These sinuses collect into a large central sinus from which the blood enters the systemic venous circulation through emissary veins.
FIGURE 4-2 Schematic diagram of the circulation of the marrow. See text for further explanation.
Vascular networks consisting of cells expressing CD31, CD34, and CD105 (endoglin) but lacking intercellular adhesion molecule 1 (ICAM-1), ICAM-2, ICAM-3, or endothelial leukocyte adhesion molecule 1 (ELAM-1, E-selectin) can form also within the stroma of long-term marrow cultures, underscoring the intimate relationship of blood vessels to hematopoietic activity.66 A study of early hematopoiesis of human marrow from long bones (ages 6 to 28 weeks) has shown an absence of CD34-positive hematopoietic progenitors before onset of hematopoiesis, a predominance of CD68-positive cells mediating chondrolysis, and CD34-positive endothelial cells developing into specific vascular structures organized by endothelial cells and myoid cells.67 The vascular endothelial growth factor (VEGF) receptors found on CD34-positive cells46 and AGM primitive stem cells underscore that common ontogeny.68,69 Subsets of CD34-positive cells expressing the AC133 antigen and the human vascular endothelial receptor-2 define the functional endothelial precursor phenotype.687
Myelinated and nonmyelinated nerve fibers are present in periarterial sheaths in marrow,70 where they are thought to regulate arterial vessel tone. Nerve terminals are distributed between layers of periarterial adventitial cells or localize next to arterial smooth muscle cells.71 Nonmyelinated fibers terminate in the hematopoietic spaces, implying that neurohumors elaborated from free-nerve terminals may affect hematopoiesis. Intimate cell-cell communication between sympathetic nerve cells and structural elements within the marrow sinuses occurs at less than 5 percent of nerve terminals that terminate within the hematopoietic parenchyma or on sinus walls. This anatomic unit, termed a neuroreticular complex, consists of efferent (autonomic) nerves and marrow stromal cells connected by gap junctions.71
Nerve growth factor receptor antibody reacts with adventitial reticular cells.72 Tachykinins have demonstrated stimulatory and inhibitory hematopoietic activities within the marrow microenvironment,73,74 and substance P stimulates CD34-positive cell proliferation by modulating stromal cell release of cytokines such as IL-3, IL-6, granulocyte colony stimulating factor, granulocyte-macrophage colony stimulating factor (GM-CSF), and KIT ligand.75,76 Interactions between neurokinins and cytokines such as platelet-derived growth factor and IL-1 result in fibroblast proliferation.77 Neurokinin 1 receptors for substance P are present on marrow vascular endothelium,78 and both noradrenergic and peptidergic innervation have been demonstrated in mouse marrow with dense fibers seen predominantly around blood vessels but also ramifying among marrow cells.79 Thus, adrenergic responses to stress may regulate marrow blood flow and cellular release directly80,81,82 and 83 or by altering endogenous nitric oxide levels within the marrow.84 Exposure of marrow mononuclear cells to hypoxia increases the expression of neurokin-2 receptor and alters the proliferation of myeloid and erythroid progenitors.85 Furthermore, the positive regulation of hematopoiesis by adrenergic agents after syngeneic marrow transplantation86 supports the concept of neural influences. This issue remains controversial. In one study, no neuronal regulation of marrow function was elicited after neonatal sympathectomy or hind limb denervation in mice.87
SINUS ARCHITECTURE AND CELLULAR ORGANIZATION
In mammals, hematopoiesis takes place in the extravascular spaces between marrow sinuses. The sinus wall is composed of a luminal layer of endothelial cells and an abluminal coat of adventitial reticular cells, which forms an incomplete outer lining (Fig. 4-3). A thin, interrupted basement lamina is present between these cell layers.
FIGURE 4-3 Transmission electron micrograph (TEM) of a mouse marrow sinus. The small arrow in the sinus lumen (L) indicates the perikaryon of an endothelial cell. Several endothelial cell junctions are present along the circumference of the sinus endothelial wall. Thus, the wall is composed of the cytoplasm of endothelial cells that overlap or interdigitate. Two adventitial reticular cells are identified by arrows at the top and upper left of the sinus. The cytoplasm of the adventitial reticular cells is discontinuous as it is followed around the sinus. Four cytoplasmic processes of adventitial reticular cells are indicated by arrows. Other, smaller processes of reticular cell cytoplasm can be found on close inspection of the sinus periphery and the hematopoietic spaces. The scattered rough endoplasmic reticulum and dense bodies are characteristic of the reticular cell cytoplasm. (Reprinted from Lichtman,70 with permission.)
Endothelial cells are broad flat cells that completely cover the inner surface of the sinus.88,89 and 90 They form the major barrier and control the system for chemicals and particles entering and leaving the hematopoietic spaces, with overlapping or interdigitating unions permitting volume expansion.89 The endothelium of marrow sinusoids is actively endocytic and contains clathrin-coated pits, clathrin-coated vesicles, lysosomes, phagosomes, transfer tubules, and diaphragmed fenestrae.91,92 Particles are endocytosed by endothelial cells primarily through clathrin-coated pits.93
Such endocytic features are in keeping with studies demonstrating colony-stimulating factor receptors on endothelial cells94 and their shared antigenic determinants with macrophages.95,96 Marrow endothelial cells express von Willebrand factor antigen,97 type IV collagen, and laminin98; they also constitutively express two adhesion molecules: VCAM-1 and E-selectin.99 The distribution of sialic acid and other carbohydrates on the luminal surface of marrow sinus endothelium is discontinued at diaphragmed fenestrae and coated pits, suggesting that such sugars play a role in endothelial membrane function.93,100 Marrow microvascular endothelium can be isolated using the Ulex europeaus lectin, as well as CD34 monoclonal antibodies.101,102,103,104 and 105 Marked attenuation of endothelial cell cytoplasm, short of discontinuity, can occur such that a short length of cytoplasm thins to approach a double plasma membrane in thickness (fenestra with a diaphragm).106
There is reciprocal regulation of CD34 expression and adhesion molecules by vascular endothelial cells exposed to inflammatory stimuli such as IL-1, interferon-g, and tumor necrosis factor-a.107 Receptors for the complement component C1q are upregulated on marrow microvascular endothelium by inflammatory cytokines.108 Other receptors that may mediate marrow cellular trafficking include fractalkine, a novel endothelial membrane-bound chemokine with a mucin stalk, also upregulated by cytokines.109 Marrow sinusoidal endothelium specifically expresses sialylated CD22 ligands, which are homing receptors for recirculating B lymphocytes.110
ADVENTITIAL RETICULAR CELLS
The abluminal or adventitial surface of the vascular sinus is composed of reticular cells.88,111,112 The reticular cell bodies are contiguous with the sinus, forming part of its adventitial coat (Fig. 4-4). Their extensive branching cytoplasmic processes envelop the outer wall of the sinus to form an adventitial sheath. This sheath is interrupted and has been estimated to cover about two-thirds of the abluminal surface area of sinuses. The reticular cells synthesize reticular (argentophilic) fibers that, along with their cytoplasmic processes, extend into the hematopoietic compartments and form a meshwork on which hematopoietic cells rest. The cell bodies, their broad processes, and their fibers constitute the reticulum of the marrow.
FIGURE 4-4 Scanning electron micrograph (SEM) of rat marrow sinus. The floor of the lumen is labeled L. The arrow on the left indicates the cell body of an adventitial reticular cell, which is just beneath the endothelial cell layer. Reticular cell processes can be seen coursing between the sinus wall and the hematopoietic compartment. Several of these are indicated by small arrows. (Reprinted from Lichtman,70 with permission.)
