CHAPTER 14 HEMATOPOIETIC STEM CELLS, PROGENITOR CELLS, AND CYTOKINES
CHAPTER 14 HEMATOPOIETIC STEM CELLS, PROGENITOR CELLS, AND CYTOKINES
PETER J. QUESENBERRY
GERALD A. COLVIN
Colony-Forming Unit Spleen
Early-Acting Erythroid Cytokines
The Other Interleukins
Other Cytokines that affect Hematopoietic Stem Cells
Inhibitors of Hematopoiesis
Features of Stem Cells
Location of Lymphohematopoietic Stem Cells
Embryonic Origin of Lymphohematopoietic Stem Cells
Stem Cell Location and Modulation
Stem Cell Phenotype
Pluripotential Lymphohematopoietic (Marrow-Repopulating) Stem Cell
Adhesion Proteins and Receptors
Stem Cell Homing and the Microenvironment
Mobilization of Stem or Progenitor Cells
Acronyms and abbreviations that appear in this chapter include: AGM, aortogonadal mesonephros; BFU-E, burst-forming unit-erythroid; BRDU, bromodeoxyuridine; CFU-E, colony-forming unit-erythroid; CFU-GM, granulocyte-macrophage colony-forming unit; CFU-S, colony-forming unit spleen; CSF-1, colony-stimulating factor-1; FOG, friend of GATA-1; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; LIF, leukemia inhibitory factor; LTC-IC, long-term culture-initiating cell; MCAP, monocyte chemotactic and activating factor; M-CSF, macrophage colony-stimulating factor; MIP, macrophage inflammatory protein; MPLV, myeloproliferative leukemia virus; NK, natural killer; PDGF, platelet-derived growth factor; PTB, phosphotyrosine binding; SHZ, Src-homology; VLA, very late antigen.
The blood in mammalian species includes a number of different cell types essential for survival. Erythrocytes transport oxygen; platelets mediate blood clotting and support tissue integrity; neutrophil, eosinophil, and basophil granulocytes and monocytes are essential to host defense against bacteria, fungi, parasites, and viruses; T lymphocytes, natural killer cells, and dendritic cells all function as antigen-presenting cells and in cell-mediated immunity; and B lymphocytes are the source of antibodies. The level of these cell types is controlled by multiple humoral and cellular factors and adjusts rapidly to meet need. Infection by a variety of microorganisms results in almost immediate release of mature neutrophils from the marrow storage pool, followed by an increase in production of granulocytes, and usually also monocytes, until the infectious agents are cleared. Hemorrhage or acute hemolysis results in a rapid release of marrow reticulocytes, followed by a sustained increase in red cell production until the red cell numbers return to normal. Platelet production and release responds to several stimuli, including decreases in platelet number, acute anemia, and tissue destruction or inflammation. The modulation of T- and B-cell production is complex and occurs in response to immune stimuli (e.g., foreign antigens), and the modulation of increased production may occur within different subsets of these cells (see Chap. 83 and Chap. 84).
Mature cell types derive ultimately from marrow stem cells, which differentiate into progenitor cells that are controlled by circulating or membrane-bound cytokines or various adhesion proteins. A very small proportion of circulating cells are progenitor cells and stem cells, which can be isolated from the blood by special techniques.
A hematolymphopoietic stem cell is defined as a cell with extensive self-renewal and proliferative potential, coupled with the capacity to differentiate into the progenitors of all the blood cell lineages, that is, erythrocytes, neutrophil, eosinophil, and basophil granulocytes, mast cells, monocytes and macrophages, platelets, B lymphocytes, T lymphocytes, natural killer cells, and dendritic cells. Self-renewal refers to the potential to produce daughter cells with identical characteristics. Self-renewal resulting in production of identical stem cells without any new differentiated characteristics has not been established experimentally, but renewal on a cell population basis clearly occurs. The sequential development of progenitor cells and mature cells from stem cells is presented in Fig. 14-1.
FIGURE 14-1 Hierarchical model of lymphohematopoiesis.
Studies of both murine and human hematopoietic cells indicate that two daughter cells from a primitive undifferentiated cell can have totally different lineages, for example, one cell giving rise to neutrophils and monocytes, while the daughter cell may give rise to erythrocytes, megakaryocytes, and mast cells.1,2,3,4,5,6 and 7 These observations suggest a less-ordered or stochastic system in which the commitment decision to produce different lineages is made within one cell cycle transit, although concordance of daughter cells is still the rule, indicating a model in which there is ordered and progressive lineage restriction with differentiation. In general, as differentiated characteristics are attained, self-renewal potential declines precipitously.
The “gold standard” for the definition of a stem cell is the ability of that single cell to repopulate long-term hematopoiesis in the whole animal. The majority of stem cell studies have been carried out in mice, although one can infer the existence of long-term repopulating cells in humans based on the repopulation in patients given marrow ablative treatment and allogeneic marrow transplant. Studies in mice using unique radiation-induced chromosome abnormalities or retroviral markers have established the capacity of a very few cells (approaching one cell) to totally repopulate the lymphohematopoietic system.8,9,10 and 11 When relatively small numbers of marked stem cells, obtained by limiting dilution of sorted marrow cells, are transplanted, lymphohematopoiesis may be clonal or oligoclonal initially. Normal polyclonal lymphohematopoiesis derives from a relatively large number of clones. Studies of competitive marrow repopulation and mathematical modeling support the model of polyclonal hematopoiesis.12
COLONY-FORMING UNIT SPLEEN
Studies on the potential of single lymphohematopoietic cells to give rise to clones of progeny cells in vivo or in vitro provided the model systems for the detailed definition of lymphohematopoietic stem progenitor cells. The observation of “bumps” on the spleen after marrow infusion into lethally irradiated mice resulted in the first clonal hematopoietic stem cell assay.13,14,15,16,17,18,19,20,21,22,23,24,25,26 and 27 These splenic nodules were clones of hematopoietic cells containing erythroid, granulocytic, and megakaryocytic lineages, and the cells giving rise to the clones were termed colony-forming unit spleen (CFU-S). This assay is rarely carried out today, but characteristics of this cell illustrate the nature of stem/progenitor cells. This cell (the CFU-S) gave rise to variable, but large, numbers of differentiated cells, was influenced by the splenic microenvironment, was in a relatively quiescent (G0/G1) state, and reproduced itself. The CFU-S assay monitors cells with varying engraftment and growth potential but did not appear to be an assay for the most primitive long-term repopulating stem cell.
Perhaps the major breakthrough in the hematopoiesis field was the description of marrow cells with the capacity to form colonies of granulocytes and macrophages in vitro in the obligate presence of stimulatory factors present in conditioned media or serum (Fig. 14-2).28,29
FIGURE 14-2 Clonal assay for granulocyte-macrophage progenitor cells.
