SEARCH:   Advanced

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Liu, F. Articles by Link, D. C. Search for Related Content PubMed PubMed Citation Articles by Liu, F. Articles by Link, D. C. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 90 No. 7 (October 1), 1997: pp. 2522-2528 RAPID COMMUNICATION The Granulocyte Colony-Stimulating Factor Receptor Is Required for the Mobilization of Murine Hematopoietic Progenitors Into Peripheral Blood by Cyclophosphamide or Interleukin-8 But Not Flt-3 Ligand By Fulu Liu, Jennifer Poursine-Laurent, and Daniel C. Link From the Division of Bone Marrow Transplantation and Stem Cell Biology, the Department of Medicine, Washington University Medical School, St Louis, MO.     ABSTRACT Abstract Introduction Methods Results Discussion References Hematopoietic progenitor cells (HPC) can be mobilized from the bone marrow into the peripheral circulation in response to a number of stimuli including hematopoietic growth factors, cytotoxic agents, and certain chemokines. Despite significant differences in their biological activities, these stimuli result in the mobilization of HPC with a similar phenotype, suggesting that a common mechanism for mobilization may exist. In this study, the role of granulocyte colony-stimulating factor (G-CSF) in progenitor mobilization was examined using G-CSF receptor (G-CSFR)-deficient mice. In contrast to wild-type mice, no increase in circulating colony-forming cells (CFU-C), CD34+ lineage- progenitors, or day 12 colony-forming unit-spleen progenitors (CFU-S) was detected in G-CSFR-deficient mice after cyclophosphamide administration. This defect was not due to a failure to regenerate HPC following cyclophosphamide administration as the number of CFU-C in the bone marrow of G-CSFR-deficient mice was increased relative to wild-type mice. Likewise, no increase in circulating CFU-C was detected in G-CSFR-deficient mice following interleukin-8 (IL-8) administration. In contrast, mobilization of HPC in response to flt-3 ligand was nearly normal. These results show that the G-CSFR is required for mobilization in response to cyclophosphamide or IL-8 but not flt-3 ligand and suggest that the G-CSFR may play an important and previously unexpected role in HPC migration.     INTRODUCTION Abstract Introduction Methods Results Discussion References THE USE OF hematopoietic progenitor cells to reconstitute hematopoiesis following myeloablative therapy has significantly improved the clinical outcome in patients with a variety of cancers. Recently, peripheral blood progenitor cells instead of bone marrow (BM)-derived progenitor cells have been used because of their reduced engraftment times and relative ease of collection. Hematopoietic progenitor cells (HPC) can be mobilized from the BM by diverse stimuli including chemotherapy, hematopoietic cytokines, and certain chemokines.1 Despite intensive study, the mechanisms that control the movement of HPC between BM and blood are incompletely understood. Hematopoietic growth factors, along with chemotherapy, are the most commonly used agents to mobilize HPC. A partial list of the hematopoietic growth factors capable of mobilizing HPC include granulocyte colony-stimulating factor (G-CSF),2-4 granulocyte-macrophage colony-stimulating factor (GM-CSF),4,5 interleukin-12 (IL-12),6 IL-7,7 stem cell factor (SCF),8,9 and flt-3 ligand.10 Despite clear differences in biologic activities, several common features are observed during mobilization with these agents. First, a broad spectrum of HPC are mobilized including primitive pluripotent as well as committed myeloid, megakaryocytic, and erythroid progenitors.6-11 Second, relative to HPC resident in the BM, mobilized HPC have decreased expression of c-kit12,13 and the -1-integrin VLA-4,14 the latter a potentially important finding given the recent reports that anti-VLA-4 antibodies can mobilize HPC.15,16 Finally, a high percentage of mobilized HPC appear to be quiescent17-19; in one recent report, 7% of mobilized HPC versus 47% of BM HPC were observed to be in S-phase.17 The observation that hematopoietic growth factors with distinct cellular targets and biologic activities result in the mobilization of HPC with a similar phenotype suggests that a common mechanism for mobilization may exist. G-CSF is the most commonly used agent to mobilize HPC because of its potency and lack of serious toxicity. In addition, G-CSF recently has been shown to act synergistically with cytotoxic agents,20,21 SCF,22,23 or flt-3 ligand24,25 to induce HPC mobilization. To explore the mechanisms of G-CSF-induced mobilization we examined HPC mobilization in mice genetically deficient for the G-CSF