Adventitial reticular cells have a high concentration of alkaline phosphatase in their membranes; express CD10, CD13, and class I HLA antigens88; react with the 6/19 and STRO-1 monoclonal antibodies114,115; and express all neurotrophin receptors including the low-affinity nerve growth factor receptor (p75LNGFR) and the Trk receptors (TrkA, TrkB, and TrkC)116 even though NGF is not a growth factor for STRO-1-derived stromal cells.117 These adventitial reticular cells can differentiate along the smooth-muscle pathway and contain alpha smooth-muscle actin, vimentin, laminin, fibronectin, and collagens I, III, and IV.118,119 Unlike embryonic fibroblasts,120 adventitial reticular cells are usually CD34-negative.89,119,121 Stromal cells display cell-cell contacts via connexin-43 gap junctions.122 These gap junctions are localized to areas of adherence of stromal cells and hematopoietic cells in marrow recovering from cytotoxic injury, underscoring the importance of direct cell-cell communication between progenitors and stromal cells during active hematopoiesis.123,124 Marrow-derived stromal cell lines display heterogeneity at the molecular—expression of cytokines such as KIT ligand, TPO, and Flt3, or differentiation regulatory genes such as human Jagged1 (hJagged1)—and functional—cobblestone formation, CD34+ cell proliferation—levels, with variable expression of ICAM-1, VCAM-1, and collagens I, III, and IV.125
More specialized contractile reticular “barrier cells” have been described in both spleen and marrow in mice after hematopoietic stress, such as malarial infection or administration of IL-1.126,127 Barrier cells increase in number and seem to enclose developing hematopoietic progenitors in these animals. These cells may regulate the release of precursors into the circulation.127 Human counterparts of barrier cells are alpha smooth-muscle-positive cells that appear in culture after 2 weeks and are represented by myoid cells lining sinuses at the abluminal side of endothelial cells in marrow biopsies.119 These cells also have been described in fetal marrow and are increased in areas of active marrow proliferation after inflammation.127
Adipocytes in marrow develop by lipogenesis in fibroblast-like cells, most likely the adventitial reticular cells (Fig. 4-5). Reticular cells in mouse marrow and human marrow can undergo transformation to fat cells in vitro and can transform into fibroblasts in culture by a process of lipolysis.88,129 Marrow fat cells are relatively resistant to lipolysis during starvation. Their proportion of saturated fatty acids is lower than in other fat deposits, but their composition depends to a certain extent on whether they are located in red, hematopoietically active, or yellow, hematopoietically inactive, marrow.129 Adipocytes express leptin, osteocalcin, and increased prolactin receptors during their differentiation, thereby promoting hematopoiesis and influencing osteogenesis.130,131,132 and 133 Adipocyte maturation in vitro is inhibited by stromal-derived cytokines such as IL-1 and IL-11.134,135 Marrow adipocyte leptin may modulate adjacent hematopoietic progenitor growth.129 Adipocyte differentiation by marrow stromal cells is inhibited by bone morphogenetic proteins136 and leptin,137 supporting the reciprocal regulation of osteogenesis and adipogenesis in the marrow microenvironment.
FIGURE 4-5 SEM of rat marrow. Several sinuses are evident. The exposed lumen of one branching sinus is labeled L. The short horizontal arrow points to the cytoplasm of a transected megakaryocyte. The longer, vertical arrow points to the remnant of a fat cell. The rat femoral marrow contains a modest number of fat cells. (Reprinted from Lichtman,70 with permission.)
Stromal cells are obtained from animal or human marrow and studied in cultures. They presumably are derived from fibroblasts. They have unique phenotypic and functional characteristics that allow them to nurture hematopoietic development in highly specialized microenvironmental niches.125 These cells express nerve growth factor receptor, VCAM-1, tenascin, endoglin, and collagens IV and VI but do not express intercellular adhesion molecules138; unlike marrow fibroblasts, marrow stromal cells fail to upregulate collagenase when exposed to IL-1.139 Stromal cells and cell lines differ in their capacities to support the growth of myeloid,140,141 and 142 pro-B,143,144 and T-cell precursors.145 This nurturing function is mediated by different combinations of early acting growth factors such as Flt3-ligand,146 KIT ligand,147 thrombopoietin,148,149,150 and 151 LIF,152 and IL-6,153 all released by stromal cells. Other interactions that regulate hematopoietic cell survival and differentiation are mediated by cell-cell contact via negative regulators of hematopoiesis such as transforming growth factor beta (TGF-b), which downregulates c-KIT expression147,154; the Notch/Jagged pathway, which inhibits myeloid differentiation155; and specific receptors (e.g., WNT protein family156 or angiogenins such as neuropilin-1157) and adhesion molecules (MUC18, CD164, and HCA) on stromal cells and hematopoietic CD34-positive cells.158,159 and 160
Osteoblasts, osteoclasts, and elongated flat cells with a spindle-shaped nucleus form the marrow endosteal lining.161 Resting endosteal cells express vimentin, tenascin, alpha smooth-muscle actin, osteocalcin, CD51, and CD56 and do not react with CD3, CD15, CD20, CD34, CD45, CD68, or CD117.162 Enriched CD56-positive, CD45-negative, CD34-negative endosteal cells grown in the presence of cytokines [insulin growth factor 1, basic fibroblast growth factor (b-FGF), KIT ligand, IL-3, and GM-CSF] do not give rise to hematopoietic cells, suggesting that they are not totipotent mesenchymal stem cells in these culture conditions.162 Cultured human bone cells have high levels of a1/b1, a3/b1, a5/b1, av/b5 integrins.163 Endosteal cells are a rich source of stem cells (using the in vivo CFU-S assay, see Chap. 14)164 and provide a homing niche for newly transplanted hematopoietic stem cells.165 Mesenchymal stem cells positive for the STRO-1 antibody can differentiate into adipocyte, chondrocytic, and osteogenic cells,166,167,168 and 169 and similar osteogenic potential is found in STRO-1-positive vascular pericytes.170 This process of mesenchymal stem cell to osteogenic differentiation is associated with the loss of the activated leukocyte adhesion molecule (CD166).171
Bone-forming osteoblast progenitor cells, like stromal precursors, reside in the CD34-negative, STRO-1-positive nonadherent marrow cell population.172,173 and 174 Bone morphogenetic protein 2, b-FGF, and TGF-b promote the growth and differentiation of these cells.172,175 Osteoblasts expand early hematopoietic progenitor survival in long-term cultures and secrete hematopoietic growth factors such as macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), GM-CSF, IL-1, and IL-6.176,177 Osteoblasts also produce hematopoietic cell-cycle inhibitory factors such as TGF-b, which may contribute to their intimate role in stem cell regulation within the marrow microenvironment.178 These cells can be transplanted in nonablated mouse179 and facilitate the engraftment of purified allogeneic hematopoietic stem cells, in keeping with their ability to support hematopoiesis.180 Subcapsular renal explants of bone are able to form a suitable hematopoietic microenvironment for early stem cells, underscoring the potential for osteoblasts to nurture hematopoiesis.181 Direct cell-cell communication has been shown in marrow123 as well as in osteoblastic cell networks,182 indicating a potential regulatory role for these anatomic gap junctions in hematopoiesis.122
Bone-resorbing osteoclasts are derived from hematopoietic progenitors (CD34-positive, STRO-1-negative) and branches from the monocyte-macrophage lineage early during differentiation.183,184 The essential role of M-CSF in osteoclastogenesis is demonstrated by the op/op mouse, which has osteopetrosis and congenital deficiency of M-CSF185 and which improves after M-CSF treatment.186 KIT ligand and M-CSF act synergistically on osteoclast maturation,187 and M-CSF is essential for the proliferation and maturation of osteoclast progenitors.188 The major form of secreted M-CSF is a proteoglycan.189 It binds to bone-derived collagens and can be extracted from the bone matrix,190 implying a local role for this factor in bone development and remodeling. Targeted disruption of oncogenes such as C-FOS191 and pp60 C-SRC192 prevents osteoclast differentiation leading to osteopetrosis. Osteoprotegrin (OPG), or osteoclastogenesis inhibitory factor, is a cytokine of the tumor necrosis factor receptor superfamily, which inhibits osteoclast differentiation.193 Osteoclast maturation requires osteoprotegrin ligand (TRANCE/RANKL), an osteoclast differentiation and activation factor (ODF) elaborated by stromal cells and osteoblasts.194 ODF together with M-CSF induces osteoclast formation without requiring stromal cells.195,196 and 197 Cross-linking antibodies to the adhesion receptor CD44 inhibit osteoclast formation in primary marrow cultures treated with 1 alpha 25-dihydroxyvitamin D3.198 Similarly, blocking the expression of cadherin-6 interferes with heterotypic interactions between osteoclasts and stromal cells, impairing their ability to support osteoclast formation.199 CD9, a tetraspan transmembrane adhesion protein on stromal cells, is known to influence myelopoiesis in long-term marrow cultures.200 Inhibition of stromal cell CD9-mediated signaling by a blocking antibody reduces ODF transcription, leading to reduced osteoclastogenesis.201 Such cell-cell cross-talk underscores the functional heterogeneity of hematopoietic inductive signals within the marrow microenvironment.