The characterization of the granulocyte-macrophage colony-forming cell (CFU-GM) and the molecules, which stimulated or inhibited its growth, was followed by the description of a number of different progenitors with different growth and lineage potential in in vitro clonal culture. These included clones with a single lineage such as granulocytic or erythroid or clones with multiple lineages including lymphocytes. In parallel with the description of these clonal entities, a growing number of cytokine regulators was described, purified, and then molecularly cloned. The different stem/progenitor clones are outlined in Table 14-1. General characteristics of lymphohematopoietic stem cells are presented in Table 14-2. Progenitor cells in general have a higher proliferative rate, i.e., are progressing through cell cycle, have less total proliferative potential, and show a restricted number of differentiated cell types. They are also responsive to a smaller number of cytokines; in essence they are defined by a limited number of cytokine receptors.
TABLE 14-1 HEMATOPOIETIC STEM/PROGENITOR CELLS ASSAYED IN VITRO
TABLE 14-2 PLURIPOTENTIAL HEMATOPOIETIC STEM AND PROGENITOR CELLS
The erythroid progenitors and their primary regulator, erythropoietin, were the first to be extensively studied. The presence of reticulocytes and iron incorporation to mark newly produced red blood cells and the capacity of induced polycythemia to shut off in vivo erythropoiesis provided an in vivo model for the study of erythroid regulation.30,31,32,33 and 34 A mouse was made polycythemic inhibiting its own erythropoiesis, a putative erythroid regulator was administered, and then red blood cell production was monitored by reticulocyte number or iron incorporation. These cumbersome in vivo models allowed for the initial definition of erythropoietin, but it took in vitro culture systems and the application of biochemical and molecular genetic techniques to provide biochemical characterization and molecular cloning of erythropoietin.
The studies with in vitro clonal culture system showed erythroid progenitors with different proliferative and differentiative potential.35,36 and 37 The more primitive erythroid progenitors termed burst-forming unit-erythroid (BFU-E) were defined by a high proliferative response to multiple cytokines, while the more differentiated colony-forming unit-erythroid (CFU-E) was responsive to erythropoietin and had limited proliferative potential (Fig. 14-3).
FIGURE 14-3 The erythroid differentiation pathway.
Erythropoietin was found to be active in vivo and in vitro30,31,35,36 and 37 and acted via a cell membrane receptor to induce erythroid differentiation38,39 and to suppress apoptosis or programmed cell death.40,41 It is one of the most specific of the lymphohematopoietic cytokines acting on erythroid cells, while many other cytokines show action on multiple lineages. The explicit actions of erythropoietin are described in Chap. 29, and its use in the treatment of anemia associated with a relative erythropoietin deficiency state (i.e., renal failure) is described in Chap. 33.
The CFU-GM, CFU-G, and CFU-M are progenitors in the granulocyte macrophage pathway regulated by a number of cytokines, but primarily granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), and macrophage CSF (M-CSF) or CSF-1 (Figure 14-4). These cytokines are active in vivo and G-CSF and GM-CSF are in use clinically for neutropenic states.
FIGURE 14-4 The granulocyte-monocyte-macrophage differentiation pathway.
The GM and G progenitors are also in cycle, have restricted lineages, and respond to a relatively small number of cytokines. As with erythropoietin, CSF-1 and to a lesser extent G-CSF are relatively lineage-specific, stimulating predominantly the production of monocyte-macrophages and granulocytes, respectively. These cytokines stimulate proliferation and differentiation and inhibit apoptosis through cell-surface–based receptors which send second messenger signals activating nuclear transcriptional mechanisms which then turn on or off various genetic programs.
There are a very large number of cytokines regulating hematopoiesis, certainly exceeding 60 to 70 in numbers. These cytokines and their most prominent hematopoietic activity are presented in Table 14-3, Table 14-4, and Table 14-5. There are an intimidating number of cytokines with a wide range of effects on lymphohematopoietic cells. These agents, however, have certain common features. The cytokines are glycoproteins acting at very low concentrations on receptor molecules to signal the cell to live, die, proliferate, differentiate, or function; many cytokines act on primitive stem cells and their functioning terminally differentiated progeny. These actions, particularly at the more primitive stem cell levels, may be on survival, proliferation, or differentiation or, alternatively, especially in mature cells, on function. Cytokines usually act on multiple lineages and multiple cell types and frequently act synergistically (or additively) to stimulate or inhibit. In many ways the progenitors are defined by their cytokine receptors.
TABLE 14-3 CYTOKINES ACTIVE ON LYMPHOHEMATOPOIESIS STEM AND PROGENITOR CELLS
TABLE 14-4 CYTOKINES ACTIVE ON LYMPHOHEMATOPOIETIC STEM OR PROGENITOR CELLS (GROWTH FACTORS)
TABLE 14-5 CYTOKINES ACTIVE ON LYMPHOHEMATOPOIETIC STEM CELLS: CYTOKINE INHIBITORY FACTORS AND OTHERS
The broad-based actions of cytokines on hematopoietic cells are complex and evolving. Most cytokines have many actions on different lineages and stages of differentiation. Descriptions of the biologic, biochemical, and molecular genetic characteristics of these cytokines follows.
Erythropoietin was first defined in in vivo assays. The initial definition was provided in the 1950s.30,31 The hormone was later purified, its sequence determined, and the gene encoding its production cloned.117,118 and 119 The clonal culture systems for BFU-E, CFU-E, and intermediate erythroid progenitor cells facilitated investigation of the biology of erythropoietin (Fig. 14-3). Erythropoietin is produced in the renal peritubular interstitial cells121,122 or renal tubular cells.123 There are also measurable erythropoietin levels in anephric animals and humans presumably of hepatic origin.124,125,126 and 127 Hepatocytes and Kupffer cells have been implicated as the cell of origin for hepatic erythropoietin.128 Marrow macrophages may also be a source of erythropoietin.129 The tissue oxygen-sensing mechanisms that are linked to erythropoietin elaboration may involve a heme protein.130 Further details of the structure, function, and regulation of erythropoietin are presented in Chap. 29.
The response of BFU-E and CFU-E to erythropoietin correlates directly with the presence of erythropoietin receptors. Two classes of erythropoietin receptor, high and low affinity, have been identified on erythroblasts obtained from the spleens of mice infected with the anemia strain of Friend virus.39 The receptor has been cloned38 and belongs to the hemopoietic family of receptor proteins. The cell cycle behavior of BFU-E131 in vivo is not influenced by hypoxia (increased erythropoietin) or hypertransfusion (decreased erythropoiesis), and BFU-E can proliferate in vitro in the absence of exogenous erythropoietin when in the presence of other cytokines.132 Actinomycin given to mice blocks the action of erythropoietin on CFU-E and more mature erythroid cells, virtually eliminating them in vivo, but has no effect on the numbers of marrow and splenic BFU-E.133 Monoclonal antibody purified blood BFU-E do not require erythropoietin until after 72 h of culture. Initially only 20 percent of BFU-E have erythropoietin receptors, but with maturation in vitro over 4 days 100 percent of the cells bind 125I erythropoietin. The peak receptor number occurs at the CFU-E stage, the main target cell for the action of erythropoietin. CFU-E does not have the proliferative potential of BFU-E but requires erythropoietin for limited proliferation, survival, and terminal maturation.88 CFU-E is responsive to low concentrations of erythropoietin.89 Adding erythropoietin to CFU-E in vitro leads to rapid expression of mRNA for alpha and beta globins, and hemoglobin synthesis commences soon thereafter.134 Erythropoietin also stimulates the proliferation of proerythroblasts and basophilic erythroblasts,135 but with maturation beyond the basophilic erythroblast stage, the erythroid cells no longer appear to require erythropoietin for maturation or function136; many erythroid cells, including late-stage erythroid progenitors, undergo programmed cell death or apoptosis, and this is prevented by erythropoietin. The action of erythropoietin on second messenger and transcriptional factors is outlined below.