receptor (G-CSFR). We previously have shown that G-CSFR-deficient mice have a quantitative defect in granulopoiesis, with the residual neutrophils appearing to be phenotypically normal.26 The defect in hematopoiesis in G-CSFR-deficient mice appears to be limited to granulopoiesis because the number and cytokine responsiveness of myeloid progenitors in the BM and spleen of these mice were near normal.26 Further, the number and function of primitive multipotent progenitors, as measured by day 12 CFU-S assays, were normal.27 In this study, mobilization of murine HPC in response to the three major types of mobilizing stimuli, cytotoxic agents (cyclophosphamide), chemokines (IL-8), and hematopoietic cytokines (flt-3 ligand) was examined. We show that HPC mobilization in G-CSFR-deficient mice by cyclophosphamide or IL-8 is markedly impaired whereas mobilization by flt-3 ligand is essentially intact.     MATERIALS AND METHODS Abstract Introduction Methods Results Discussion References Mice The G-CSFR-deficient mice (outbred C57BL/6 × 129 SvJ) were generated in our laboratory as described previously.26 The inbred 129 SvJ G-CSFR-deficient mice were generated as follows. The production of chimeric mice using a single RW4 ES clone containing a targeted null mutation of the G-CSFR has been described previously.26 The chimeric mice were intercrossed with 129 SvJ mice and their progeny genotyped to identify heterozygous G-CSFR mutant mice; these mice were then interbred to generate homozygous G-CSFR mutant mice on a 129 SvJ genetic background. All mice were housed in a specific-pathogen free environment and examined daily by veterinary staff for signs of illness. Peripheral Blood, Spleen, and BM Analysis Blood was obtained by retro-orbital venous plexus sampling in polypropylene tubes containing EDTA. Complete blood counts were determined using a Baker-9000 automated cell counter (Serono-Baker, Allentown, PA). BM was obtained by flushing both femoral bones with 3 mL of -Minimum Essential Medium (-MEM) containing 2% fetal bovine serum (FBS). Manual leukocyte differentials were performed on Wright-stained blood smears or cytospin preparations of BM mononuclear cells. Colony-Forming Cell Assay (CFU-C) BM and spleen mononuclear cells were enumerated using a hemacytometer. 2.5 × 104 BM, 1 × 105 spleen mononuclear cells, or 40 µL of EDTA-anticoagulated whole blood were plated in 1.25 mL of methylcellulose media supplemented with erythropoietin and pokeweed mitogen-stimulated murine spleen cell conditioned medium (MethoCult M3430; Stem Cell Technologies, Vancouver, BC, Canada) and placed at 37°C in a humidified chamber with 5% CO2 . Colonies containing at least 50 cells were scored on day 7-8. Flow Cytometry CD34+ lineage- cells were enumerated as described.28 Red blood cell-depleted peripheral blood mononuclear cells were incubated with biotin-conjugated rat-antimouse CD34 (RAM34, IgG2a ) and the following cocktail of lineage-restricted fluorescien isothiocyanate (FITC)-conjugated rat monoclonal antibodies: antimouse B220 (M1/70, IgG2b ), antimouse CD3 (M1/70, IgG2b ), and antimouse CDllb (M1/70, IgG2b ). After this incubation, cells were incubated with phycoerythrin (PE)-conjugated streptavidin (GIBCO-BRL, Gaithersburg, MD). FITC-conjugated rat IgG2b (R35-38) and biotin-conjugated rat IgG2a (R35-95) were used as isotype controls. All antibodies were purchased from Pharmingen (San Diego, CA). All cells were analyzed on a FACScan flow cytometer (Becton Dickinson, San Jose, CA). CFU-Spleen (CFU-S) Assay Day 12 CFU-S numbers were determined as described.29 Peripheral blood was obtained from donor mice by retro-orbital venous plexus sampling and approximately 200 µL injected into each of five lethally irradiated (900 cGy, single dose) wild-type recipient mice. Mice were killed after 12 days, their spleens harvested, and macroscopic colonies counted after overnight fixation in Tellesniczky's solution. No colonies were observed in saline-injected controls (data not shown). Progenitor Mobilization in Mice G-CSF. Recombinant human G-CSF (Amgen, Thousand Oaks, CA) was administered by daily subcutaneous injection at a dose of 250 µg/kg/d for 5 days. Peripheral blood was obtained before the first G-CSF dose and 4 to 6 hours after the final G-CSF dose. Cyclophosphamide. Cyclophosphamide (Sigma, St Louis, MO) was reconstituted in sterile water and (200 mg/kg) administered as a single intraperitoneal injection. Mice were analyzed at the indicated times. IL-8. Recombinant human IL-8 was a generous gift from Dainippon Pharmaceutical Co, Ltd (Osaka, Japan). rhIL-8 (30 µg/mouse) was administered by a single intraperitoneal injection and peripheral blood obtained at the indicated times. To minimize the effect of repeated phlebotomies, no mouse was subjected to more than three blood draws within 1 day. Flt-3 ligand. Recombinant human flt-3 ligand was a generous gift from Immunex (Seattle, WA). rhFlt-3 ligand (10 µg/mouse/d) was given by subcutaneous injection for 10 days. Mice were analyzed in the morning following the final injection. Statistical Analysis Data are presented as mean ± SEM. Statistical significance was assessed by two-sided Student's t-test.     RESULTS Abstract Introduction Methods Results Discussion References G-CSF is a potent stimulus for HPC mobilization in mice.2,4,5 To examine G-CSF-induced mobilization in G-CSFR-deficient mice, we stimulated mice (n = 6) with 250 µg/kg/d of human G-CSF for 5 days and measured their mobilization response. Wild-type mice had the expected increase in blood neutrophils (18.2 ± 4.3-fold increase over baseline) and CFU-C (48.3 ± 21.4-fold increase over baseline). In contrast, no significant increase in circulating neutrophils (0.6 ± 0.1-fold increase over baseline) or CFU-C (1.3 ± 1.3-fold increase over baseline) was detected after G-CSF stimulation of G-CSFR-deficient mice. These data show that G-CSF-induced HPC mobilization requires the G-CSFR. Mobilization of HPC in Response to Cyclophosphamide Is Markedly Impaired in G-CSFR-Deficient Mice Cyclophosphamide treatment is another potent stimulus for HPC mobilization in mice.20,30,31 To determine whether cyclophosphamide-induced mobilization requires the G-CSFR, we challenged G-CSFR-deficient mice with this agent (Fig 1). In comparison with wild-type mice, neutrophil recovery was delayed and blunted in G-CSFR-deficient mice. Wild-type mice had the expected mobilization response with a 40-fold increase in blood CFU-C observed 8 days after cyclophosphamide.31 In contrast, no increase in CFU-C was detected in the blood of G-CSFR-deficient mice at any time during this study. Likewise, a significant increase in circulating CD34+ lineage- HPC was detected in wild-type but not G-CSFR-deficient mice (Fig 1C). To determine whether the defect in HPC mobilization in G-CSFR-deficient mice extended to more primitive HPC, we measured the level of CFU-S (d12) progenitors in peripheral blood on day 8 after cyclophosphamide administration (Fig 2). As reported previously,31 a significant increase in peripheral blood CFU-S (d12) progenitors was detected in wild-type mice. In contrast, no increase in CFU-S (d12) was detected in the blood of G-CSFR-deficient mice. View larger version (17K): [in this window] [in a new window]   View larger version (18K): [in this window] [in a new window]   View larger version (20K): [in this window] [in a new window]   Fig 1. Mobilization of hematopoietic cells into peripheral blood in response to cyclophosphamide. Peripheral blood was obtained at the indicated times after a single intraperitoneal injection of 200 mg/kg of cyclophosphamide and analyzed for (A) absolute neutrophil count (ANC), (B) colony-forming cells (CFU-C), and (C) CD34+ lineage- progenitors as described in Materials and Methods. Four to six age- and sex-matched mice were analyzed at each time point. Data represent the mean ± SEM. View larger version (10K): [in this window] [in a new window]   Fig 2. Mobilization of day 12 CFU-S into the peripheral blood after cyclophosphamide. Peripheral blood from donor mice was obtained 8 days after cyclophosphamide and 200 µL injected into each of five lethally irradiated recipient mice. Recipient mice were killed 12 days later and macroscopic spleen colonies enumerated (CFU-S [d12]). Two age- and sex-matched donor mice of each genotype were analyzed. The horizontal bars represent the mean of the data. To exclude the possibility that the lack of an increase in peripheral HPC was due to an inability of G-CSFR-deficient mice to regenerate HPC after cyclophosphamide administration, we quantitated CFU-C in the BM, spleen, and blood of these mice (Fig 3 and Table 1). A similar increase from baseline of total body CFU-C was observed in wild-type and G-CSFR-deficient mice (Table 1) and, in fact, the absolute number of CFU-C present in the BM of G-CSFR-deficient mice on day 8 after cyclophosphamide administration was significantly increased relative to wild-type mice. However, despite the increase in total body CFU-C, no redistribution of these CFU-C from the BM to peripheral blood or spleen was observed. Interestingly, mature neutrophils (PMN) showed a similar pattern; the number of PMN in the BM was increased without a concomitant increase in circulating PMN (Table 1). Similar analyses were performed on day 12 after cyclophosphamide administration and showed that the number of CFU-C in the BM, spleen, and blood of both wild-type and G-CSFR-deficient mice had returned to near baseline levels (data not shown). View larger version (20K): [in this window] [in a new window]   Fig 3. Tissue distribution of hematopoietic progenitors after cyclophosphamide administration. Bone marrow (BM), spleen, and peripheral blood were obtained 8 days after cyclophosphamide and assayed for colony-forming cell (CFU-C) content. The baseline level of CFU-C present in each tissue is indicated by arrowheads. Four to six age- and sex-matched mice were analyzed. Data represent the mean ± SEM. (), Wild type; (), G-CSFR (-/-).   View this table: [in this window] [in a new window]   Table 1. Tissue Distribution of Neutrophils and Hematopoietic Progenitors at Baseline or Following Cyclophosphamide or flt-3 Ligand Treatment A recent report suggested that the magnitude of HPC mobilization after G-CSF varied significantly between mouse strains.32 We therefore examined the HPC mobilization response to cyclophosphamide in inbred 129 SvJ G-CSFR deficient mice. No increase from baseline in peripheral blood or spleen CFU-C was detected on day 8 after cyclophosphamide administration in 129 SvJ G-CSFR (-/-) mice despite a significant increase (albeit less than wild-type C57BL/6 × 129 SvJ outbred mice) in circulating CFU-C in wild-type 129 SvJ mice (data not shown). Collectively, these results clearly show that the G-CSFR is required for HPC mobilization in response to cyclophosphamide treatment in mice. The Mobilization of CFU-C in Response to IL-8 Is Impaired in G-CSFR-Deficient Mice The chemokine IL-8 mobilizes HPC with kinetics distinct from cytotoxic therapy or hematopoietic growth factors; IL-8 administration in mice33 or rhesus monkeys34 induces a much more rapid increase (within 15 to 30 minutes) in circulating HPC raising the possibility that distinct mechanisms of HPC mobilization are being used. To determine whether IL-8-induced mobilization also requires the G-CSFR, we challenged G-CSFR-deficient mice with IL-8 (Fig 4). Although both wild-type and G-CSFR-deficient mice had the expected transient neutropenia after IL-8 administration, only the wild-type mice had the expected rebound neutrophilia (Fig 4A). As reported previously,33 IL-8 administration in wild-type mice induced a rapid (peak response at 15 minutes) fourfold increase in circulating CFU-C. In contrast, no increase in circulating CFU-C was detected at any time after IL-8 administration in G-CSFR-deficient mice. Similar results were obtained with 129/SvJ G-CSFR-deficient mice (data not shown). These results indicate that the G-CSFR also is required for IL-8-induced HPC mobilization in mice. View larger version (16K): [in this window] [in a new window]   View larger version (20K): [in this window] [in a new window]   Fig 4. Mobilization of hematopoietic cells into peripheral blood after IL-8 administration. Peripheral blood was obtained at the indicated times after a single intraperitoneal injection of 30 µg of human recombinant IL-8 and analyzed for (A) absolute neutrophil count (ANC) and (B) colony-forming cells (CFU-C). Four to six age- and sex-matched mice were analyzed at each time point. Data represent the mean ± SEM. The Mobilization of HPC in Response to flt-3 Ligand Is Near Normal in G-CSFR-Deficient Mice The hematopoietic cytokine flt-3 ligand is a potent stimulator of HPC mobilization in mice.10 However, unlike G-CSF, the administration of flt-3 ligand in mice leads to an absolute increase in total body HPC as well as a redistribution of HPC from the BM to the periphery.10 Therefore, we examined the ability of flt-3 ligand to induce HPC mobilization in G-CSFR-deficient mice (Fig 5 and Table 1). Although reduced relative to wild-type mice, flt-3 ligand administration for 10 days resulted in a significant expansion of total body CFU-C in G-CSFR-deficient mice. Further, in sharp contrast to cyclophosphamide treatment, treatment with flt-3 ligand clearly resulted in the redistribution of HPC from the BM to the spleen and blood (Table 1). Interestingly, flt-3 ligand treatment also resulted in the mobilization of PMN to the peripheral circulation. These data show that the G-CSFR is not required for flt-3 ligand-induced HPC mobilization. View larger version (21K): [in this window] [in a new window]   Fig 5. Tissue distribution of hematopoietic progenitors after flt-3 ligand administration. Bone marrow (BM), spleen, and peripheral blood were obtained after 10 days of treatment with flt-3 ligand and assayed for colony-forming cell (CFU-C) content. The baseline level of CFU-C present in each tissue is indicated by arrowheads. Five age- and sex-matched mice were analyzed. Data represent the mean ± SEM. (), Wild type; (), G-CSFR (-/-).     DISCUSSION Abstract Introduction Methods Results Discussion References Hematopoietic progenitors can be mobilized from the BM into the peripheral circulation in response to a number of stimuli including hematopoietic growth factors, cytotoxic agents, and certain chemokines. Despite significant differences in their biologic activities, these stimuli result in the mobilization of HPC with a similar phenotype, suggesting that a common mechanism for mobilization may exist. In this study we have examined the contribution of the G-CSFR to HPC mobilization and show that, in mice, the G-CSFR is required for mobilization by cyclophosphamide or IL-8 but not flt-3 ligand. Myeloablative therapy with or without hematopoietic growth factors is used extensively to mobilize HPC in patients.1 The mechanisms that mediate this response are unknown; however, a role for hematopoietic growth factors can be postulated because the level of certain hematopoietic growth factors is markedly elevated following myeloablative therapy.35,36 In this study, we show that G-CSFR-deficient mice have a marked defect in HPC mobilization in response to cyclophosphamide (as measured by CFU-C and CFU-S [d12] assays and by flow cytometry for CD34+ lineage- cells). Although none of these progenitor assays directly measure hematopoietic stem cell activity, it seems unlikely that mobilization of hematopoietic stem cells is normal in G-CSFR-deficient mice because the mobilization of hematopoietic stem cells is closely associated with mobilization of more committed HPC. The defect in HPC mobilization after cyclophosphamide in G-CSFR-deficient mice appears to be secondary to a failure to release HPC from the BM rather than to a failure to regenerate HPC since the total number of CFU-C present in these mice (at a time when peak HPC mobilization should have occurred) is actually increased relative to wild-type mice. These results may provide an explanation for the observation that G-CSF and cyclophosphamide act synergistically to mobilize HPC in mice20; cyclophosphamide may provide the major stimulus for HPC proliferation with G-CSF providing the stimulus for HPC migration from the BM. The chemokine IL-8 can induce HPC mobilization in mice33 and rhesus monkeys.34 Several observations have lead to the hypothesis that IL-8 activation of neutrophils may be critical for IL-8-induced HPC mobilization. First, the rapid kinetics of IL-8-induced mobilization (initial response within 5 minutes after parenteral administration) suggests a direct mechanism for IL-8.33,34 Second, neutrophils are the major known target for IL-8.37 Third, IL-8 is a potent activator and chemoattractant for neutrophils.37 Although controversial, receptors for IL-8 may be present on endothelial cells, suggesting that alterations in endothelial cell function also may be important for IL-8-induced mobilization.38,39 In the present study, we show that IL-8-induced HPC mobilization in G-CSFR-deficient mice is impaired. In isolated cases, we have observed G-CSFR-deficient mice that have normal levels of circulating neutrophils; these mice still fail to mobilize HPC in response to IL-8, suggesting that neutropenia per se is not solely responsible for the mobilization defect. Although the residual neutrophils in G-CSFR-deficient mice appear phenotypically normal as assessed by morphology, expression of myeloperoxidase, Gr-1, and CDllb, and by their ability to emigrate in response to intra-peritoneal thioglycollate,26 these results suggest that an unidentified functional defect in G-CSFR-deficient neutrophils may exist. Experiments are underway to examine the in vitro IL-8 responses of neutrophils isolated from G-CSFR-deficient mice. Flt-3 ligand is a potent stimulus for HPC mobilization in mice and, unlike G-CSF, results in an increase in total body HPC.10 Recently, G-CSF has been shown to act synergistically with flt-3 ligand to mobilize HPC.24,25 In this study, we show that flt-3 ligand-induced mobilization is essentially intact; although twofold fewer total body number of CFU-C were detected in G-CSFR-deficient mice relative to wild-type mice, the distribution of these progenitors into peripheral blood, spleen, and BM compartments was similar to wild-type mice. These observations show that the G-CSFR is not required for the efficient flt-3 ligand-induced migration of HPC from the BM to periphery. In this respect, it is interesting to note that flt-3 ligand treatment is not associated with the defect in neutrophil release from the BM noted after cyclophosphamide treatment. The submaximal increase in total body CFU-C in G-CSFR-deficient mice following flt-3 ligand treatment suggests two possibilities: that G-CSFR signals contribute significantly to flt-3 ligand-induced HPC proliferation in vivo, or that fewer flt-3 ligand responsive progenitors exist in G-CSFR-deficient mice. In support of the first possibility, a synergistic effect of G-CSF and flt-3 ligand on HPC proliferation has been detected in vitro.40 In summary, this study provides evidence that the G-CSFR plays an important and previously unexpected role in HPC mobilization. The G-CSFR is primarily expressed on hematopoietic cells including pluripotent and myeloid-committed progenitors and neutrophils.41 In addition, the G-CSFR is expressed on endothelial cells and can induce their proliferation in vitro.42 The current results suggests that G-CSFR signals generated in progenitor cells, neutrophils, or BM stromal endothelial cells are critical for mobilization. Studies are in progress to test this hypothesis and to further define the mobilization defect in G-CSFR-deficient mice.     FOOTNOTES    Submitted June 9, 1997; accepted July 16, 1997.    Supported by the James S. McDonnell Foundation.    Address reprint requests to Daniel C. Link, MD, Washington University Medical School, Division of Bone Marrow Transplantation and Stem Cell Biology, Box 8007, 660 S Euclid Ave, St Louis, MO 63110-1093.    The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hearly marked ``advertisment'' in accordance with 18 U.S.C. section 1734 solely to indicate this fact.     ACKNOWLEDGMENT We thank Nancy Link for her expert technical assistance. We thank Dr Joost Oppenheim for his assistance in obtaining the recombinant human IL-8.     REFERENCES Abstract Introduction Methods Results Discussion References 1. To L, Haylock D, Simmons P, Juttner C: The biology and clinical uses of blood stem cells. Blood 89:2233, 1997[Free Full Text] 2. Duhrsen U, Villeval J, Boyd J, Kannourakis G, Morstyn G, Metcalf D: Effects of recombinant human granulocyte colony-stimulating factor on hematopoietic progenitor cells in cancer patients. Blood 72:2074, 1988[Abstract/Free Full Text] 3. Molineux G, Pojda Z, Hampson IN, Lord BI, Dexter TM: Transplantation potential of peripheral blood stem cells induced by granulocyte colony-stimulating factor. Blood 76:2153, 1990[Abstract/Free Full Text] 4. Lane T, Law P, Maruyama M, Young D, Burgess J, Mullen M, Mealiffe M, Terstappen LW, Hardwick A, Moubayed M, Oldham F, Corringham R, Ho A: Harvesting and enrichment of hematopoietic progenitor cells mobilized into the peripheral blood of normal donors by granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF: Potential role in allogeneic marrow transplantation. Blood 85:275, 1995[Abstract/Free Full Text] 5. Socinski MA, Elias A, Schnipper L, Cannistra SA, Antman KH, Griffin JD: Granulocyte-macrophage colony stimulating factor expands the circulating haemopoietic progenitor cell compartment in man. Lancet 2:1194, 1988[Medline] [Order article via Infotrieve] 6. Grzegorzewski K, Komschlies K, Mori M, Kaneda K, Usui N, Faltynek C, Keller J, Ruscetti F, Wiltrout R: Administration of recombinant human interleukin-7 to mice induces the exportation of myeloid progenitor cells from the bone marrow to peripheral sites. Blood 83:377, 1994[Abstract/Free Full Text] 7. Jackson J, Yan Y, Brunda M, Kelsey L, Talmadge J: Interleukin-12 enhances peripheral hematopoiesis in vivo. Blood 85:2371, 1995[Abstract/Free Full Text] 8. Bodine D, Seidel N, Zsebo K, Orlic D: In vivo administration of stem cell factor to mice increases the absolute number of pluripotent hematopoietic stem cells. Blood 82:445, 1993[Abstract/Free Full Text] 9. Andrews R, Bensinger W, Knitter G, Bartelmez S, Longin K, Bornstein I, Appelbaum F, Zsebo K: The ligand for c-kit, stem cell factor, stimulates the circulation of cells that engraft lethally irradiated baboons. Blood 80:2715, 1992[Abstract/Free Full Text] 10. Brasel K, McKenna H, Morrissey P, Charrier K, Morris A, Lee CC, Williams D, Lyman S: Hematologic effects of flt3 ligand in vivo in mice. Blood 88:2004, 1996[Abstract/Free Full Text] 11. To L, Haylock D, Dowse T, Simmons P, Trimboli S, Ashman L, Juttner C: A comparative study of the phenotype and proliferative capacity of peripheral blood (PB) CD34+ cells mobilized by four different protocols and those of steady-phase PB and bone marrow CD34+ cells. Blood 84:2930, 1994[Abstract/Free Full Text] 12. Simmons P, Leavesley D, Levesque J-P, Swart B, Haylock D, To L, Ashman L, Juttner D: The mobilization of primitive hemopoietic progenitors into the peripheral blood. Polyfunctionality of hemopoietic regulators: The Metcalf forum. Stem Cells 12:187, 1994 (suppl 1) 13. Mohle R, Haas R, Hunstein W: Expression of adhesion molecules and c-kit on CD34+ hematopoietic progenitor cells: Comparison of cytokine mobilized blood stem cells with normal bone marrow and peripheral blood. J Hematother 2:483, 1993[Medline] [Order article via Infotrieve] 14. Dercksen M, Gerritsen W, Rodenhuis S, Dirkson M, Slaper-Cortenbach I, Schaasberg W, Pinedo H, Borne Avd, Schoot Cvd: Expression of adhesion molecules on CD34+ cells: CD34+ L-selectin+ cells predict a rapid platelet recovery after peripheral blood stem cell transplantation. Blood 85:3313, 1995[Abstract/Free Full Text] 15. Papayannopoulou T, Nakamoto B: Peripheralization of hemopoietic progenitors in primates treated with anti-VLA4 integrin. Proc Natl Acad Sci USA 90:9374, 1993[Abstract/Free Full Text] 16. Papayannopoulou T, Craddock C, Nakamoto B, Priestley G, Wolf N: The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen. Proc Natl Acad Sci USA 92:9647, 1995[Abstract/Free Full Text] 17. Roberts A, Metcalf D: Noncycling state of peripheral blood progenitor cells mobilized by granulocyte colony-stimulating factor and other cytokines. Blood 86:1600, 1995[Abstract/Free Full Text] 18. Ponchio L, Conneally E, Eaves C: Quantitation of the quiescent fraction of long-term culture-initiating cells in normal human blood and marrow and the kinetics of their growth factor-stimulated entry into S-phase in vitro. Blood 86:3314, 1995[Abstract/Free Full Text] 19. Uchida N, He D, Friera A, Reitsma M, Sasaki D, Chen B, Tsukamoto A: The unexpected G0/G1 cell cycle status of mobilized hematopoietic stem cells from peripheral blood. Blood 89:465, 1997[Abstract/Free Full Text] 20. Neben S, Marcus K, Mauch P: Mobilization of hematopoietic stem and progenitor cell subpopulations from the marrow to the blood of mice following cyclophosphamide and/or granulocyte colony-stimulating factor. Blood 81:1960, 1993[Abstract/Free Full Text] 21. Schwartzberg L, Birch R, Hazelton B, Tauer K, Lee P, Altemose M, George C, Blanco R, Wittlin F, Cohen J, Muscato J, West W: Peripheral blood stem cell mobilization by chemotherapy with and without recombinant human granulocyte colony-stimulating factor. J Hematother 1:317, 1992[Medline] [Order article via Infotrieve] 22. Yan X-Q, Hartley C, McElroy P, Chang A, McCrea C, McNiece I: Peripheral blood progenitor cells mobilized by recombinant human granulocyte colony-stimulating factor plus recombinant rat stem cell factor contain long-term engrafting cells capable of cellular proliferation for more than two years as shown by serial transplantation in mice. Blood 85:2303, 1995[Abstract/Free Full Text] 23. Bodine D, Seidel N, Orlic D: Bone marrow collected 14 days after in vivo administration of granulocyte colony-stimulating factor and stem cell factor to mice has 10-fold more repopulating ability than untreated bone marrow. Blood 88:89, 1996[Abstract/Free Full Text] 24. Molineux G, McCrea C, Yan X, Kerzic P, McNiece I: Flt-3 ligand synergizes with granulocyte colony-stimulating factor to increase neutrophil numbers and to mobilize peripheral blood stem cells with long-term repopulating potential. Blood 89:3998, 1997[Abstract/Free Full Text] 25. Sudo Y, Shimazaki C, Ashihara E, Kikuta T, Hirai H, Sumikuma T, Yamagata N, Goto H, Inaba T, Fujita N, Nakagawa M: Synergistic effect of flt-3 ligand on the granulocyte colony-stimulating factor-induced mobilization of hematopoietic stem cells and progenitor cells into blood in mice. Blood 89:3186, 1997[Abstract/Free Full Text] 26. Liu F, Wu HY, Wesselschmidt R, Kornaga T, Link DC: Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor deficient mice. Immunity 5:491, 1996[Medline] [Order article via Infotrieve] 27. Liu F, Poursine-Laurent J, Wu H, Link DC: IL-6 and the G-CSF receptor are major independent regulators of granulopoiesis in vivo but are not required for lineage commitment or terminal differentiation. Blood 90:2583, 1997[Abstract/Free Full Text] 28. Graubert T, DiPersio J, Russell J, Ley T: Perforin/granzyme-dependent and independent mechanisms are both important for the development of graft-versus-host disease after murine bone marrow transplantation. J Clin Invest (in press) 29. Lord B: Haemopoiesis: A Practical Approach (ed 1). New York, NY, Oxford University Press, 1993 30. Morrison S, Wright D, Weissman I: Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization. Proc Natl Acad Sci USA 94:1908, 1997[Abstract/Free Full Text] 31. Craddock CF, Apperley JF, Wright EG, Healy LE, Bennett CA, Evans M, Grimsley PG, Gordon MY: Circulating stem cells in mice treated with cyclophosphamide. Blood 80:264, 1992[Abstract/Free Full Text] 32. Roberts A, Foote S, Alexander W, Scott C, Robb L, Metcalf D: Genetic influences determining progenitor cell mobilization and leukocytosis induced by granulocyte colony-stimulating factor. Blood 89:2736, 1997[Abstract/Free Full Text] 33. Laterveer L, Lindley I, Hamilton M, Willemze R, Fibbe W: Interleukin-8 induces rapid mobilization of hematopoietic stem cells with radioprotective capacity and long-term myelolymphoid repopulating ability. Blood 85:2269, 1995[Abstract/Free Full Text] 34. Laterveer L, Lindley I, Heemskerk D, Camps J, Pauwels E, Willemze R, Fibbe W: Rapid mobilization of hematopoietic progenitor cells in rhesus monkeys by a single intravenous injection of interleukin-8. Blood 87:781, 1996[Abstract/Free Full Text] 35. Rabinowitz J, Petros W, Stuart A, Peters W: Characterization of endogenous cytokine concentrations after high-dose chemotherapy with autologous bone marrow support. Blood 81:2452, 1993[Abstract/Free Full Text] 36. Haas R, Gericke G, Witt B, Cayeux S, Hunstein W: Increased serum levels of granulocyte colony-stimulating factor after autologous bone marrow or blood stem cell transplantation. Exp Hematol 21:109, 1993[Medline] [Order article via Infotrieve] 37. Hoch R, Schraufstatter I, Cochrane C: In vivo, in vitro, and molecular aspects of interleukin-8 and the interleukin-8 receptors. J Lab Clin Med 128:134, 1996[Medline] [Order article via Infotrieve] 38. Koch A, Polverini P, Kunkel S, Harlow L, DiPietro L, Elner V, Strieter R: Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258:1798, 1995 39. Schonbeck U, Brandt E, Petersen F, Flad H, Loppnow H: IL-8 specifically binds to endothelial but not to smooth muscle cells. J Immunol 154:2375, 1995[Abstract] 40. Hudak S, Hunte F, Culpepper J, Menon S, Hannum C, Thompson-Snipes L, Rennick D: FLT3/FLK2 ligand promotes the growth of murine stem cells and the expansion of colony-forming cells and spleen colony-forming units. Blood 85:2747, 1995[Abstract/Free Full Text] 41. Demetri GD, Griffin JD: Granulocyte colony-stimulating factor and its receptor. Blood 78:2791, 1991[Free Full Text] 42. Bocchietto E, Guglielmetti A, Silvagno F, Taraboletti G, Pescarmona GP, Mantovani A, Bussolino F: Proliferative and migratory responses of murine microvascular endothelial cells to granulocyte-colony-stimulating factor. J Cell Physiol 155:89, 1993[Medline] [Order article via Infotrieve] © 1997 by The American Society of Hematology. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. Yamamura, K. Ohishi, M. Masuya, E. Miyata, Y. Sugimoto, S. Nakamura, A. Fujieda, H. Araki, and N. Katayama Ex Vivo Culture of Human Cord Blood Hematopoietic Stem/Progenitor Cells Adversely Influences Their Distribution to Other Bone Marrow Compartments After Intra-Bone Marrow Transplantation Stem Cells, February 1, 2008; 26(2): 543 - 549. [Abstract] [Full Text] [PDF] A. M. Wengner, S. C. Pitchford, R. C. Furze, and S. M. Rankin The coordinated action of G-CSF and ELR + CXC chemokines in neutrophil mobilization during acute inflammation Blood, January 1, 2008; 111(1): 42 - 49. [Abstract] [Full Text] [PDF] J.-P. Levesque, I. G. Winkler, J. Hendy, B. Williams, F. Helwani, V. Barbier, B. Nowlan, and S. K. Nilsson Hematopoietic Progenitor Cell Mobilization Results in Hypoxia with Increased Hypoxia-Inducible Transcription Factor-1{alpha} and Vascular Endothelial Growth Factor A in Bone Marrow Stem Cells, August 1, 2007; 25(8): 1954 - 1965. [Abstract] [Full Text] [PDF] Q.-s. Zhu, L. Xia, G. B. Mills, C. A. Lowell, I. P. Touw, and S. J. Corey G-CSF induced reactive oxygen species involves Lyn-PI3-kinase-Akt and contributes to myeloid cell growth Blood, March 1, 2006; 107(5): 1847 - 1856. [Abstract] [Full Text] [PDF] A. Hidalgo, A. J. Peired, L. A. Weiss, Y. Katayama, and P. S. Frenette The integrin {alpha}M{beta}2 anchors hematopoietic progenitors in the bone marrow during enforced mobilization Blood, August 15, 2004; 104(4): 993 - 1001. [Abstract] [Full Text] [PDF] J.-P. Levesque, F. Liu, P. J. Simmons, T. Betsuyaku, R. M. Senior, C. Pham, and D. C. Link Characterization of hematopoietic progenitor mobilization in protease-deficient mice Blood, July 1, 2004; 104(1): 65 - 72. [Abstract] [Full Text] [PDF] J. W. Watters, E. F. Kloss, D. C. Link, T. A. Graubert, and H. L. McLeod A mouse-based strategy for cyclophosphamide pharmacogenomic discovery J Appl Physiol, October 1, 2003; 95(4): 1352 - 1360. [Abstract] [Full Text] [PDF] S. N. Robinson, V. M. Pisarev, J. M. Chavez, R. K. Singh, and J. E. Talmadge Use of Matrix Metalloproteinase (MMP)-9 Knockout Mice Demonstrates that MMP-9 Activity Is not Absolutely Required for G-CSF or Flt-3 Ligand-Induced Hematopoietic Progenitor Cell Mobilization or Engraftment