MACROPHAGES AND LYMPHOCYTES
Macrophages and lymphocytes form part of the marrow microenvironment through growth factor production (IL-3, MIP-1a) and cell-cell interactions with developing progenitors.70,88,202,203,204,205 and 206 Macrophages207 and lymphocytes140,208 are an integral part of the adherent monolayer found in long-term lymphohematopoietic cultures. Mature T and B lymphocytes and plasma cells are found near foci of granulopoiesis in the adherent layers of long-term cultures in humans.209 Marrow stroma can support thymocyte differentiation,210 and an early T-cell progenitor maturation pathway occurs in the marrow.211 Marrow stroma regulates B lymphopoiesis by different stromal cell niches and homing receptors (VCAM-1) and the production of cytokines such as Flt3 ligand, KIT ligand, IL-7, and TGF-b.212,213 and 214 Stromal cells facilitate the maturation of natural killer cells,215 an effect likely mediated by stromal-derived Flt3 ligand and IL-15.216
Stromal cells elaborate and respond to peptide growth factors such as platelet-derived growth factor (PDGF).217 PDGF upregulates M-CSF secretion by stromal cells, establishing a paracrine stimulatory loop between these two cell types.218 The addition of PDGF to macrophages expressing PDGF receptors upregulates interleukin-1 secretion and thereby activates primitive hematopoietic cells.219 Macrophages also modulate the structure and composition of the extracellular matrix and its fibronectin content.220 Marrow macrophage phenotype221 is regulated by adjoining stromal cell–accessory cell–derived colony-stimulating factors and cytokines,222 such as M-CSF upregulation of a4b1 and a5b1 integrin expression223 and Flt3 ligand-promoting macrophage outgrowth with B-cell-associated antigens.224 Macrophages express sialic-acid-binding receptors225 and play an integral role in erythropoiesis.226
Mesenchymal cells forming the cellular stroma in marrow are active in laying down a rich carpet of extracellular matrix proteins (ECMs)227 such as proteoglycans or glycosaminoglycans (GAGs),227,228 fibronectin,227,229 tenascin,227,230 collagen,227,230 laminin,98,230 hemonectin,231 and thrombospondin.227,232 Localizing signals are provided by stromal, ECM hematopoietic cell adhesive interactions,233,234 in concert with chemoattractant small molecules, the chemokines235 and cytokines, bound to heparin-like structures in the GAGs.236 These interactions form specialized niches that may facilitate lymphocytic (B and T) or lineage-specific development along the erythroid, myeloid, or megakaryocytic pathways.237,238 Other functions of these niches include stem cell survival239 and quiescence.237,240 Cytokines that are presented on the surface of stromal cells and matrix-binding chemokines and cytokines are shown in Table 4-1.236,241,242,243,244,245,246,247,248,249,250,251,252 and 253 Sl/Sld mice that have a deficient hematopoietic microenvironment as a result of a deficiency in KIT ligand147,254 processing or membrane presentation are anemic and have alterations in their extracellular matrix composition.255 The addition of hemonectin improves stem cell adhesion to a stromal line derived from Sl/Sld mice.256
TABLE 4-1 CELL MEMBRANE PRESENTATION AND MATRIX ASSOCIATION OF CYTOKINES AND CHEMOKINES
In long-term marrow cultures, collagen, fibronectin, and laminin are secreted early, and extracellular deposition of these proteins coincides with active hematopoiesis.255 GM-CSF is found to prominently stain adipocyte membranes.257 Cultures actively generating granulocyte-macrophage precursors produce M-CSF and GM-CSF and, to a lesser extent, KIT ligand and G-CSF within the adherent layer.258 GM-CSF, G-CSF, and b-FGF are detected on the surface of endothelial cells and fibroblasts, and GM-CSF localizes to the extracellular matrix as shown by double-labeling of heparan sulfate proteoglycans and GM-CSF.259 Negative regulators like TGF-b exert their effects early on long-term marrow cultures by limiting megakaryocyte progenitor and stem cell expansion.260
Proteoglycans are polyanionic macromolecules (heparan sulfate, dermatan, chondroitin sulfate, and hyaluronic acid) that are distributed on the surface of adventitial reticular cells as well as within the extracellular matrix.227,261 Heparan sulfate is the main cell-surface glycosaminoglycan in long-term marrow cultures, and chondroitin sulfate is the major secreted species.255,262 D-xylosides, which stimulate artificial sulfated glycosaminoglycan synthesis, cause an increase in chondroitin sulfate synthesis and hematopoietic cell production.262 Hyaluronic acid and chondroitin sulfate-containing proteoglycans are prominent in the adherent and nonadherent compartments of long-term marrow cultures.261 Heparin-containing and heparan-sulfate-containing proteoglycans interact with laminin and type IV collagen263 and may play a role in cell-cell interactions, cytokine presentation, and cell differentiation.264,265,266 and 267 They also mediate progenitor binding to stroma, along with other extracellular matrix molecules such as fibronectin.268,269,270,271 and 272
Another important lymphocyte-progenitor cell-associated proteoglycan, CD44, uses hyaluronate as a ligand and promotes stromal adhesive interactions.208,273 A binding site for lymphocyte CD44 on the carboxy-terminal heparin-binding domain of fibronectin is present,274 and neutralizing antibodies to CD44 inhibit hematopoiesis in long-term marrow cultures.275 Cytokines (GM-CSF, IL-3, and KIT ligand) rapidly induce CD44 expression and increase CD44-mediated adhesion of CD34-positive hematopoietic progenitors to hyaluronan.276 Chondroitin sulfates A and B mediate monocyte and B-cell activation via a CD44-dependent pathway,277 while hyaluronate, the CD44 ligand, enhances hematopoiesis by releasing IL-1 (CD44-dependent) and IL-6 (CD44-independent pathway), supporting the important role of this proteoglycan receptor in hematopoiesis.278 Heparan sulfate mediates IL-7-dependent lymphopoiesis249 and modulates hematopoiesis and stromal cell-matrix remodeling282 by anchoring both hepatocyte growth factor250,279 and b-FGF.280,281 and 282 Marrow stromal cell surface heparan-sulfate-containing proteoglycans consist mainly of syndecan-3 and -4 and glypican-1, while the major extracellular matrix-associated form is perlecan.283 Syndecan-3 is expressed in marrow stromal cells as a variant form with a core protein of 50 to 55 kDa, suggesting it may play a role in hematopoiesis.283 Perlecan promotes b-FGF receptor binding and mitogenesis and is able to bind GM-CSF.277,284 Heparan sulfate expression is also induced in early erythroid differentiation of multipotential hematopoietic stem cells.285 Glypican-4, another member of this family, has been found on marrow stromal cells and progenitor cells.286 Syndecan-1 expression in B lymphoid cells is reduced by IL-6, which may imply similar regulatory pathways in other cell types.287 Biglycan, a matrix glycoprotein sc1 with homology to osteo-nectin, and the molecule SIM selectively increase IL-7-dependent pro-liferation of B cells.288 Interactions of B cells with other components of the immune system are mediated by syndecan-4, which facilitates the formation of dendritic processes289 and regulates focal adhesion, stress fiber formation, and cell migration.290 Taken together, these observations underscore the major contribution of proteoglycans in the formation of specialized microenvironmental niches to promote lineage-specific hematopoiesis.