EARLY-ACTING ERYTHROID CYTOKINES
A critical observation was that erythropoietin does not act on BFU-E or other early progenitors alone, but rather in concert with other cytokines. These include IL-3,137,138 GM-CSF,139 IL-9,140 steel factor,137 interleukin 4,141 and insulin-like growth factor.1 This list will grow with increased purity of the progenitors or omissions of serum from the cultures.
There are strong similarities between erythropoietin growth control and the action of other lymphohematopoietic cytokines. These include (1) an action on proliferation and maturation; (2) an effect on cell survival inhibiting apoptosis; (3) an action mediated through cell surface receptors; and (4) synergistic interactions with a number of other cytokines.
These were first defined by the stimulation of granulocyte-macrophage colonies in soft agar culture. The four colony-stimulating factors are CSF-1 or M-CSF, GM-CSF, G-CSF, and IL-3 (multi-CSF).
GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR
GM-CSF was first defined by its ability to stimulate colonies of neutrophils and macrophages in soft-agar culture, but it acts on many cell types, including relatively early multipotential stem cells, megakaryocyte, eosinophil erythroid, dendritic progenitors, and mature neutrophils and macrophages.83,84,85,86 and 87 GM-CSF was first isolated from murine lungs142 and later from a human T-cell leukemia line.143 Human GM-CSF is a glycoprotein with a Mr of 22,000, and murine GM-CSF is a glycoprotein with a Mr of 23,000.
The murine gene was cloned from a murine lung cDNA library144 while the human cDNA was isolated from a human leukemia cell line.145,146 The human GM-CSF contains 127 amino acids with an Mr of 14,000, and the human gene was isolated on chromosome 5 147,148 with a control region 5 prime of the gene.149 GM-CSF stimulates proliferation and maturation of bipotential neutrophil and macrophage progenitors and has multiple actions on mature cells including stimulation of synthesis of membrane and nucleoproteins in murine granulocytes,87 increased adhesion protein expression in neutrophils,150 inhibition of neutrophil migration,143 and stimulation of cytotoxic and phagocyte activity against bacteria, yeast, parasites, and antibody-coated tumor cells,151,152,153 and 154 enhanced survival and cytotoxicity of human neutrophils and eosinophils in vitro,155 and increased basophil histamine release. GM-CSF also increases neutrophil superoxide production in response to bacterial chemoattractants and increases neutrophil arachidonic acid release and leukotriene B4 synthesis in response to calcium ionophore and chemoattractants.156,157 GM-CSF also induces changes in neutrophil calcium flux and pH after treatment with a chemotactic agent.
GM-CSF mediates its effects by binding to a specific cell receptor (see below).158,160 GM-CSF controls the proliferation of GM-CSF–dependent cells during the GI phase of cell cycle.161
The availability of recombinant growth factor has permitted studies of bioactivity of GM-CSF in vivo. Administration of GM-CSF to murine species and to primates causes increases in granulocytes, monocytes, eosinophils, and, to a lesser extent, other white cell types in both normal animals or animals subjected to cytotoxic or irradiation-induced marrow suppression.162,163,164,165,166,167 and 168 GM-CSF may also raise the platelet count and possibly the reticulocyte level,162,164,166 although in some patients the platelet count is lowered.
Administration of GM-CSF to humans with AIDS results in a dose-dependent increase in neutrophils, eosinophils, and monocytes.169 The administration of GM-CSF during chemotherapy lessens the fall in the neutrophil count.170,171 GM-CSF stimulates proliferation of about one-third of human cancer cell lines, including small-cell lung carcinoma, ovary, breast, colon, and melanoma. Other effects of GM-CSF include lowering of serum cholesterol, mobilization of blood progenitors, induction of inflammatory recall, and a capillary leak syndrome. GM-CSF is licensed for therapeutic use.
GRANULOCYTE COLONY-STIMULATING FACTOR
G-CSF was first defined as a factor that had the capacity both to stimulate normal granulocyte colonies and to induce maturation of leukemic cell lines.81,82 It has been purified to homogeneity from mouse lung (Mr = 25,000).172 Human G-CSF has a similar molecular size and cross-reacts with both human and murine cells. cDNAs for both murine and human G-CSFs have been cloned.172,173 The human cDNA encodes a polypeptide with a 30 amino acid signal sequence followed by mature G-CSF sequence of 177 amino acids. The molecular mass is 19 KD. These proteins stimulate predominantly neutrophil colony formation. The gene for human G-CSF has been localized on chromosome 17.174 G-CSF can initiate the proliferation of some granulocyte-macrophage progenitors but does not sustain this beyond several days. G-CSF interacts with a number of cytokines to stimulate blast colony and high proliferative potential colony-forming cell development in vitro, induces terminal maturation in WEHI-3B myelomonocytic leukemic cells,85 and stimulates pre-B cells in vitro.175 G-CSF also affects mature progeny; priming human neutrophils to undergo oxidative metabolism in response to formyl-methionlleucylphenylanine, as well as increasing antibody-dependent cell-mediated cytotoxicity of human neutrophils. G-CSF primes human neutrophils for enhanced arachidonic acid release, and receptors for G-CSF have been identified on both human neutrophils and leukemic cell lines.176 G-CSF also stimulates proliferation and variable degrees of maturation in acute myelogenous leukemia blast cells177,178 and stimulates proliferation of a variety of human solid tumor cell lines. G-CSF is active in vivo in mice, hamsters, primates, and humans, stimulating impressive neutrophil increases with lesser increases of monocytes, lymphocytes, and possibly platelets.179,180,181,182,183,184,185,186,187 and 188
G-CSF has been licensed for therapeutic use.
COLONY-STIMULATING FACTOR 1 (MACROPHAGE COLONY-STIMULATING FACTOR)
CSF-1 (M-CSF) stimulates a population of progenitor cells with a high predilection for macrophage maturation, although early in the culture period there may be some granulocyte production. CSF-1 binds rapidly to mature macrophages and is internalized and degraded. Low levels of CSF-1 support survival of murine marrow macrophages while decreasing their level of protein catabolism. Higher levels of CSF-1 stimulate protein synthesis, cell division,189,190 and various macrophage functions, including antitumor activity,191 secretion of products of oxygen reduction,192 and plasminogen activator.193,194 and 195 CSF-1 also induces production of IL-1 from macrophages.196 The product of the FMS gene is the receptor for CSF-1.197,198 and 199 The receptor is a tyrosine kinase, which autophosphorylates. The number of monocyte receptors increases with maturation and may be induced by other growth factors, including IL-3 and IL-1, explaining the synergistic effects of the combinations either of CSF-1 or IL-3 and IL-1 on in vitro macrophage colony formation.79,200,201 CSF-1 induces macrophage cell lines to progress through cell cycle by modulating levels of specific cyclins.202 CSF-1 can increase neutrophil levels and lower cholesterol in vivo.
CSF-1 has been purified to homogeneity79,80,203,204 and 205 from both murine and human sources. Human urinary CSF-1 is a heavily glycosylated homodimer of 45 kD,206 whereas the material purified from L-cell-conditioned medium is a glycoprotein of 70 kD.79,80,203 Its basic structure is that of a homodimeric protein of 28 kD consisting of two 14-kD peptide chains. Varying degrees of glycosylation explain, in part, different estimates of molecular size. Genes for both human and murine CSF-1 have been cloned and expressed in vitro.207,208 The human CSF-1 gene is a single gene encoding several differentially spliced mRNA transcripts ranging from 1.5 to 4.5 kb. Several different sizes of human CSF-1 have also been purified from natural sources; the smaller variety possibly being a proteolytic degradation product of a larger 70- to 90-kD glycoprotein. Higher-molecular-weight forms bound to proteoglycans have been reported.209
INTERLEUKIN-3 (MULTI-COLONY-STIMULATING FACTOR)
A fourth murine T-cell-derived regulator, interleukin-3 (IL-3) or multi-CSF, has been characterized,49 purified,210,211,212,213 and 214 and genetically cloned.215,216,217,218 and 219 It stimulates growth of granulocytes and monocytes, but also has megakaryocyte, erythroid, mast cell, and possibly T-cell growth stimulatory activity. Il-3 was cloned from a gibbon T-cell line.50 Il-3 was initially believed to be T-cell specific49,220 but has now been established as a major multilineage stimulator with direct megakaryocyte-, mast cell–, basophil-, B-cell-, and eosinophil-stimulating ability. It also interacts with erythropoietin to stimulate primitive erythroid stem cells,221 with CSF-1, GM-CSF, and IL-1a to stimulate the growth of high proliferative potential colony-forming cells222 and supports the formation of early multilineage blast cells in vitro.223 It is identical to the “stem cell activating factor” that induced CFU-S to proliferate. Recombinant IL-3 is an activating factor for basophils, mast cells, and eosinophils but not neutrophils. In vivo administration to mice induces 10-fold increases in blood eosinophils and 3-fold increases in granulocytes and monocytes. Splenic hematopoiesis is increased with prominent effects on mast cells, and many tissues show an increase in macrophages or mast cells.47 Single injections of IL-3 induce most types of murine marrow progenitors into cell cycle. In murine species, IL-3, GM-CSF, and CSF-1 in low doses, act synergistically to induce progenitor cell cycling,48,224 and sequential treatment of primates with recombinant human IL-3 followed by low-dose recombinant human GM-CSF synergistically increases blood neutrophil, monocyte, lymphocyte, and eosinophil levels. IL-3 alone augments reticulocyte and platelet levels in nonhuman primates.225 Administration of IL-3 to normal or myelosuppressed humans stimulates increases in a similar range of cell types, but its ability to raise platelet levels has been marginal.226,227 This, along with a relatively high incidence of toxic side effects, has lessened the enthusiasm for the use of IL-3 as a single agent in therapy.
THE OTHER INTERLEUKINS
Cytokines with pleiotropic actions are referred to as interleukins. Their principal actions on lymphohematopoiesis are presented in Table 14-3.
IL-1, identical with the previously described endogenous pyrogen- and lymphocyte-activating factor, was initially defined as a macrophage product that induces IL-2 receptor expression on T lymphocytes.42,43 It is produced by many different cell types in response to inflammatory stimuli and has two molecular forms, IL-1-a and IL-1-b, which have a low level of homology but similar activities and share a common receptor. The activity of IL-1 is further modulated by the IL-1 receptor antagonist.228 IL-1 shares many properties with IL-6 (and probably also IL-11) and is involved in the regulation of the immune system, induction of fever, acute phase protein production, tissue repair, and cytotoxicity.42,43,229 IL-1 has apparent direct effects on early hemopoietic stem cells and acts synergistically with many other factors to augment proliferation of high proliferative potential colony-forming cells, CFU-blast, and myelogenous leukemia blasts.230,231,232,233 and 234 IL-1 is also an inducer of other growth factors such as G-CSF, GM-CSF, and IL-3 from different cell types including fibroblasts, endothelial cells, monocytes, keratinocytes, and thymic nonlymphoid cells.235,236,237,238,239 and 240 Studies in vivo in mice and humans indicate that IL-1 augments hemopoietic recovery probably by an action on early stem cells.241,242 In addition, it interacts synergistically in vivo with other cytokines to accomplish the same end. Its use as a sole agent clinically may be limited by toxic manifestations including hypotension, hypoglycemia, fever, rigors, and headache.
IL-2 is T-cell growth factor44 (see Chap. 84). It augments production of other lymphokines such as gamma interferon and is produced by T cells and stimulates and activates B cells and natural killer cells, modulating the expression of histocompatibility antigens.243 IL-2 may inhibit both granulocyte-macrophage colony formation and erythropoiesis.45,46 The immune modulatory functions of IL-2 have been applied to the treatment of cancers. IL-2 alone, or in combination with other cytokines and cell populations, has some effects against melanoma and renal cell carcinoma.
IL-4, also known as B-cell stimulating factor 1, B-cell differentiation factor, and IgG induction factor,51,52,244,245 stimulates B-cell maturation, immunoglobulin synthesis, and generation of cytotoxic and helper T lymphocytes (see Chap. 83 and Chap. 84). It interacts with a variety of other growth factors to stimulate granulocyte-macrophage, mast cell, erythroid, and megakaryocyte proliferation in murine systems.246,247 It also interacts with IL-11 to stimulate the proliferation of dormant hemopoietic progenitors cells247 and conversely may exert inhibitory influences on IL-3–dependent erythroid colony formation.248 It also stimulates proliferation and differentiation of dendritic cells.
IL-5, also known as T-cell replacing factor,249 B-cell growth factor-2,250 and eosinophil differentiation factor,53 supports the proliferation, maturation, and function of eosinophils (see Chap. 68). IL-5 also can stimulate both proliferation and differentiation of different leukemic blasts from different subsets of patients with acute myelocytic leukemia. IL-5 has a variety of effects on promoting maturation of proliferation of B cells and like CSF-1 is a homodimer.
IL-6, also previously called interferon B-2, hybridoma growth factor, B-cell stimulating factor 2, B-cell differentiation factor, and hybridoma plasmacytoma growth factor, is produced by a variety of different cell types and was originally cloned from a T-lymphocyte cDNA library as a molecule inducing immunoglobulin production by B lymphocytes.56,57,251,252 and 253 IL-6 also has direct proliferative effects on hemopoietic cells and interacts synergistically with other growth factors to stimulate myeloid proliferation.57,254,255 and 256 It is a potent mitogen for B cells and also induces T-cell growth and maturation. It has activity on hematopoietic blast colony-forming cells and is a major factor in the immune response and inflammation. IL-6 augments colony formation induced by other growth factors and stimulates granulocyte-macrophage and megakaryocyte colony formation. IL-6 also has in vivo activity stimulating platelet production in normal and myelosuppressed mice, primates, and humans.257,258 and 259 Neutrophil elevations are also seen. IL-6 stimulates blasts from patient with acute myelocytic leukemia260 and has been implicated as an autocrine or paracrine factor in multiple myeloma (see Chap. 106).261 Other diseases in which IL-6 may play a role, and be responsible for the systemic manifestations, include atrial myxoma, Castleman’s disease, and rheumatoid arthritis.262
IL-7, also known as lymphopoietin-1, is a B-cell activating factor that appears to have effects on T-cell stimulation and on immature blood granulocyte and splenic megakaryocyte regeneration in irradiated mice.58,59,263 IL-7 shows potent interactions with KIT ligand in inducing pre-B cells in culture264 (see Chap. 94).
IL-8 is a chemotactic factor for granulocytes that has been termed neutrophil-activating peptide.60,61 and 62 It induces immediate inflammatory responses on intracutaneous injection and a granulocytosis after intravenous injection, apparently by redistributing blood and/or splenic granulocytes.63,64 It is part of the family of proinflammatory molecules linked by amino acid homology, chromosome location of their genes, and a position-invariant cysteine motif.64 These include, under the chemokine b classification, Gro-a, macrophage inflammatory protein-2-b (MIP-2-b), platelet factor 4 (PF4), IL-8, neutrophil activating protein-2 (NAP-2) and interferon-inducible protein-10 (IP-10).64,265,266 and 267 The following all inhibit in progenitor assays: MIP-1a, MIP-2a, PF4, IL-8, IP-10, and monocyte chemotactic and activating factor (MCAF); they also show synergistic inhibition when tested in combination.267 These molecules tend to inhibit more primitive progenitors and may stimulate growth of more mature progenitors. They are potent mobilizers of stem and progenitor cells.
IL-9, or mouse T-cell growth factor, P40, supports the development of erythroid bursts (BFU-E) in cultures supplemented with erythropoietin.268,269 Recombinant murine and human IL-9 were cloned from T-cell lines, and the sequence of recombinant human IL-9 bears homology with mouse T-cell growth factor, P40.269,270 IL-9 also has mast cell growth-promoting activity and stimulates maturation of multilineage and myeloid colony-forming cells from fetal cells.65,271
IL-10 was initially characterized as cytokine synthesis inhibitory factor and is able to inhibit interferon-g production by activated T-cell clones.272 IL-10 also appears to have direct effects on mature T cells, increasing the frequency of cytotoxic T-cell precursors and increasing cytotoxic effect or function.273 It also synergistically stimulates mast cell growth and induces MHC class II antigen expression on and increased viability of B cells.66,274
IL-11 has many of the biologic effects produced by IL-6.67,68 and 69,275,276 and 277 IL-11 stimulates B-cell, megakaryocyte, and mast cell lineages, along with early multipotential progenitor cells (e.g., CFU-blast).68,69,275,276 and 277 IL-11 stimulates platelet production in mice and primates278,279 but also stimulates increased neutrophil levels.
IL-12 is a natural killer cell stimulatory factor or cytotoxic lymphocyte maturation factor.70,280,281,282,283 and 284 IL-12, in synergy with IL-2, increases generation of cytotoxic T cells and of lymphokine-activated killer cells, increases cytotoxic activity of natural killer cells, promotes proliferation of activated T cells and natural killer cells, and induces interferon-g production by resting or activated natural killer cells and T cells.
IL-13, a T-cell–derived cytokine, was cloned and shown to share many biologic activities with IL-4.71,285 Both IL-4 and IL-13 inhibit cytokine production by blood monocytes, affect the proliferation and maturation of B cells to antibody-producing cells,285 and cause a switch to IgG4- and IgE-producing cells by naive human B cells. IL-13, in contrast to IL-4, induces the production of interferon-g by large granular lymphocytes and, in contrast to IL-4, has growth stimulatory effects on activated T cells.
IL-14, also known as high-molecular-weight B-cell growth factor, induces B-cell proliferation, inhibits immunoglobulin synthesis/secretion, and acts as a B-cell growth stimulant for certain subpopulations.286,287 IL-14 is produced by T cells and some B-cell malignancies such as B-cell precursor acute lymphocytic leukemia, chronic lymphocytic leukemia, and B-cell lymphoma.287,288 and 289 Exogenous IL-14 has been shown to have putative proliferative activity on B-lymphoma cells in vitro when other B-cell stimulatory cytokines such as IL-2, IL-4, IL-6, or tumor necrosis factor do not have increased activity, suggesting a paracrine effect. IL-14 also has been shown to have an autocrine growth factor effect for intermediate to high-grade B-lymphoma cells. In fact, in vitro studies suggest that many of the B-cell malignancies could be immunomodulated to inhibit proliferation by an antisense oligonucleotide to IL-14.288
IL-15 shares biologic activity with IL-2 as well as components of the IL-2 receptor. IL-15 is a cytokine, having multiple levels of receptor and signaling pathways and expression control. Expression occurs at many tissue beds throughout the body, stimulating the proliferation of activated CD4+, CD8+, gd subset of T cells, natural killer (NK) cells, and mast cells. Il-15 acts as a potent T-cell chemoattractant and acts as a costimulator with IL-12 to facilitate production of IFNg and TNFa. IL-15 may act as an anabolic agent that increases muscle mass and help with the differentiation and maturation of the immune system. Unlike IL-2, IL-15 is not expressed by T cells, but it does stimulate mast cells and is believed to be responsible for inducing the pathological propagation of mast cells that leads to mastocytosis.290,291,292,293 and 294
IL-16 is an immunomodulatory and proinflammatory cytokine that acts as a CD4+ T-lymphocyte chemoattractant and growth factor stimulant.295,296 IL-16 is synthesized as an 80-kDa peptide precursor molecule that gets processed to a biologically active 14- to 17-kDa protein. Functional bioactivity is dependent on autoaggregation of the pepide to homotetramers (56 kDa).296 The gene is located on chromosome 15 (q26.1).297 The gene location and IL-16 structure are unique, without significant homology to other interleukins or chemokines. IL-16 synthesis is produced by stimulated CD4 and CD8 T cells, eosinophils, mast cells, and epithelial lung cells stimulated by chronic inflammation of asthma.295,296 and 297 Prominent immunomodulatory effects are seen with this cytokine with repression of HIV/SIV transcription and replication.295,296,297 and 298 IL-16 activity has been associated with granulomatous disease states (sarcoidosis, tuberculosis), asthmatic inflammation,299 primary IgA nephropathy,300 rheumatoid synovitis (possible anti-inflammatory effects),301 systemic lupus erythematosus,320 and allergic contact dermatitis.303
IL-17, also referred to as cytotoxic T-lymphocyte–associated antigen 8 or murine CTLA-8 is a 155 amino acid glycoprotein homodimer, which stimulates adherent cells such as macrophage, epithelial, endothelial, keratinocyte, or fibroblast to secrete a variety of cytokines including IL-6, IL-8, G-CSF, LIF, TNF-alpha, IL-1 beta, IL-10, IL-12, and IL-1R antagonist. It induces ICAM-1 surface expression, proliferation of T cells, growth and differentiation of CD34+ human progenitors into neutrophils when cocultured with irradiated fibroblasts, and osteoclast progenitor differentiation to osteoclasts.304,305,306,307,308,309,310,311,312,313,314,315,316 and 317 It also inhibits IFN-gamma- and TNF-alpha-induced production of Rantes. It stimulates granulopoiesis in vivo, and it is produced by CD4+ and CD8+ T cells and alpha-beta TCR + CD4 – CD8-T cells.308,318,319
Interleukin-18 is also known as interferon-g–inducing factor or interleukin-1 g. Functional properties are similar to IL-12. Produced by a wide variety of cells, it augments cell-mediated immunity, modulates T, B, and NK function, induces interferon gamma in type 1 helper T and NK cells, initiating immune and antitumor effects, augmenting GM-CSF, and decreasing IL-10 production. Pretreatment or early treatment with IL-18 in mice confers resistance or protection in many types of tumors.320,321,322,323,324,325,326,327,328,329,330,331,332,333 and 334
KIT LIGAND (STEEL FACTOR)
The SI/SId and W/Wv mice exhibit macrocytic anemia, pigmentation, and germ cell defects.335,336,337,338,339,340,341,342 and 343 These mice have a macrocytic anemia and other more subtle defects in multilineage hematopoiesis. They also have germ cell (sterility) and melanocyte (coat color) defects. The W/Wv mouse has a CFU-S stem cell deficiency, whereas the S1/S1d mouse has a stromal cell (microenvironmental) defect, since stromal (irradiated spleen) cells from W/Wv will cure the anemia of S1/S1d mice, while marrow stem cells from S1/S1d will cure the anemia of W/Wv mice. The defect in W/Wv mice was found to be due to abnormalities in the tyrosine kinase KIT receptor,344,345,346,347,348,349,350 and 351 while subsequently the defect in S1/S1d has found to be due to a deficiency of the ligand for the KIT receptor.352,353,354 and 355 This protein exists in both membrane and soluble forms and may serve both to bind and stimulate stem cells. This protein KIT ligand is the same as hemolymphopoietic growth factor-1175 and synergizes with a large number of cytokines to stimulate early high proliferative potential colony form cells, possibly acting as a survival factor. It exerts action on all myeloid pathways and in the presence of IL-7 stimulates pre-B cell generation in vitro. It also stimulates the functional activation of mast cells. KIT-ligand has multilineage effects in mice, primates, and humans, but its mast cell activation and associated allergic toxicities may limit its clinical use, at least as a single agent.
A number of investigators strived to define the humoral regulator of megakaryocytopoiesis and platelet production.356,357 and 358 Critical insights were generated studying the transforming oncogene (v-mpl) of MPLV, an acute transforming murine retrovirus,359,360 which induces a pan-myeloid disorder.361 Thrombopoietin was cloned in 1994362,363,364 and 365 and was found to be the ligand for c-Mpl, the normal cellular receptor and counterpart to v-Mpl. Thrombopoietin appears to be the major regulator of megakaryocyte proliferation, differentiation, and platelet production. It also induces platelet-specific proteins and ultrastructural features and increased endomitosis.366 It also has action on multiple other hematopoietic lineages and is a major regulator of primitive multilineage stem cells. Administration of thrombopoietin to normal or myelosuppressed mice increased progenitor cells of all hematopoietic lineages and hastened hematopoietic recovery.367,368 Other studies have indicated that thrombopoietin exerts potent effects on early multipotent hematopoietic stem cells inducing entry into cell cycle369 maintaining or expanding LTC-IC in vitro.370 Furthermore, hematopoietic repopulating cells appear to be localized to the mpl + population371 and disruption of the mpl gene reduces murine stem cells as assayed in a competitive repopulation assay.372
OTHER CYTOKINES THAT AFFECT HEMATOPOIETIC STEM CELLS
There are a daunting number of other regulators that impact on the lymphohemopoietic pathways either as stimulators or inhibitors, some showing both effects dependent on the stage of maturation of the lineage under consideration. Leukemia inhibitory factor (LIF), which supports proliferation of the IL-3-dependent cell line DA-1,108 also sustains the proliferation of embryonic stem cells, inhibits adipogenesis, induces renal cell differentiation, neuronal development and differentiation, and bone remodeling. It stimulates proliferation of megakaryocyte progenitors and possibly CFU-S.109
Basic fibroblast growth factor also is a pleiotropic growth factor that stimulates primitive marrow stem cells, megakaryocyte progenitors, and marrow stromal cells.113,114 and 115 Insulin-like growth factors I and II stimulate erythroid and myeloid progenitors,110,111 and hepatocyte growth factor synergizes with other factors at the progenitor’s cell level.112 Platelet-derived growth factor acts on erythroid and granulopoietic progenitors and indirectly on early multilineage stem cells.116
Flt-3 ligand acts on relatively primitive progenitor stem cells showing synergies with G-CSF, GM-CSF, M-CSF, IL-3, and SCF and stimulates dendritic cell formation90,91,92 and 93; Flt-3 ligand can also induce tumor regression in vivo.94
INHIBITORS OF HEMATOPOIESIS
Inhibitors of hematopoiesis have been difficult to study due to questions of the specificity and physiologic relevance of their effects. However, with the progressive definition of cytokines, coupled with advances in cell purification and the use of serum-free culture systems, a number of molecules have been established as having specific inhibitory effects on different stem or progenitor cells. Some of these molecules may exert inhibitory effects on early, more primitive stem cells, while stimulating their latter, more differentiated progeny. A number of inhibitors with varying action are presented in Table 14-5.
Transforming growth factor beta has received the most attention for its ability to inhibit early stem cells, while stimulating more mature cells,103,104 possibly through modulating surface cytokine receptor expression.373
The chemokine family of inhibitors and the small peptides are presented in Table 14-5. The chemokine family was outlined in the description of IL-8. The beta subfamily contains a position invariant cysteine-x-cysteine motif, and its genes are on human chromosome 17, while the alpha subfamily contains position invariant cysteine-x-cysteine motif, and its genes are on human chromosome 4. These inhibitor molecules are potential marrow cell protectors, since they can block entry of stem cell into S phase of the cell cycle (tetrapeptide),107 remove cells from S phase (pentapeptide),106 or do both (MIP-1a and related family members) in a rapid and reversible manner.
Cytokines influence cell behavior by binding to cell-surface-receptor proteins and then sending messages for various cell responses. There are a number of receptor families that have been described.
The hematopoietic receptor family includes IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, G-CSF, GM-CSF, and erythropoietin.374,375,376 and 377 The extracellular binding domains of these receptors contain four conserved cysteine residues and a WS-X-WS motif (X is a variable nonconserved amino acid). Some also have immunoglobulin-like structures. GM-CSF, IL-3, and IL-5 receptors contain specific low-affinity alpha chains and a high-affinity beta chain shared by each receptor.377 The common beta chain plays a role in the competitive binding of these ligands.
The tyrosine kinase receptor family includes receptors for FLT-3 ligand, c-KIT, PDGF, CSF-1, and thrombopoietin.90,197,198 and 199,349,350 and 351 These receptors have an immunoglobulin-like structure and conserved cysteines in the extracellular domain with tyrosine kinase activity in the cytoplasmic domain.
Typical steps for the action of a cytokine on a hematopoietic cell (or any other cell) include receptor oligomerization with activation of tyrosine kinase activity, phosphorylation of the receptor, and recruitment of Src-homology (SHZ) and phosphotyrosine binding (PTB) domain proteins to the receptor. What follows varies between different cytokines but in essence represents a series of enzymatic phosphorylation-dephosphorylation steps with final evolution of a protein or protein complex that binds to DNA to initiate genetic programs. Signaling through the GM-CSF, IL-3, and IL-5 receptors, which share a common beta chain, illustrates some specifics of these complex and evolving second messenger systems. The beta chain without kinase activity induces tyrosine phosphorylation of itself along with an increasing number of cytoplasmic proteins including kinases such as PI-3 kinase,378 adapters illustrated by Grb2,379 the insulin receptor substrate-2,380 Cbl,381,382 and SHC383,384; guainine nucleotide exchange factors such as Vav382,383,385; phosphatases such as SH-2–domain protein tyrosine phosphatase-2378,379,383,386 and SH2 containing inositol phosphatase387 and transcription factors such as STAT 5.386,387 and 388 Receptor phosphorylation is mediated by receptor-associated kinases such as JAK2389 and Src-family kinases.390 These sequential interactions lead to proteins, usually in complexes that bind to regions of DNA and in turn prompt initiation of transcription, guiding different genetic programs which modify or effect cell death, proliferation, differentiation, or function.391
These transcription factors have been characterized in adult mammals and perhaps most extensively in a variety of developmental studies utilizing mouse, xenopus, drosophila, c. elegans, and zebra fish and employing transgenic techniques for knock-outs, knock-ins, and overexpression. This is also an evolving field, but certain transcription factors appear to be responsible for certain differentiation pathways. Factors acting at the earliest stem cell levels include C-myb, p45-NF-E2, GATA-2, AML-1, and tal-1/SCL, while IKaros and PU-1 may act at the earliest lymphoid level. In the myeloid pathways, PU-1 appears to influence granulocyte and monocyte differentiation; PAX-5 B-lymphoid development; GATA-1 erythroid, mast cell, and megakaryocyte lineages; and P45-NF-EC the megakaryocyte lineage. FOG (friend of GATA-1) acts in concert with GATA-1.392
These transcription factors appear to act in complexes, binding to DNA regions. An example is the recently described complex of SCL, LMO-2, GATA-1, E47, and Lbdl/NLI.393 Further definition of these systems promises to define the genetic bases for lymphohematopoietic regulation.
FEATURES OF STEM CELLS
LOCATION OF LYMPHOHEMATOPOIETIC STEM CELLS
Current theories of hematopoietic stem cell sites of origin and the hematopoietic potential of marrow cells have been reexamined as a result of unexpected findings. Convincing evidence has been found that cloned neural (brain) stem cells can repopulate an irradiated host giving rise to multilineage hematopoiesis.394 Further studies have indicated that isolated muscle satellite cells can also give rise to hematopoiesis.395 These data indicate that cells in other tissues when exposed to the hematopoietic microenvironment may have lymphohematopoietic potential. Moreover, marrow contains mesenchymal stem cells capable of giving rise to muscle cells, adipocytes, chondrocytes, and osteocytes396 and cells that give rise to hepatocytes.397 The relationship of these mesenchymal stem cells to lymphohematopoietic stem cells is yet to be elucidated.
EMBRYONIC ORIGIN OF LYMPHOHEMATOPOIETIC STEM CELLS
Controversy exists over the embryonic origin of lymphohematopoietic stem cells, either from the yolk sac or from the aortogonadal mesonephros (AGM) mesenchymal region. One line of study indicates that hematopoietic stem cells originate in murine yolk and from there migrate to fetal liver and then to marrow. Alternatively, a mesenchymal region has been proposed as the source for stem cells for both avian and murine species.399,400,401,402,403,404 and 405 It now appears that during development, there are two temporally separate phases of hematopoiesis, the first in the yolk sac giving rise to primitive hematopoiesis restricted to nucleated embryonic erythrocytes, while definitive hematopoiesis arises later in the aortagonadal mesonephric area, giving rise to all hematopoietic lineages and cells that can repopulate lethally irradiated recipients. A cell bipotential for vascular and hematopoietic lineages, the hemangioblast may give rise to the hematopoietic lineages.406 The yolk sac region may also be a source of some definitive hematopoiesis407 (see Chap. 4 and Chap. 7).
STEM CELL LOCATION AND MODULATION
Hematopoietic stem cells in the adult reside most prominently in the marrow and less so in the spleen. Stem cells are also present in blood, and the number in blood may be dramatically increased by a number of hematopoietic stresses (anemia, endotoxin, infection), by cytotoxic therapy (e.g., cyclophosphamide) or by the administration of a variety of cytokines (most prominently G-CSF, KIT ligand, FLT-3, IL-8, GM-CSF, or thrombopoietin).
STEM CELL PHENOTYPE
The hematopoietic stem cell in both murine and human species has been characterized as to surface protein, physical, metabolic, and cell cycle characteristics and these characteristics used to purify stem cells. Early stem cells express a relatively large number of cytokine receptors at low levels, with a restricted number of receptors expressed at higher levels after differentiation.408 Certain other proteins have been found to be present on relatively primitive classes of stem cells: in the mouse, Ly6, c-Kit, c-mpl, CD34, Thy-1, and Flk-2/Flk-3,371,409,410,411 and 412 and in the human, CD34, c-Kit, Thy-1, Flk-2/Flt-3, and AC133.412,413,414 and 415 Other features of primitive stem cells include lack of expression of HLA-DR, CD38, and differentiated lineage markers.416,417 Human and mouse CD34 negative cells may have significant stem cell potential and give rise to CD34+ cells418,419 or, alternatively, that CD34 expression may vary, depending on the activation state of the stem cell.420 The most primitive stem cells appear to be dormant in G0 or a prolonged G1. The stem cell membrane has a strong p170 membrane pump activity. This pump is the MDR-1 which extrudes certain chemotherapeutic agents and the supravital dyes, rhodamine and Hoechst, from cells.421 Thus the most primitive stem cells are characterized by an absence of lineage markers and low staining with rhodamine and Hoechst.422,423,424 and 425 These properties have been used to purify or selectively enrich stem cells for study and clinical application.
PLURIPOTENTIAL LYMPHOHEMATOPOIETIC (MARROW-REPOPULATING) STEM CELL
This cell is ultimately defined by in vivo repopulation and renewal; as noted above, under the appropriate circumstances a single stem cell may renew and restore hematopoiesis in a mouse.9,10 and 11 Thus the cell has tremendous renewal, proliferation, and differentiation potential. These cells have been characterized most definitively in murine species, where in vivo repopulation or population can be assessed in detail. In humans, of necessity, this cell has been defined by surrogate assays of questionable validity. This cell appears to be quiescent (G0 or prolonged G1). BRDU studies suggesting a constant cycling state for these cells426 may be monitoring DNA damage and repair rather than cell cycling.427 However, the stem cell is easily stimulated to enter active cell cycle transit by in vitro exposure to cytokines428 or by in vivo engraftment.429 This cell also appears to have a high level of baseline motility and is rapidly stimulated to demonstrate directed movement by exposure to a variety of cytokines, perhaps most prominently, stromal-derived factor-1 (SDF-1) and KIT ligand.430 It rapidly binds in vitro to stromal populations,431 expresses a variety of adherence proteins (vide infra), and migrates toward stromal cells. The murine lineage negative, rhodamide low, Hoechst low cells appear to respond to SFD-1 and KIT ligand in the presence of stroma with extension of lamellipodia in up to 10 to 15 percent of cells.430 These cells may also differ from differentiated cells in their adhesion receptor profile.
The stem cell appears capable of renewal and expansion under certain experimental conditions such as MDR-1 transfection,432 or certain serial transfer experiments, but most attempts to expand the engraftable stem cells in vitro, usually in the presence of stroma and/or cytokines, have been unsuccessful.413 There has been intense interest in such approaches for their potential for retroviral vector-based gene therapy or stem cell transplantation.
A critical feature of this cell is its plasticity, especially with cell cycle transit. The engraftment phenotype of this cell varies dramatically and reversibly when stimulated by cytokines (IL-11, IL-3, IL-6, steel factor) to transit the cell cycle.433,434 and 435 During the first cell cycle transit, long-term engraftment appears to be lost in late S-early G2 and regained in G1.435 Multiple other phenotypic features of this cell change with cytokine-induced cell cycle transit, including cytokine and adhesion receptor, transcription factor, and cell cycle factor expression.436,437,438 and 439 The critical observation is that the phenotype of this cell can go from high to low to high engraftment. These observations suggest a cell cycle model of hematopoiesis.
ADHESION PROTEINS AND RECEPTORS
Adhesion receptors and their ligands mediate cell-to-matrix and cell-to-cell interaction and include the selectins, the integrins, the immunoglobulin family, and miscellaneous others. First defined in studies on lymphoid homing, these proteins now have been found to play a role in anchoring of hematopoietic cells in marrow or in the promotion of differentiation.440,441 The integrin class of adhesion receptors are heterodimers of the noncovalently associated a and b chains. There are at least 18 different a and b chains. The b chain associates with a1 through a6 to form the very late antigen (VLA) group. a5b1 is the classical fibrinogen receptor, and a6b1 is a laminin receptor. L-selectin, PECAM-1, CD44, b1, and a4 through a6 are all expressed on primitive human or murine stem cells, and their modulation appears to correlate with engraftment efficiency. Immature blasts, erythroid progenitors, monocytes, and CD34+ cells show a4 and a5, and these decrease with maturation. There also appears to be differential binding of hematopoietic cells to different extracellular matrix components: erythroid cells to fibronectin442,443 and CFU-GM and BFU-E to collagen.444 Several groups have implicated VLA-4 and VCAM-1 or CD44 in marrow homing and engraftment. VLA-4 binding to the CS-1 peptide of alternatively spliced fibronectin mediates binding of murine CFU-S445 or human long-term marrow culture initiating cells,446 and an antibody to VLA-4 caused mobilization of hematopoietic progenitors in normal or cytokine-treated primates or mice.447,448 c-KIT receptor was also found to be important for optimal mobilization by anti-VLA-4 or VCAM-1 in W/Wv or S1/S1d mice.449
The non-integrin adhesion receptors also play a role in engraftment. These include CD44,450 PECAM,451 and a receptor for a ligand bearing galactosyl and mannosyl residues from stroma.452 Both PECAM and L-selectin are affected by cytokines, and hematopoietic progenitors can bind to thrombospondin,453,454 interleukin-3, and KIT ligand,448 and these cytokines bind to heparin sulfate proteoglycans. Studies with E- and P- selectin knockout mice,455 also employing VCAM-1 blocking antibodies, has implicated the selectins and VLA-4 as receptors that are critical for stem cell homing. Adhesion receptor expression on hematopoietic progenitor or stem cells is summarized in Table 14-6.
TABLE 14-6 HEMATOPOIETIC STEM AND PROGENITOR CELL ADHESION RECEPTORS AND LIGAND
STEM CELL HOMING AND THE MICROENVIRONMENT
A critical aspect of hematopoiesis is the milieu in which hematopoietic stem cells reside: the microenvironment. The latter consists of stromal cells and the extracellular matrix. Stem cells home to stromal cells during development, in the steady state, or after transplantation, and these same cells function to regulate hematopoiesis.456,457,458,459 and 460 Early studies showed the dramatic influence of microenvironment in the spleen on lineage expression in spleen colonies,26,27 and 28 and the introduction of the Dexter long-term stromal-based culture system provided an in vitro model of stromal supported hematopoiesis.461,462 In this latter system adherent stromal cells, consisting of hematopoietically derived macrophages, preadipocytic fibroblasts, and other cells (variable with the system) could support virtually all engraftable stem cells, CFUs, and a variety of different progenitor cells.463,464,465 and 466 The marrow stromal cells in this system produce a variety of cytokines and express a number of adhesion molecules, both playing important roles in regulation of lymphohematopoiesis.467,468,469,470 and 471 Adhesion proteins are critical for stem cell binding to stromal cells in vitro and homing to marrow in vivo when stem cells are infused subsequently and move to the endosteal surface of marrow (Chap. 4).472
MOBILIZATION OF STEM OR PROGENITOR CELLS
Long-term repopulating stem cells and their progenitors are mobilized into the blood by a number of cytokines including GM-CSF, CSF-1, IL-1, KIT ligand, FLT-3, IL-11, IL-12, IL-3, IL-8, IL-7, MIP-1a, and epo.473,474,475,476,477,478,479 and 480 In addition, previous exposure to cyclophosphamide or other cytoxic agents also mobilizes stem cell, presumptively as a result of cytokine effects. Mobilization has been utilized to collect stem and progenitor cells for transplantation. Pretreatment with cyclophosphamide followed by treatment with KIT ligand and G-CSF may be the most potent mobilization regimen. In general, mobilized progenitor and stem cells appear to restore hematopoiesis more rapidly than unstimulated marrow, although marrow “primed” with in vivo cytokines may be equivalent to mobilized blood cells for rapid engraftment. Whether these mobilized stem cells will have the same long-term repopulation capacity as marrow cells remains to be established (Chap. 4 and Chap. 141).
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn