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Stem Cells 2004;22:696-703 www.StemCells.com
© 2004 AlphaMed Press

Elevation of Platelet Activation Markers and Chemokines during Peripheral Blood Stem Cell Harvest with G-CSF

Shosaku Nomura, Norihito Inami, Shigenori Kanazawa, Toshiji Iwasaka, Shirou Fukuhara

First Department of Internal Medicine, Kansai Medical University, Osaka, Japan

Key Words. Peripheral blood stem cell harvest • Platelet-derived microparticle Granulocyte colony-stimulating factor

Correspondence: Shosaku Nomura, M.D., First Department of Internal Medicine, Kansai Medical University, 10–15 Fumizono-cho, Moriguchi, Osaka 570-8507, Japan. Telephone: 81-66-992-1001; Fax: 81-72-532-1113; E-mail: shosaku-n{at}mbp.ocn.ne.jp


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The kinetics of peripheral blood stem cell mobilization in response to recombinant human granulocyte colony-stimulating factor is well established. However, there have been few investigations of platelet activation markers during peripheral blood stem cell harvest. We measured the levels of the platelet activation markers, chemokines, and soluble factors in plasma obtained from patients undergoing peripheral blood stem cell harvest. The number of leukocytes, CD34+ cells, neutrophils, monocytes, and lymphocytes peaked on day 5 after granulocyte colony-stimulating factor treatment, but the numbers of eosinophils and basophils showed no significant change. Regulated on activation normally T-cell expressed and secreted (RANTES) level increased through day 10, and the monocyte chemotactic peptide-1 (MCP-1) level peaked on day 5. Platelet counts continued to increase through day 10. The level of thrombopoietin significantly increased on day 3, peaked on day 5, and decreased slightly by day 10. The levels of soluble CD40 ligand and soluble P-selectin increased up to day 5. The platelet-derived microparticle level peaked on day 5, and then began to decline. CD34+ cell numbers significantly correlated with those of leucocytes, neutrophils, monocytes, and lymphocytes, as well as levels of MCP-1, and the CD34+ cells exhibited changes similar to platelet-derived microparticles. The patterns of change in MCP-1, platelet-derived microparticles, and the CD34+ cell count are similar in that each peaks on day 5 and decreases thereafter. Further study is required to determine if a cause-and-effect relationship in their pattern of change exists among them.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The kinetics of peripheral blood stem cell (PBSC) mobilization in response to recombinant human granulocyte colony-stimulating factor (rhG-CSF) have been well established [1–3]. However, there have been few investigations on platelet activation markers during PBSC harvest.

Vesicles derived from the platelet membrane, known as microparticles, are detected when platelets are activated by collagen in vitro and are also found in the blood of patients with intravascular platelet lysis [4–6]. These platelet-derived microparticles (PDMPs) have been detected in various clinical situations associated with platelet activation [6–9]. In addition, some cytokines such as G-CSF, interleukin-6, and thrombopoietin (TPO) modulate platelet activation [5, 10–12]. Recently, it has been reported that PDMPs have roles in cell interaction, since they express functional adhesion receptors, including {alpha}IIbß3, P-selectin, and other platelet membrane receptors [5, 13–15]. In addition, it is reported that PDMPs bind to hematopoietic stem cells and enhance their engraftment [16, 17].

Chemokines are a superfamily of chemotactic cytokines. They activate and direct the migration of leucocytes [18–20]. Monocyte chemotactic peptide-1 (MCP-1) is a C-C chemokine for monocytes and can amplify the inflammatory response by recruiting additional peripheral blood monocytes across the vascular endothelium to the inflammatory site [21, 22]. Regulated on activation normally T-cell expressed and secreted (RANTES), another C-C chemokine, is a potent chemoattractant of memory T lymphocytes, monocytes, eosinophils, and basophils [23]. Stromal cell–derived factor-1 (SDF-1) is a CXC chemokine and a known chemotactic for lymphocytes and monocytes [24]. SDF-1 can induce platelet activation, and platelets are in contact with cells that produce chemokines. The CXCR4 molecule constitutes the receptor for the SDF-1 and is expressed on CD34+ cells [25, 26]. Both SDF-1 and its receptor are implicated in the migration of CD34+ cells in vivo [25–29]. We measured and compared levels of platelet activation markers, chemokines, and soluble factors in patients undergoing PBSC harvest, since they may participate in the process of PBSC mobilization by G-CSF.


   MATERIALS AND METHODS
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Between March 2000 and August 2002, 12 patients with malignant lymphoma having a poor prognosis were enrolled in this study. There were eight men and four women aged from 43 to 57 years (median: 49 years). Histopathological types of these patients were as follows: seven diffuse large B, three follicular large, one follicular mixed, and one marginal zone B type. All of them were scheduled for high-dose consolidation chemotherapy. Written informed consent was obtained from all of the patients. Fifteen nonmalignant controls were recruited from among our hospital staff and other individuals. None of the control subjects had any clinical evidence of malignancy, and none were taking any medications.

PBSC Harvest
For mobilization of PBSCs, the malignant lymphoma patients received priming chemotherapy consisting of CHOP-E (cyclophosphamide, doxorubicin, vincristine, prednisolone, and etoposide). All patients were treated with CHOP-E followed by the administration of rhG-CSF (filgrastim 300 µg/body). Leukapheresis was performed with a cell separator (COBE Spectra, Gambro, K.K., Tokyo). The procedure was commenced when the white blood cell count recovered to 1 x 109/L, and continued until the number of harvested mononuclear cells exceeded 3 x 108/kg body weight. A total blood volume of 10 L was processed in each apheresis session. The apheresis product was enriched for mononuclear cells, cryopreserved in 6% hydroxyethyl starch, 5% dimethyl sulfoxide, and 4% human albumin and then stored at –80°C.

CD34 Analysis
A sample of each leukapheresis product was analyzed according to the method of Bender et al. [30]. All samples were washed to remove platelets and were stained with a CD34 monoclonal antibody (QBEND-10, Immunotech, Marseilles, France) [31]. After staining, the erythrocytes were lysed with ammonium chloride. Flow cytometric analysis was performed using Ortho Cytoron Absolute (Ortho Diagnostic Systems, Tokyo), with 65,500 cells being analyzed per sample [32]. After gating for forward and right scatter, a second gate was drawn around the CD34+ low-right scatter population to determine the percentage of hematopoietic progenitors corrected for the control.

Assessment of PDMPs
PDMPs were detected using a modification of the previously reported method [4–6]. Whole blood anticoagulated with 3.8% sodium citrate (9:1, v/v) containing 0.8 µl/ml prostaglandin E1 was centrifuged at 200 g for 10 minutes at room temperature. After centrifugation, the supernatant consisting of dilute platelet-rich plasma was collected without disturbing the other fractions. Ten microliters of platelet suspensions (3x 108/ml) was added to 100 µl of HEPES/Tyrodes buffer containing 5 mmol/1 EGTA, and both intact and aggregated platelets were removed by centrifugation at 1000 g for 15 minutes to yield a supernatant that contained only PDMPs. Next, 10 µl of washed intact platelets (3 x 108/ml) was added to the supernatant, and incubation with KMP-9 (the fluorescein isothiocyanate [FITC]–labeled antiplatelet glycoprotein IX [GPIX] monoclonal antibody) [33] was performed for 30 minutes at room temperature and in the dark. After incubation, samples were diluted 1:10 with HEPES/Tyrodes buffer containing 5 mmol/1 EGTA and analyzed using an Ortho Cytoron Absolute analyzer (Ortho Diagnostic Systems). Only the cells and particles positive for GPIX were gated to distinguish platelets and PDMPs from electronic noise. To differentiate between platelets and PDMPs, the lower limit of the platelet gate was set at the left-hand border of the forward-scatter profile of resting platelets. Ten thousand FITC-positive particles in the PDMP gate were then counted to determine the number of PDMPs released per 10,000 platelets.

Chemokine Evaluation
We collected blood samples from the patients into plastic tubes and centrifuged them immediately afterward to obtain serum. The serum was divided into aliquots and frozen at –30°C until use. As a positive control, we used recombinant products in each assay, as well as the standard solutions provided with the commercial kits. We purchased human MCP-1, RANTES, and eotaxin enzyme-linked immunosorbent assay (ELISA) kits from BioSource International, Inc. (Camarillo, CA), and SDF-1 from R & D Systems (Minneapolis). Serum levels of cytokines were measured according to the manufacturers’ instructions. Normal ranges were as follows: MCP-1: 170–570 pg/ml, RANTES: 23.9–58.5 ng/ml, eotaxin: 66.2–199.5 pg/ml, and SDF-1: 1300–2800 pg/ml.

Measurement of Soluble P-selectin, Soluble CD40L, and TPO
The soluble P-selectin ELISA kit was from BioSource International, the soluble CD40L ELISA kit was from Chemicon International, Inc. (Temecula, CA), and the TPO ELISA kit was from IBL Inc. (Gunma, Japan). For measurement of soluble P-selectin, soluble CD40L, and TPO in serum, all kits were used according to the manufacturers’instructions. Normal ranges were as follows: soluble P-selectin: 111–266 ng/ml, soluble CD40L: 0.1–1.8 ng/ml, and TPO: 400–700 pg/ml.

Statistical Analysis
Results are shown as the mean ± standard deviation. The significance of differences in the variable was determined by analysis of variance (ANOVA). Student’s t-test and Scheffe’s F-test were used for statistical comparisons. Linear regression analysis was used to compare CD34+ cells and some other factors. A p value less than .05 was considered to indicate a significant difference.


   RESULTS
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Table 1Go shows the change of leukocytes and platelets before and after PBSC harvest. The numbers of all leucocytes, CD34+ cells, neutrophils, monocytes, and lymphocytes peaked on day 5 after rhG-CSF treatment. Neither the eosinophils nor the basophils showed any significant change. Platelet counts continued to increase up to day 10.


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  		Table 1. Levels of leukocytes before and after granulocyte colony-stimulating factor (G-CSF) treatment in patients with peripheral blood stem cell (PBSC) harvesting
 
Figure 1Go shows the changes in chemokines after PBSC harvest. Level of RANTES continued to increase up to day 10 (d5: p < .05, d10: p < .01). The level of MCP-1 peaked on day 5 (d3: p < .05, d5: p < .01). The level of SDF-1 slightly increased on day 3 and then began to decline; however, these changes were not significant. The level of eotaxin did not exhibit significant change.



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  		Figure 1. Changes of chemokines (ng/ml and pg/ml) after peripheral blood stem cell harvest. d1 to d10 are apheresis collections in 5 consecutive days. CNT was 15 healthy blood donors. Error bars represent + standard deviation. Student’s t-test was used for statistical comparisons.Abbreviations: CNT, control; MCP-1, monocyte chemotactic peptide-1; N.S., not significant; RANTES, regulated on activation normally T-cell expressed and secreted; SDF-1, stromal cell–derived factor-1.

 
Figure 2Go shows the changes in the platelet activation markers and TPO level after PBSC harvest. The levels of soluble CD40L and soluble P-selectin continued to increase up to day 5 (d5: p < .05, d10: p < .01). The level of PDMPs peaked on day 5 (d5: p < .01, d10: p < .05) and then began to decline. The level of TPO significantly increased on day 3 and peaked on day 5, and then decreased slightly after this (d3, d5, and d10: p < .01).



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  		Figure 2. Changes in platelet activation markers (ng/ml and 104 plt) and thrombopoietin (pg/ml) after peripheral blood stem cell harvest. d1 to d10 are apheresis collections in 5 consecutive days. Control was 15 healthy blood donors. Error bars represent + standard deviation. Student’s t-test was used for statistical comparisons. Abbreviations: CNT, control; N.S., not significant; PDMP, platelet-derived microparticle; plt, platelet; TPO, thrombopoietin.

 
Figure 3Go presents the results obtained by studying the correlation between CD34+ cells and other parameters after PBSC harvest. The CD34+ cells significantly correlated with leukocytes (p <.0001), neutrophils (p <.0001), monocytes (p <.0001), lymphocytes (p <.0031), and MCP-1 (p <.002). However, CD34+ cell number did not correlate with other parameters such as eosinophils, basophils, platelets, PDMPs, soluble P-selectin, soluble CD40L, TPO, RANTES, SDF-1, and eotaxin (data not shown).



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  		Figure 3. Correlations between CD34+ cells and some other factors before and after peripheral blood stem cell harvest. (A): WBCs. (B): Neutrophils. (C): Monocytes. (D): Lymphocytes. (E): MCP-1. CD34+ cell number was significantly correlated with numbers of leukocytes, neutrophils, monocytes, and lymphocytes and level of MCP-1. Student’s t-test and Scheffe’s F-test were used for statistical comparisons. Abbreviations: MCP-1, monocyte chemotactic peptide-1; WBC, white blood cell.

 
Figure 4Go shows the changes in CD34+ cells and PDMPs on days 0, 5, and 10 after PBSC harvest. PDMPs exhibited changes similar to those of CD34+ cells, although no significant difference between both types of cells was seen.




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  		Figure 4. Changes in CD34+ cells (µl) and PDMPs (104 plts) on days 0, 5, and 10 after peripheral blood stem cell harvest. PDMPs exhibited changes similar to those of CD34+ cells, although there was no significant correlation between the kinds of cells. Student’s t-test was used for statistical comparisons. Abbreviation: PDMP, platelet-derived microparticle.

 

   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The relationship between CD34+ cells and MCP-1 suggests that, on the one hand, the mobilization of CD34+ cells may be similar to the inflammatory conditions in which MCP-1 is involved. On the other hand, RANTES exhibited dynamic changes quite unlike MCP-1, and there was no correlation between RANTES and CD34+ cells. RANTES is a potent chemoattractant of memory T lymphocytes, monocytes, eosinophils, and basophils [23]. It also exists in platelets [34]. In the study reported here, the increase of RANTES seems to be related to platelet activation, since RANTES was in the dynamic phase similar to soluble CD40L and soluble P-selectin. This increase in RANTES may be involved in the mobilization of T cells and eosinophils after CD34+ cell mobilization. The levels of soluble CD40L and soluble P-selectin exhibited the same changes as CD34+ cells from day 0 to day 5. However, these platelet activation markers continued increasing after day 5, while CD34+ cells decreased. When CD34+ cells are mobilized into peripheral blood vessels, TPO has an important role [35]. In our study, TPO also correlated with platelet counts, as in a previous report. In addition, it is reported that TPO can activate platelets [5, 12]. Therefore, one of the reasons for the increases of soluble CD40L and soluble P-selectin at the time of CD34+ cell elevation appears to be increase in TPO.

We also measured SDF-1; SDF-1 is a multifunctional chemokine, and it has recently been reported that SDF-1 can activate platelets [36–38]. In our study, the involvement of SDF-1 in platelet activation in CD34+ cell mobilization appeared to be slight, since SDF-1 exhibited different changes, unlike the platelet activation markers. PDMPs exhibited changes similar to those of CD34+ cells, and this change was opposite those of soluble CD40L and soluble P-selectin. This suggests the possibility that PDMPs have a role in the elimination of CD34+ cells from peripheral blood vessels.

The CD34 antigen was found to have adhesion properties, although the exact ligand has not yet been identified [39]. In addition, CD34+ cells express well-defined adhesion molecules such as L-selectin and very late-acting antigen (VLA)–4 which are thought to play an important role in the release of CD34+ cells to the peripheral blood during mobilization and in homing to the bone marrow in the process of engraftment. In fact, the expression on CD34+ cells of adhesion molecules, such as VLA-4 and L-selectin, take placebo the extent of their correlations with the mobilization of PBSC [40–42]. In particular, Gazitt et al. [43] observed a marked decrease in the expression of L-selectin on CD34+ cells in the PBSC apheresis collections relative to the steady-state peripheral blood and bone marrow. This suggests that the mobilization of CD34+ cells to the peripheral blood seems essential to prevent their adhesion to the endothelial cells in the peripheral blood vessels, which seems to be the optimum condition for the differentiation of mobilized CD34+ cells that have matured in the blood vessels. However, it is difficult to imagine that all mobilized CD34+ cells are differentiated; instead, it seems likely that some CD34+ cells will home to the bone marrow. For this reason, a mechanism is needed for upregulating the adhesive molecules of the CD34+ cells. We considered that CD34+ cells have a role in upregulation of these adhesion molecules, since PDMPs exhibited changes similar to those of CD34+ cells after day 5. In addition, it is reported that PDMPs bind to hematopoietic stem cells and enhance their engraftment [16]. Moreover, PDMPs directly promote leukocyte–leukocyte interaction and may have caused upregulation of adhesive molecules [13–15]. Our results suggest that platelet activation may be related to the disappearance of CD34+ cells from the peripheral blood vessels.

PDMPs express P-selectin on the surface [44]. In addition, PSGL-1, which is the ligand of P-selectin, is broadly expressed in cells of myeloid, lymphoid, and dendritic lineage and in some nonhematopoietic cells [45]. It is reported that CD34+ cells also possess hematopoietic progenitors [46], and a hematopoiesis stop, when P-selectin reacts with PSGL-1 [47]. As described previously, the expression of VLA-4 and L-selectin on the CD34+ cells newly mobilized to the peripheral blood was decreased, and adhesion to the blood vessels becomes difficult. Selectin may generate an outside-to-inside signal when it binds to the ligand [48]. Thus, when P-selectin on PDMPs binds to the PSGL-1 on the CD34+ cell, it may cause upregulation of the adhesive molecule. In this manner, PDMP generation after PBSC harvesting seems to relate to the differentiation and migration of CD34+ cells. However, further examination is necessary to establish the exact mechanism.


   ACKNOWLEDGMENTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
This work was partly supported by a grant from the Japan Foundation of Cardiovascular Research and by a Research Grant for Advanced Medical Care from the Ministry of Health and Welfare of Japan.


   REFERENCES
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received April 23, 2003; accepted for publication August 5, 2003.



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STEM CELLS THE ONCOLOGIST CME ALPHAMED PRESS JOURNALS
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