Fibronectin localizes at sites of attachment of hematopoietic cells and marrow stromal cells in vitro,229,291 at sites of interaction between these cells and developing granulocytes or monocytes.292 Early erythroid progenitors attach to the cell-binding domain of fibronectin,293,294 and this association can be inhibited by blocking antibodies to the fibronectin integrin receptors a5b1 and a4bA1.295 Adhesion of hematopoietic progenitor cells to stroma is mediated in part by fibronectin,268,296 and this binding can be enhanced by protein kinase C activators such as phorbol esters, suggesting the involvement of integrin receptors in this process.297,298 and 299 The alternatively spliced form of fibronectin (type III connecting segment, IIICS) is expressed uniquely within the marrow microenvironment122,299 and associates with the a4b1 integrin receptor on hematopoietic stem cells.300 Additional IIICS fibronectin variants have been detected in marrow stroma, providing for a fine control using mRNA splicing of progenitor–stem cell interactions.301 Fibronectin adhesion to peptide domains, such as the CS1 domain (which activates alpha4 integrins) or stromal cells, has dual effects of stimulation as well as inhibition of hematopoietic progenitor growth.302,303,304 and 305
The integrins very late antigen 4 (VLA-4) and VLA-5, as well as CD44, cooperate to promote these fibronectin adhesive interactions.302,306,307 and 308 Cytokines such as IL-3, KIT ligand, and thrombopoietin augment the magnitude of the fibronectin-mediated hematopoietic progenitor cell adhesion and migration.309,310,311 and 312 Fibronectin facilitates the maturation of CD34-positive progenitor-derived dendritic cells313 and is involved in the adhesion of mature cells like megakaryocytes,314,315 mast cells,316 chemokine-activated T lymphocytes,317 eosinophils,318 and neutrophils.319 Fibronectin is required for the expression of gelatinase in macrophages320 and regulates the cytokine release by M-CSF-activated macrophages321 and chondrocytes.322 These interactions of fibronectin and its integrin counterreceptors on hematopoietic cells are associated with activation of the sodium-hydrogen exchanger and result in improved cell survival or stimulation.323
Tenascin is an extracellular matrix glycoprotein family consisting of three members: tenascin-C, tenascin-R (restrictin), and tenascin-X.230,324 Tenascin-C is expressed on the surface of stromal cells in the marrow and, like fibronectin and collagen III, is found in the microenvironment surrounding maturing hematopoietic cells.227,325 In a long-term marrow culture system (Whitlock-Witte), the thiol 2-mercaptoethanol induced the expression of tenascin-C and improved lymphoid-lineage differentiation.326 Glucocorticoids, on the other hand, promote myeloid differentiation in long-term marrow cultures and downregulate tenascin expression.327 Tenascin-C has distinct functional domains that promote hematopoietic cell adhesion to stroma or extracellular matrix proteins, or mediate a strong mitogenic signal to marrow mononuclear cells.328 In tenascin-C-deficient mutant mice, the colony-forming capacity of marrow is markedly decreased.329 Long-term marrow cultures from these tenascin-deficient animals result in a decreased progenitor cell output.329 Addition of tenascin-C to these cultures restores hematopoietic cell production.329 Mutant tenascin-C-deficient animals also display decreased fibronectin in their marrow, suggesting a possible mechanistic interaction between tenascin-C and fibronectin in the marrow microenvironment.330 These studies underscore the important role of extracellular matrix proteins such as fibronectin and tenascin-C in hematopoiesis.
Collagen type I and type III are associated with microvascular walls, whereas type IV collagen is confined to basal lamina beneath endothelial cells.96,255,331 Marrow-derived capillary networks grow in collagen gel cultures,332 and inhibition of collagen synthesis reduces hematopoiesis in vitro,333 underscoring the importance of the underlying matrix in reconstituting an intact hematopoietic microenvironment.262,334 Erythroid and granulocytic progenitors adhere to collagen type I in vitro,335 and a low-molecular-weight collagen has been described in lithium-stimulated marrow cultures,336 emphasizing the effects of cytokines on matrix composition and stromal support of hematopoiesis.220,337 Marrow-derived fibroblasts and stromal cells synthesize collagens I, III, IV, V, and VI.338 Collagen VI is a strong cytoadhesive component of the marrow microenvironment. It binds von Willebrand factor.339 Collagen type XIV, another fibril-associated collagen, promotes hematopoietic cell adhesion of myeloid and lymphoid cell lines.340 Collagen-induced, intracellular calcium-mediated signaling events occur in mega-karyocytes.341 In situ immunolocalization of ECMs in murine marrow showed that collagen types I, IV, and fibronectin localize to the endosteum.342 The distinct spatial distribution of these matrix proteins underscores their role in the preferential homing of engrafted hematopoietic stem cells to marrow.165
A multidomain glycoprotein with mitogenic and adhesive sites, laminin is a major component of the extracellular matrix and basement membranes.227,343 Laminin interacts with collagen type IV and basement membrane components such as proteoglycans and entactin344 and thus can regulate leukocyte chemotaxis.345,346 Similarly, CD34-positive granulocytic progenitors,347 mature monocytes,348 and neutrophils349 adhere to laminin. Its role within the cytomatrix may be to strengthen adhesive interactions with integrin receptors, a5b1 (VLA-5) and a6b1 (VLA-6), on hematopoietic cells.350,351 VLA-6 mediates mast cell adhesion to laminin,352 while the Lutheran blood group glycoproteins serve as laminin receptors on erythroid cells.353 A 67-kDa laminin receptor has been identified on acute myeloid leukemia cells displaying monocytic differentiation. Laminins are heterodimers composed of alpha, beta, and gamma polypeptides. Laminin-1 (a1b1g1) is not expressed in marrow, which expresses laminin-2 (a2,b1,g1), laminin-8 (a4b1g1), and laminin-10 (a5b1g1).355 Laminins containing the a5 chain bind to multipotential hematopoietic cells (FDCP-mix cells), in contrast to laminin-1 heterodimers.355 Stromal cells in cultures as well as cytokine-expanded CD34-positive cells also express laminin b2, which is found in the pericellular space in marrow and intracellularly in megakaryocytes.354,356 Laminin promotes the M-CSF-dependent proliferation of marrow-derived macrophages and macrophage cell lines. This effect is partially mediated via an a6 integrin subunit.357
Hemonectin, a 60-kDa glycoprotein, mediates the attachment of granulocytes to marrow.231 This protein is expressed in hematopoietic tissues as they develop in murine embryos.358 Hemonectin is related to the plasma glycoprotein fetuin.359 Granulocytic adhesion to marrow-derived hemonectin is mediated by galactose and mannose.360 The exact nature of this molecule and its receptor has yet to be identified, hence the role of hemonectin in the marrow hematopoietic microenvironment remains unclear.
Thrombospondin (TSP) is a 450-kDa multifunctional extracellular matrix protein, initially identified in platelet a granules. TSP has domains that interact with collagen and fibronectin and may participate in stem cell lodgement.361 Receptors on hematopoietic and nonhematopoietic cells can interact with thrombospondin, including CD36362,363 and 364 and a protein, CLA-1, of the CD36/LIMP II gene family.365 Perlecan mediates the binding of thrombospondin to endothelial cells.366 The TSP receptor CD36 is expressed during erythroid (CFU-E stage) and megakaryocytic maturation.367 TSP has a dual range of activities from suppression of megakaryopoiesis,368 to an early stimulatory effect on early hematopoietic stem cells,271 erythropoiesis,369 and natural killer cells.370 The inhibition of megakaryocytopoiesis is partially reversed by a low-molecular-weight heparin, suggesting a role for the N-terminal heparin-binding domain in this interaction.368 Other modulatory effects like the natural killer cell expansion, are a consequence of TSP’s ability to activate latent TGF-b.370,371 All-trans retinoic acid-induced granulocytic differentiation of HL-60 cells is associated with an increase in TSP secretion. This process is delayed by a blocking anti-TSP antibody.372 TSP decreases the proliferation and promotes the differentiation of HL-60 cells; these effects are not mediated by latent TGF-b activation.372 A 140-kDa fragment of TSP binds b-FGF and has antiangiogenic properties.373 Endothelial cell TSP expression is inhibited by proangiogenic inflammatory cytokines such as IL-1 and TNF-a.374 TSP stimulates matrix metalloproteinase-9 activity in endothelial cells375 and is chemotactic to monocytes and neutrophils.376 These multiple cellular and microenvironmental interactions underscore TSP’s importance in hematopoietic stem cells homing and differentiation.
Vitronectin, also known as serum spreading factor, is a 75-kDa protein present in plasma, platelets, and connective tissue.230 Vitronectin, a major cytoadhesive glycoprotein, binds to specific integrin receptors (avb3) on fibroblasts, endothelial cells, and mature hematopoietic cells,378 namely, megakaryocytes,379 mast cells,380 bone cells381 such as osteoblasts and osteoclasts,382,383 monocyte-macrophages,384,385 neutrophils, and platelets.386 Transendothelial migration of monocytes and neutrophils is mediated through the aVb3 vitronectin receptor.385,386 Metargidin (ADAM-15) is a type I transmembrane glycoprotein (ADAM, a disintegrin and metalloprotease domain) that binds the avb3 receptor on a monocytic cell line.387 It uses a different integrin receptor (a5b1) to mediate adhesion of a lymphoid cell line, underscoring the complexity of cell adhesive interactions in different hematopoietic cells. The aVb3 vitronectin receptor cooperates with TSP and CD36 in the recognition and phagocytosis of apoptotic cells.388,389 and 390 Vitronectin and a platelet-derived GAG, serglycin, augment mega-karyocyte proplatelet formation.391,392 and 393 Soluble vitronectin inhibits b-FGF-mediated endothelial cell adhesion by interfering with its interaction with the avb3 receptor.394 Cytotoxic T lymphocytes,395 g/d lymphocytes396 and natural killer cells,397 utilize the aVb3 vitronectin receptor as a costimulatory molecule mediating activation signals and cell proliferation. The TSP receptor integrin-associated protein CD47, together with the aVb3 vitronectin receptor, mediate monocyte activation and cytokine release after interacting with soluble CD23.398 Hence, vitronectin appears to contribute mainly to terminal megakaryocyte maturation and platelet formation, while exerting a major role in apoptotic cell clearance, cellular activation, and trafficking to areas of inflammation, bone remodeling, and angiogenesis.
The hematopoietic cells lie in cords or wedges between the vascular sinuses. Erythroblasts are arranged against the outside surface of the vascular sinuses in distinctive clusters, erythroblastic islands,399 which consist of one or more concentric circles of erythroblasts closely surrounding a macrophage. The inner erythroblastic cells are less mature than the peripheral ones. The central macrophage sends out extensive slender membranous processes that envelop each erythroblast and may phagocytize defective erythroblasts and extruded nuclei.400 The optimal microenvironmental niche for the terminal erythroid maturation into erythroblasts and erythrocytes consists of closely associated fibroblasts, macrophages, and endothelial cells.401 Erythropoiesis is stimulated by stromal cell-derived activin A,402,403 a member of the TGF-b family, while mesodermal erythroid islands are induced by stromal cell-derived growth factors acting in concert, BMP-4 plus activin A or b-FGF.404 The additional ability of b-FGF and HGF to enhance erythropoiesis405,406 underscores the complex cell-cell interactions required for steady-state erythropoiesis in vivo.
Megakaryocytes also lie directly outside the vascular wall407 in normal and myeloproliferative diseases,408 while granulocytes mature deeper in the hematopoietic cords, away from the vascular sinuses. Such discrete spatial structural distribution may be determined by specific adhesive interactions and the provision of specific growth factors for a given cell lineage.88,231,409 The intimate relation of megakaryocyte to sinus endothelium is explained by their expression of CXCR4, the receptor for the marrow endothelial cell-derived chemokine (SDF-1).410 SDF-1 increases transendothelial migration of megakaryocytes and, unlike thrombopoietin, enhances platelet formation.411,412 Thrombopoiesis is also regulated by locally produced synergistic cytokines such as IL-11,413 KIT ligand,414 IL-6,153,415 LIF,152,416 thrombopoietin,148,417 and extracellular matrix proteins.315,391 Stem cells and granulocytic progenitor cells are concentrated in the subcortical regions of the hematopoietic cords.418
Lymphocytes and macrophages concentrate around arterial vessels, near the center of the hematopoietic cords. Computer-assisted three-dimensional reconstruction analysis of human marrow confirms the megakaryocyte apposition against the sinus wall and the position of granulocytic cells along the wall of the central arteriole.419 Erythropoietic cells located mainly around the sinus wall form a continuous network or cord instead of separate “islands.” On this basis, the unitary structure of marrow has been defined as a hematopoietic cord with a central arteriole and surrounded by sinuses.419 A similar structure termed a hematon serves as a multicellular functional unit of marrow and contains adipocytes, stromal elements, macrophages, and hematopoietic stem cells in a compact spheroid.420
Macrophages are a source of stem cell stimulators, such as IL-1, and inhibitors, such as macrophage inflammatory protein (MIP) 1 alpha and tumor necrosis factor a, and play an important role in local control of hematopoiesis.421,422 and 423 Stromal cells and accessory cells are needed for optimum hematopoietic cell development.424 Signals regulating the pluripotential hematopoietic stem cells are not entirely defined but require intimate cell-cell contact for signaling through cytokine-chemokine receptors, integrin receptors, alone or together with heparan sulfate or chondroitin-sulfate-containing glycoproteins.
This regulatory paradigm is underscored by several studies: (1) a neutralizing antibody to KIT, while able to abrogate myelopoiesis in stromal–stem cell cocultures, did not affect stem cell survival425; (2) stromal-cell-derived BMPs (BMP-2, -4, -7) regulate the proliferation and differentiation of CD34-positive, CD38-negative, lineage-negative cells, with high amounts of BMP-2 and -7 inhibiting proliferation and maintaining repopulating capacity, while BMP-4 at higher concentrations extends the survival of these repopulating cells ex vivo426; (3) several adhesion receptors of the sialomucin family mediate inhibitory signals to limit stem cell expansion or differentiation427; (4) direct contact of enriched CD34-positive, lineage-negative cells and stroma induces a soluble factor that increases primitive hematopoietic cell production.428
CELL ADHESION AND HOMING
Hematopoietic stem-progenitor cells (mostly expressing the CD34 antigen12) have multiple adhesion receptors, allowing them to attach to cellular and matrix components within the marrow sinusoidal spaces,295,296,297,298,299 and 300 thereby facilitating their homing and lodgement in the marrow, and providing the close cell-cell contacts required for cell survival and regulated steady-state proliferation.427,429 Adhesive receptors and their ligands, present on hematopoietic stem-progenitor cells, and components of the hematopoietic microenvironment, are shown in Table 4-2. Six subgroups of receptors, the integrins,299,430 immunoglobulins,427,431 lectins (selectins),432,433 sialomucins,434,435 hyaladherin (CD44, H-CAM),436,437 and other receptors such as CD38 (ADP-ribosyl cyclase),438 CD144 439,440 (cadherin), and CD157 (BST-1),441 are shown, listing mostly interactions involving CD34-positive cells and progenitors.429,442 Thus receptor-ligand interactions that regulate the trafficking of mature leukocytes are not included exhaustively.443
TABLE 4-2 HEMATOPOIETIC AND MICROENVIRONMENT ADHESION RECEPTORS AND THEIR LIGANDS
Members of this family are divalent cation-requiring heterodimeric proteins (17 a and 8 b subunits), and they mediate important cellular functions including embryonic development, cell differentiation, and adhesive interactions between hematopoietic cells and inflammatory cells and surrounding vascular and stromal microenvironment.299,444 They are subdivided based on the b-chain composition, and as shown in Table 4-2, a chains can associate with more than one b-chain subunit. The principal integrin receptors of the b1 subgroup involved in hematopoietic stem cells endothelial and stromal interactions are a4b1 (VLA-4), a5b1 (VLA-5), and aLb2 (LFA-1) of the b2 subgroup. a4b1-based stromal adhesion events in vitro,445 or in vivo,446 alone or in conjunction with the integrin-associated protein (IAP, CD47)447 regulate erythropoiesis. This receptor also mediates selective granulopoiesis over established marrow stromal cells in cooperation with PECAM-1 (CD31), an immunoglobulin superfamily member,448 and is essential for pre-B cell growth and differentiation over stromal cells expressing IL-7, KIT ligand, and Flt3 ligand.449,450,451 and 452 An acquired defect in stromal function, characterized by a deficiency in VCAM-1 and IL-7 expression,453,454,455,456 and 457 accounts for the delayed B lymphoid reconstitution seen after marrow transplantation.
Integrins also are signaling molecules,458,459 and after engaging their ligands, or subsequent to activation by monoclonal antibodies, multiple events (tyrosine phosphorylation of focal adhesion kinase, paxillin, and ERK-2) are triggered (inside-out signaling), culminating with RAS activation.460,461,462,463 and 464 Integrin receptor cross-talk465 with other adhesive receptor members, such as the immunoglobulin superfamily [natural killer cell-T cell (aLb2 /DYNAM-1), CD34-positive-endothelial cell PECAM-1,466,467,468 and 469 or selectins470], results also from outside-in signaling events that regulate receptor-binding affinity451,471 and mediates inhibitory signals for erythroid, myeloid, and lymphoid progenitor growth.472,473,474,475 and 476 Also, integrin-binding to their counterreceptors, such as a4b1/VCAM-1477 or a4b1/FN,312 in early CD34-positive progenitors, is associated with a decreased rate of apoptosis. Unchecked tyrosine kinase activation, as is the case in chronic myeloid leukemia cells,478 alters integrin affinity and allows the cells to egress from the marrow.479 Inhibition of the Abl kinase activity directly,480 or indirectly, using alpha interferon,481 restores the adhesive properties of these progenitors.
The immunoglobulin superfamily233 designates a group of molecules containing one or more amino acid repeats also found in immunoglobulins and consists of PECAM-1 (CD31), ICAM-3/R (CD50) and ICAM-1 (CD54), LFA-3 (CD58), ICAM-2 (CD102), VCAM-1 (CD106), KIT (CD117),482,483,484,485,486,487,488,489,490,491,492,493,494,495,496,497,498,499,500,501,502 and 503 and PRR2, a molecule related to CD155, which serves as a poliovirus receptor.503 (See Table 4-2.) VCAM-1 is upregulated by inflammatory cytokines (IL-4, IL-13).500,501 Immunoglobulin-like adhesion molecules also include NCAM, a neural adhesion molecule that binds lymphocytes but not hematopoietic progenitors; Thy-1, a stem cell antigen MHC classes I and II; and CD2, CD4, and CD8.233 (See Table 4-2.)
Homing of stem cells requires lectin receptors with galactosyl and mannosyl specificities.504,505 The selectins are a family of adhesion molecules, each containing type C lectin structures. The leukocyte selectin (L-selectin, CD62L) is expressed on hematopoietic stem-progenitors506 and mediates adhesive interactions with other receptors (addressins), such as the CD34 sialomucin present on specialized endothelium, using sialylated fucosyl-glucoconjugates. (See Table 4-2.) The CD34 receptor on stem cells, however, does not bind L-selectin,506 as a putative L-selectin ligand yet to be defined exists on these cells. The selectin family also contains CD62E, which is an E-selectin constitutively expressed on marrow sinusoidal endothelium, and regulates the transmigration of leukocytes as well as CD34-positive stem cell homing. The third member of this family is P-selectin, which is found on platelets and is able to bind hematopoietic stem cells, using a mucin receptor, the P-selectin glycoprotein ligand (PSGL-1), which binds to all three selectins. (See Table 4-2.) These proteins are responsible for leukocyte rolling over endothelial surfaces and tethering, thereby allowing integrin-mediated firm adhesion to the endothelium to form, and mediating cellular homing events using specialized high endothelial venule lymphocyte homing sites.507,508,509,510,511,512,513,514,515 and 516
The mucin family includes the CD34 stem cell antigen,517,518 not an L-selectin ligand on these cells,519 and CD43, an antiadhesion large glycoprotein (leukosialin)520 able to regulate hematopoietic progenitor survival.521 Both CD34 and CD43 signal via tyrosine kinases when capping their surface receptors517,522,523 and, in the case of CD43, clustering of cytoskeleton with CD44 and ICAM-2.522 CD162 (PSGL-1) is important in cell trafficking and stem cell homing,524,525,526,527,528,529 and 530 CD164 (MGC-24v), another sialomucin receptor,531 transmits inhibitory signals to stem-progenitor cells like CD162 and CD34.233 Lastly, CD166, the hematopoietic cell antigen (HCA, ALCAM), forms homodimers (CD166) and heterodimers with CD6.532
The fifth subgroup shown in Table 4-2 is the cartilage-related proteoglycan, CD44, also known as the lymphocyte homing cell adhesion molecule (HCAM). This adhesion receptor is expressed on hematopoietic stem-progenitor cells and facilitates their homing and adhesion to marrow in concert with VLA-4 and ICAM-1, -3. CD44 has several isoforms expressed in normal and tumor tissues. The CD44 variant v10 has been shown to regulate hematopoietic progenitor mobilization, underscoring its importance in mediating cellular matrix-stromal cell adhesion.533,534,535 and 536
OTHER ADHESION MOLECULES
CD38 is a newly recognized adhesion receptor that binds the CD31 receptor and matrix hyaluronan. It is expressed on early T and B cells and subsets of CD34-positive hematopoietic progenitors.537,538 Cadherins are large molecules involved in cell-cell junctions and vascular integrity. CD144, E-cadherin, is expressed on CD34-positive progenitors as well as marrow stroma and endothelial cells, thereby providing another pathway for stem cell lodgement.539 The stromal adhesion receptor BST-1, CD157, is an ADP-ribosyl cyclase, with similarity to CD38. CD157 is expressed on marrow stroma, T and B cells, and myeloid cells and promotes pre-B cell adhesion and growth.540,541,542 and 543
The control of lymphocyte and leukocyte cellular trafficking544,545 is a multistep process that involves: (1) selectin-mediated tethering and rolling over vascular endothelial cells expressing in a tissue-specific distribution selectin-binding sialomucins like GlyCAM-1 on lymphatic tissue high endothelial venules,546 MAdCAM-1 on Peyer’s patch endothelium,547 the peripheral lymph node addressin PNAd,548 and the vascular adhesion protein 1 (VAP-1)549 molecule (both mediating CD8 T-lymphocyte migration)547; (2) a triggering step, at sites of inflammation, by short-acting signals such as platelet activating factor,550 cytokine551,552 or chemokine-activating553,554; integrins; (3) tight adhesion and spreading of cells over endothelial surfaces mediated by the immunoglobulin receptors (ICAM-1, -2, VCAM-1)555,556 and 557; (4) CD31-mediated diapedesis,558 in concert with selectin-mediated tethering at vascular endothelial cell junctions.559 Other molecules can promote rolling of cells, such as tenascin,560 and cooperation between different adhesion receptors is frequently seen during the transmigration process.561
Chemokines bind heparan sulfate proteoglycans and thereby play a central role in directing cellular trafficking at sites of inflammation244,245,562 and, in the case of SDF-1,247 regulate cellular trafficking under steady-state conditions. Fractalkine, an endothelial transmembrane mucin-chemokine hybrid molecule, is strategically placed on the surface of activated endothelium and mediates the rapid capture, firm adhesion, and activation under physiologic flow of circulating monocytes, resting or IL-2-activated CD8 lymphocytes, and natural killer (NK) cells.563 The cytokines, TNF-a, and IL-1 upregulate fractalkine, in keeping with the need to recruit effector cells rapidly at sites of inflammation.564 Tissue-restricted chemokines modulate hematopoietic cell adhesive interactions by providing local activation signals, thereby enhancing the specificity of cellular trafficking.235
Unlike lymph nodes, no specific marrow sinusoidal addressins have been defined. A study comparing the adhesive capacity of human marrow or umbilical-cord-derived endothelial cell lines565 did not show any major differences in CD34-positive progenitor adhesion. This interaction is blocked to varying degree by combinations of monoclonal antibodies against a4b1, CD18, and/or E-selectin.565 These findings support the concept of a complex stem cell homing and lodgement process that relies on several short-range signals–adhesive interactions between homing CD34-positive cells and marrow sinusoidal endothelial cells.566,567
Thus, stem cell homing and lodgement to the marrow appears to rely on the distinct characteristics of marrow endothelium and stroma and intrinsic properties of hematopoietic stem and progenitor cells. First, the marrow sinusoidal endothelial cells express constitutively E-selectin, and upon activation both E-selectin and P-selectin are upregulated568; they also express VCAM-1,569,570 while the homing CD34-positive progenitors express PSGL-1 (CD162), a highly glycosylated sialomucin that binds all selectins,524,525 as well as the integrin receptor a4b1, which engages VCAM-1.451 Secondly, L-selectin on CD34-positive progenitors571 may influence the engraftment process by providing a carbohydrate interaction with sinus cavity E-selectin510 and with underlying stroma; L-selectin may also improve progenitor survival as shown by its ability to improve the clonogenic potential of CD34-positive cells.572,573 While the sinusoidal endothelial cells rarely express PSGL-1 (CD162), they display other L-selectin ligands such as chondroitin sulfate574 and heparan sulfate proteoglycans,575 in addition to VEGF-driven E-selectin.576 Thirdly, stromal cells and endothelial cells elaborate SDF-1, a potent chemokine known to enhance integrin activation,576 mediate endothelial CD34-positive cell arrest under flow,577 and enhance CD34-positive cell transmigration.570,576 The fourth element in this complex homing process is based upon the constitutive stromal cell expression of VCAM-1,573 leading to a4b1 integrin-mediated firm adhesion to marrow stroma,573 of a4b1-positive early reconstituting hematopoietic stem cells41 and CD34-positive progenitor cells.54,55
Additional homing signals could result from a5b1 integrin binding to fibronectin,297,311 CD44 binding to cytomatrix hyaluronan,276 ubiquitin binding sites on stroma cells interacting with progenitors,578 and L-selectin interacting with PCLP1.40,516 This heterotypic adhesion occurs because both CD34-positive stem cells and endothelial cells express this receptor/ligand pair. Other immunoglobulin superfamily receptors, PECAM-1 (CD31), ICAM-1, -2 (CD54, CD102), and CD117, also participate in the stem cell lodgement process.427 CD117 (KIT) can interact with membrane-bound KIT ligand to promote adhesion as well as cross-activate other integrin receptors.427
Another homotypic adhesion receptor in this family is the human poliovirus receptor-related 2 protein (PRR2), which is expressed on endothelial cells at the intercellular junctions and on the majority of CD34-positive cells, as well as precursors differentiating along the myelomonocytic and megakaryocytic lineages (CD33- and CD41-positive).503 PRR2 isoforms can homodimerize or heterodimerize, on the cell surface of endothelial cells, in a fashion similar to PECAM-1 (CD31)-mediated aggregation. The latter PECAM-1-signaling events involve phosphorylation of tyrosine on the receptor’s intracytoplasmic tail and by recruitment and activation of Src homology 2 domain-bearing protein tyrosine phosphatase 1 (SHP-1) and SHP-2.579
This cellular trafficking model is supported by experiments in mutant mice deficient in E and P selectins,573 showing decreased marrow progenitor homing in vivo. Similar results are obtained after the administration of blocking antibodies to VLA-4-VCAM-1566,567 or to SDF-1-CXCR4.579 These events result in decreased stromal–stem cell adhesion451 and in diminished CD34-positive cell–endothelial cell transmigration,53,570 leading to impaired homing of transplanted stem cells.580
CELL PROLIFERATION AND MATURATION
The earliest stem cells are pluripotential and capable of differentiation to either lymphopoietic or hematopoietic multipotential stem cells (Chap. 14). These pluripotential stem cells and progenitor cells are in a dormant state12 and are able to withstand the normal hypoxic milieu within the marrow sinusoidal spaces.581 Hematopoietic stem-progenitor cells are prevented from unchecked proliferation by matrix-associated negative regulators such as BMPs426 and TGF-b,582,583 and 584 alone or with locally induced inhibitory chemokines like MIP-1a585 and MCP-1.586,587 Direct inhibitory signals are also triggered by stromal-hematopoietic progenitor binding using sialomucins such as CD34,427 CD162,512 and CD164.159
Later unipotential progenitor cells respond to lineage-specific cytokines and mature into precursor cells that may undergo four or five cell divisions before terminating in functional blood cells (Chap. 14). Hematopoietic growth factors and cytokines are produced locally by stromal cells and other cellular elements of marrow. Such factors as KIT ligand are expressed in a membrane-bound form,147 bind to proteoglycans and heparan sulfate moieties within the cytomatrix, and mediate hematopoietic cell attachment, where they are presented in an active form to receptor-bearing hematopoietic progenitors.284,588 (See “Extracellular Matrix” and Table 4-1.) Cellular attachment to the marrow cytomatrix is an active process leading to signaling and activation of focal adhesion kinases within regions of integrin receptor clustering.589 These properties explain the ability of stromal cells to promote the self-renewal of stem cells590 and inhibit apoptosis of hematopoietic cells.591,592,593 and 594
After maturation of committed progenitor cells, the erythroid and granulocytic blast cells undergo four to five mitotic divisions, while the megakaryocytic blast cells divide perhaps once and then undergo five or six endomitotic (nuclear) divisions. The number of precursor cells in the marrow of humans has been calculated primarily through the study of marrow films and sections relating differential counts of marrow samples to their content of injected radioactive iron. A number of assumptions and approximations need to be made,595 but the summary data given in Table 4-3 agree well with many other observations on the cellular content and kinetics of normal marrows.
TABLE 4-3 NORMAL PRECURSOR CELL KINETICS
Cell migration occurs between adventitial cells but through endothelial cell channels that develop at the time of cell transit. Migrating cells make the hole that develops in the endothelial cell cytoplasm. A number of releasing factors have been implicated in the initiation of marrow egress. The best characterized are those for granulocytes, which include G-CSF,596,597 GM-CSF,598 the C3e component of complement,599 zymosan-activated plasma-containing complement fragments,600 glucocorticoid hormones,601 androgenic steroids,602 and endotoxin.603 Cellular migration is under the complex control of a family of small cytokines termed chemokines with overlapping tissue and target cell specificity, allowing them to regulate effector cell trafficking throughout the body. The chemokine superfamily has several branches based on the cysteine motifs: the “C-X-C” family (platelet factor 4, IL-8, melanocyte growth-stimulating activity/groa, neutrophil activating protein 2, and granulocyte chemotactic protein 2), all mediating neutrophil migration and activation, and the “C-C” family (MIP-1a and b, RANTES, and MCP-1, -2, -3, -4, -5) mediating mostly monocyte and in some cases lymphocyte chemotaxis.235,564 Neutrophils residing in the marrow venous sinusoids are rapidly released into the circulation by IL-8.604 Eosinophil and eosinophil progenitors are recruited from marrow selectively in allergic states, after exposure to IL-5,605 by the chemokines eotaxin606 or RANTES.607 In both systems, migration is inhibited by blocking the b2 integrin CD18, underscoring the importance of integrin activation as well as surface proteolytic activation in mediating transendothelial migration.607,608 Similarly, SDF-1 and KIT ligand cooperate to enhance hematopoietic progenitor chemotaxis.609 Table 4-4 has a detailed listing of chemokine receptors as well as cellular targets and ligands interacting with each receptor subgroup.610,611,612,613 and 614 Chemokines-receptors active on CD34-positive cells are shown in bold font.
TABLE 4-4 CHEMOKINE RECEPTORS, INTERACTING CHEMOKINE LIGANDS, AND CELLULAR SPECIFICITY
Releasing factors for reticulocytes and platelets have been more difficult to identify and may also be of less biological significance, since early release of these cells has little impact on the large pool of circulating cells. Erythropoietin therapy in uremic patients accelerates the egress of reticulocytes.615 Adventitial reticular cell cytoplasm is a barrier to the reticulocytes on the abluminal surface of the endothelium.616 Phlebotomy, phenylhydrazine-induced hemolytic anemia, and erythropoietin result in marked reduction of the adventitial cell cover of the sinus, a process that is thought to facilitate cell egress through the endothelium.617
To leave the marrow, the reticulocyte depends on a pressure gradient across the membrane to drive it through the pore616,617 (see Fig. 4-6). The pressures within the marrow sinuses are pulsatile, and pressures sufficient to cause egress may be transient.618 Anemia and the administration of erythropoietin markedly increase blood flow to marrow and bone,83,619 while G-CSF increases blood flow to marrow only.620 This effect is not blocked by denervation83 and may explain the egress of cells after G-CSF administration.620
FIGURE 4-6 Composite TEM of reticulocytes in egress. (A) Small protrusion of marrow reticulocyte into sinus lumen (L). (B) A reticulocyte in egress with about half the cell in the sinus lumen. (C) A reticulocyte virtually completely in the sinus. Egress occurs through a migration pore which is parajunctional in position (arrows point to endothelial cell junctions). (Reprinted from Lichtman and Waugh,400 with permission.)
Electron micrographs of leukocytes partially translocated across endothelium indicate that marked deformation of these cells occurs as they penetrate the cytoplasm of the endothelial cell to enter the sinus lumen.621 As with reticulocytes, egress occurs adjacent to junctions of endothelial cells.400 The nucleus of the granulocyte, usually segmented, does not require as marked a deformation to traverse the migration pore as do the nuclei of monocytes and lymphocytes.621 The immature granulocytes in marrow are anchored to adventitial reticular cells through lectinlike adhesion molecules. Gradual loss of these molecules (e.g., shedding of L-selectin) during maturation or after activation, could permit movement toward the sinus wall.622 Transient changes in surface glycoproteins (upregulation of a-2,6 sialylation of CD11b and CD18) of maturing marrow myeloid cells lead to decreased stromal and fibronectin adhesion and may favor contact with endothelium and cell egress.623 Activated neutrophils can adhere under flow using the VLA-4 integrin pathway.624 Neutrophil egress occurs mostly at the endothelial cell borders and is entirely P selectin mediated.625 C5a and G-CSF administration recruit neutrophils by altering integrins (low CD11a with G-CSF) and decreased L-selectin expression (with both agents).626,627 Similar findings obtained in mice lacking two or all three selectins underscore the essential role selectins play in neutrophil recruitment.628
The release of platelets is initiated by megakaryocytes that invaginate the abluminal surface of the marrow sinus endothelial cell until a pore is made. Cytoplasm flows through this pore into the marrow sinus and is eventually separated from the body of the megakaryocyte, resulting in a multiplatelet fragment or proplatelet.407,629 The proplatelets often are stringbean-shaped structures and are found in the marrow sinus lumen. Eventually they fragment into single platelets.391,392 and 393 Megakaryocyte nuclei are left in marrow after platelet release and are degraded and phagocytized there.630 The entry of either nuclear remnants or entire megakaryocytes with residual cytoplasm has been observed in both normal individuals631 and patients with marrow disorders.632 The latter regulatory events are mediated by the chemokine SDF-1411 and by c-Mpl ligand.412
Occasional immature granulocytes and megakaryocyte nuclei or whole megakaryocytes are present in cell concentrates of normal blood.631 Nucleated red cells rarely escape from the marrow under normal conditions. The absence of circulating erythroblasts may also relate to the capacity of the spleen to sequester and enucleate circulating erythroblasts. The late myelocytes and metamyelocytes have the capacity to move, respond to chemoattractants, and deform, albeit less well than the mature neutrophils, and thus may occasionally exit marrow by normal mechanisms. The invasion of marrow by neoplastic cells or the replacement of marrow by fibrous tissue is associated with an increased prevalence of immature cells in the circulation. Damage to the architecture of marrow with a breakdown of the integrity of sinus walls may allow cells to enter the circulation less discriminately. Tumor cells elaborate chemoattractive cytokines (chemokines), and this explains their ability to facilitate cell egress from marrow.633
The intramedullary expression of SDF-1 and KIT ligand may allow stem cells to localize to that space.634 KIT ligand upregulates CXCR4 expression on CD34-positive cells, enhancing their chemotactic response, while mobilized blood CD34-positive progenitors have a defective response to SDF-1.635 CXCR4 is expressed on early lymphohematopoietic progenitors,636 providing a model in which mobilized CD34-positive cells have alterations in their adhesion repertoire and chemotactic capacities, allowing them to leave their sinusoidal niches to the peripheral circulation.637 Enhanced hematopoietic progenitor mobilization is also seen when the chemokine MIP-2 is combined with G-CSF.638
The homing and egress processes require the interaction between separate adhesion pathways on hematopoietic stem and progenitor cells and marrow endothelium and stroma, as seen in a mouse model using blocking antibodies to a4b1 and CD44.639 Marrow stem cell homing depends on the a4b1/VCAM-1 adhesion pathway, while CD44 affects homing to marrow and spleen. Inhibition of CD44 and/or a4b1adhesion rapidly mobilized stem cells.639 The CS1 domain FN fragment did not mobilize progenitors, and antibody to a5b1 did not alter homing.640 G-CSF augments the mobilizing action of a4b1/VCAM-1 integrin-blocking antibodies in primates,641 while c-KIT signaling cooperates with this integrin-based mobilization process,642 confirming the complexity of the stem cell egress process.643
STEM CELL CIRCULATION
Stem cells circulate in the blood and can reenter marrow and reestablish hematopoiesis in the marrow cords. Whole-body irradiation of an animal with shielding of a single bone results in the repopulation of the irradiated marrow, strongly implying transfer of stem cells from shielded marrow into irradiated marrow.644 Also, marrow or blood cells from a syngeneic or histocompatible allogeneic donor can reenter marrow and reconstitute hematopoiesis of an animal or human recipient.645 The expression of L-selectin,646 and CD44,647 in blood CD34-positive progenitors seems to correlate with faster engraftment and platelet recovery. Umbilical cord blood CD34-positive cells express L-selectin on their surface in higher amounts than steady-state adult blood progenitors, thereby displaying a preferential homing capacity to the marrow.648 High proliferative potential colony-forming cells in the CD34-positive, CD38-negative subgroup are detectable in the circulation, very early after allogeneic transplantation, coinciding with rapid recovery of blood counts and implying a role for in vivo stem cell recirculation leading to a sustained engraftment process.649
The entry of stem cells into the marrow is mediated by a lectin-sugar interaction650,651 and may be facilitated by alterations in the sinus endothelium induced by the conditioning therapy.652,653 However, c-KIT-positive primitive hematopoietic stem cells, when infused in a nonirradiated host model, home more efficiently to areas of marrow, spleen, lung, and thymus than after sublethal irradiation.654 Unpurified marrow cells labeled with the membrane dye PKH-2 appear to be governed by a nonspecific seeding process rather then by a selective homing signal,655 suggesting that stem cells display adhesive and chemotactic properties that allow them to preferentially seek marrow endothelial sinusoidal spaces. Indeed, marrow endothelial cells under the influence of VEGF constitutively express E-selectin and VCAM-1 and elaborate chemotactic signals such as SDF-1 to attract CD34-positive cells.656,657 Similar findings have been seen when the in vivo homing of long-term repopulating stem cells is analyzed in a serial marrow transplantation model.658
Blood stem cell mobilization for marrow transplantation has been facilitated by improvements in CD34 cell collection and processing659 and the growing availability of recombinant cytokines660 such as G-CSF, GM-CSF, Flt3 ligand, KIT ligand, IL-3, interleukin-7, and thrombopoietin, all of which enhance the release of stem cells into the circulation.661,662,663,664,665,666 and 667 The KIT ligand receptors are downregulated in certain hematopoietic cell lines exposed to growth factors.668 This explains the propensity of KIT ligand to mobilize stem cells, since it can alter receptor affinity and/or density and thus decrease the anchorage of stem cells to the membrane-bound KIT ligand on marrow stromal cells.147,637
As discussed earlier, both CD44-mediated adhesion and a4b1/VCAM-1 interactions affect hematopoietic stem cell egress and homing.539,643 Antibodies directed to the CD44v10 isoform release hematopoietic progenitors into the circulation.536 Moreover, intracellular pools of hyaluronate receptor (RHAMM) and CD44 have been identified in early stem cells (CD34-positive, CD45-low/medium). Steady-state marrow CD34-positive progenitors have larger intracellular CD44 and intracellular RHAMM pools then do cells obtained from G-CSF mobilized blood collections which show a depleted intracellular RHAMM compartment.669 Progenitor adhesion is blocked by anti-CD44 and anti-b1 integrin antibodies, whereas motility is inhibited by antibodies to b1 integrin and RHAMM, suggesting a reciprocal role between these two molecules during stem cell trafficking.
A working model of stem cell egress can be divided into five events shown in Table 4-5. This complex process does not rely on any one feature of stem cells and the marrow microenvironment; rather, the process assumes a continuous series of interactions affecting blood flow,620 adventitial reticular cell-microvascular endothelial cell contraction,670 altered integrin, selectin, cytokine and cytoskeletal receptor expression,669 or functional activation. Chemokines such as IL-8 can efficiently mobilize hematopoietic stem cells.671 IL-8, a potent activator of neutrophil integrin function, causes shedding of L-selectin and degranulation, exposing nearby matrix components to proteolytic enzymes such as elastase and gelatinase B, known also as matrix metalloproteinase 9 (MMP-9).235,433,610 Antibodies against gelatinase B inhibit stem cell mobilization in this model.672 Also, G-CSF administration in vivo is accompanied by a surge in IL-8 that may potentiate stem cell release.673 This action is an indirect one, since long-term repopulating stem cells mobilized by IL-8 do not express aLb1,674 while anti-aLb1 antibody administration blocks IL-8-induced stem cell egress.675
TABLE 4-5 FACTORS REGULATING MARROW STEM CELL EGRESS
Another example of cooperation between cytokines and chemoattractants is provided by the study of G-CSF receptor (GCSFR)-deficient neutrophils, showing that a functional GCSFR is needed for b integrin activation.676 In that GCFR knockout model, Flt3 ligand mobilizes progenitors, whereas IL-8 fails to do so.677 Indeed, a functional GCFR is needed to activate b2 integrins and mediate the IL-8 activation process, with subsequent gelatinase B release.678 The inhibitory effects of anti-aLb1 antibodies and the requirement for a functional G-CSF receptor imply that this mobilization process involves intramedullary activation of neutrophils, leading to enhanced stem cell egress.675 This localized proteolysis (elastase, gelatinase B) is necessary for active cell migration679 and is enhanced by cooperating signals from IL-8-, G-CSF-activated neutrophils adhering to matrix heparan sulfates.680,681,682 and 683 In addition, CD34-positive progenitor cells elaborate gelatinase A and B, a process also augmented by cytokines.684
Hence, stem cell egress is affected by gelatinase expression coupled with altered integrin-, hyuloronan-based anchorage-migration (a4b1-VCAM-1, CD44), by cytokine enhanced blood flow, and by E-selectin-chemokine driven transendothelial migration. This model (see Table 4-5) also takes into account the ability of antibody to gelatinase B, and to b2 integrin, to block the IL-8 mobilization cascade. Integrin signaling and cross-talk with CD44, and the localized production of cytokines (such as KIT ligand, Flt3 ligand, G-CSF, thrombopoietin), create a complex matrix of interactions resulting in upmodulation (or downregulation) of CD34 active chemokine-chemokine receptors (SDF-1/CXCR4, IL-8/CXCR2, RANTES/CCR1, MIP-1a/CCR1, and SLC/CCR7), thereby setting the stage for multiple stem cell mobilization strategies.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn