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,
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Department of Pediatrics and
Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan;
Shinshu University Graduate School of Medicine, Institute of Organ Transplants, Reconstructive Medicine and Tissue Engineering, Matsumoto, Japan;
Blood Transfusion Service, Shinshu University Hospital, Matsumoto, Japan;
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Department of Pediatrics, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki, Japan;
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Department of Pediatrics, University of Tokushima, Tokushima, Japan;
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Pharmaceutical Research Laboratory, Kirin Brewery Co. Ltd., Takasaki, Japan; and
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Medical Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RI). Mast cells
originate from pluripotent hemopoietic cells within the marrow. Mast
cell progenitors depart from the bone marrow
(BM)3 and migrate into
the connective or mucous tissues, where they differentiate into the
mature form. In the human system, mast cell progenitors are positive
for CD34, c-kit, CD13, and CD38, but lack HLA-DR
(6, 7, 8, 9). Stem cell factor (SCF) has been reported to act as
a major growth and differentiation factor for the human mast cell
development from cord blood mononuclear cells (10), BM
cells (11, 12), and fetal liver cells (13).
In contrast, our recent study showed that the addition of
thrombopoietin (TPO) to culture containing SCF is a requisite for
the significant production of mast cells from
CD34+ BM cells (14). It is demonstrated that PBMCs or CD34+ cells generate mast cells in the presence of SCF with or without IL-3 (7, 12). In addition, Rottem et al. (7) reported that the number of mast cells arising per CD34+ cell is greater in patients with aggressive mastocytosis than normal subjects. However, little is known about the kinetics of mast cell progenitors in allergic disorders. In this study, we compared the production of mast cells from CD34+ peripheral blood (PB) cells between asthmatic patients and normal controls, using a serum-deprived culture system.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six normal donors for allogeneic PB stem cell transplantation aged 7.5 ± 4.7 (range, 3–15) years were enrolled in this study. They had no known diseases including allergic disorders, and took no medications. All donors and/or their parents provided written informed consent. Donors received G-CSF (Chugai Pharmaceutical, Tokyo, Japan) s.c. at a dose of 10 µg/kg for 5 consecutive days, and blood sampling was performed on day 5. The protocol was approved by the ethics committee of Shinshu University School of Medicine.
PB samples (10 ml) were harvested by venous puncture from a total of 10
males and three females with bronchial asthma aged 6.5 ± 4.0
(2–15) years after obtaining the fully informed consent of each
patient and/or the parents. The asthma was defined according to the
criteria of the American Thoracic Society. Twelve aged-matched healthy
subjects and three nonallergic patients with lower respiratory tract
infection were used as the control group. Based on the guidelines for
the diagnosis and management of asthma established by the National
Heart, Lung, and Blood Institute (15), five cases were
classified as mild and the rest as moderate. None of the patients had
had an asthmatic attack within 1 month before the study. In moderate
cases, oral theophylline with or without a 
-adrenergic agonist was
given. All medications were withdrawn 12 h before blood sampling.
The mean PB eosinophil count was 0.83 ± 0.27 x
109/L (0.56–1.36 x
109/L), and the total serum IgE concentration was
1448 ± 1340 IU/ml (256–4711 IU/ml). All of the patients had
positive immediate skin reactions to several Ags including house dust
mite. Specific IgE against mite Ag was scored as 4 or more in all of
the patients according to the radioimmunosorbent assay. PB samples were
also collected from two infants with atopic dermatitis, and from a
6-year-old boy with allergic rhinitis after informed consent.
Cytokines, reagents, and Abs
Human recombinant SCF, TPO, and IL-3 were provided by Kirin Brewery (Takasaki, Japan). Human recombinant IL-6 was a gift from Ajinomoto (Kawasaki, Japan).
For immunocytochemical staining, purified mAbs for tryptase (MAB1222) and chymase (3D5) were purchased from Chemicon International (Temecula, CA) and Biogenesis (Sandown, NH), respectively. Anti-CD2 mAb (T11) and anti-CD41 mAb (SZ.22) were obtained from Immunotech (Marseilles, France). Anti-CD11b mAb (2LPM19c), anti-CD15 mAb (C3D-1), anti-CD19 mAb (HD37), and anti-glycophorin A (anti-GPA) mAb (JC159) were obtained from Dako (Glostrup, Denmark).
For the flow cytometric analysis and cell sorting, mAbs for CD34 (8G12, FITC) and c-kit (104D2, PE) were purchased from Becton Dickinson Immunocytometry Systems (Mountain View, CA). The mAb for CD13 (Immu103.44, PE-cyanin 5.1, PC5) was obtained from Immunotech.
Cell preparation
PB samples were aspirated in heparinized plastic syringes. PBMCs were separated by density centrifugation over Ficoll-Paque (Pharmacia, Piscataway, NJ), washed twice, and suspended in Ca2+- and Mg2+-free PBS containing 1 mmol/L EDTA-2Na and 2.5% FBS (HyClone, Logan, UT). After treatment with Silica (Immuno-Biological Laboratories, Fujioka, Japan) for 30 min at 37°C, CD34-positive cells were enriched using a Dynal CD34 Progenitor Cell Selection System (Dynal, Oslo, Norway). Briefly, 1–4 x 107 cells were mixed with the same number of polystyrene beads coated with mAb specific for CD34 (Dynabeads M-450 CD34) and incubated for 30 min at 4°C. Bead-rosetted cells were separated by a magnet. For the detachment of the beads from the cells, affinity-purified polyclonal Abs against the Fab portion of anti-CD34 Ab (Detach-a-Bead CD34) were added, and incubation was conducted for 45 min at room temperature. The detached beads were removed by the magnet, and the cells were collected as CD34+ cells. Approximately 90% of the isolated cells were CD34-positive, as determined by FACScan flow cytometry (Becton Dickinson).
Suspension cultures
Unless otherwise specified, serum-deprived liquid cultures were
conducted in 24-well culture plates (no. 3047; Becton Dickinson) using
a modification of the technique described previously (14, 16, 17, 18). CD34+ cells (2 x
104/well) were cultured in 2 ml of 
-medium
supplemented with 1% deionized BSA; 300 µg/ml fully iron-saturated
human transferrin (
98% pure; Sigma); 16 µg/ml soybean lecithin
(Sigma); 9.6 µg/ml cholesterol (Nacalai Tesque, Kyoto, Japan); and 10
ng/ml of SCF, 10 ng/ml of TPO, 100 U/ml of IL-3, or 50 ng/ml of IL-6,
alone or in combination. In dose-response studies,
CD34+ cells were plated at 1 x
104 cells in a well containing 200 µl of the
serum-free culture medium. The plates were incubated at 37°C in a
humidified atmosphere flushed with a mixture of 5%
CO2, 5% O2, and 90%
N2. Half of the culture medium was replaced
weekly with fresh medium containing the factor(s). The number of viable
cells was determined by a trypan-blue exclusion test using a
hemocytometer. We presented the actual counts of progeny in the
results. Preliminary experiments showed that SCF at 10 ng/ml or higher
was required for maximal cell growth by mobilized
CD34+ cells in the presence of 10 ng/ml of
TPO.
Serum-deprived single-cell culture
Single-cell sorting was performed by a two-step process, as described previously (14, 16, 17). PBMCs (1–4 x 107) were incubated with 20 µl of FITC-conjugated anti-CD34 mAb for 30 min at 4°C. As negative controls, the cells were stained with FITC-conjugated mouse IgG1 (Becton Dickinson). After two washes, CD34+ cells were individually sorted in 5-ml tubes by a FACStarPlus flow cytometer. The percentages of CD34+ cells in PBMCs were 0.13 ± 0.10% (0.03–0.21%) in asthmatic children and 0.26 ± 0.26% (0.09–0.64%) in normal controls. The CD34+ cells were then resorted into individual wells of a 96-well U-bottom tissue culture plate (no. 3077; Becton Dickinson) containing 100 µl of serum-deprived culture medium supplemented with 10 ng/ml of SCF with or without 10 ng/ml of TPO, using the FACStarPlus flow cytometer equipped with an automatic cell deposition unit (Becton Dickinson). Ninety-nine percent of the wells contained a single cell on the first day of culture. The plates were incubated at 37°C in a humidified atmosphere flushed with a mixture of 5% CO2, 5% O2, and 90% N2. If the constituent cells numbered 20 or more at 4 wk under direct microscopic visualization, aggregates were scored as colonies. Then, colonies were picked up with a 3-µl Eppendorf micropipette and pooled. The constituent cells were stained with anti-tryptase mAb.
Flow cytometric analysis
For the analysis of surface markers on CD34+ PB cells, 1–2 x 107 PBMCs were incubated with 20 µl FITC-conjugated anti-CD34 mAb, 20 µl PE-conjugated anti-c-kit mAb, and 10 µl PC5-conjugated anti-CD13 mAb for 30 min at 4°C, as described previously (14). The cells were washed twice, after which their surface markers were analyzed with the FACScan flow cytometer, using the Lysis 2 software program. The lymphoblastic region was gated on the basis of their forward light and side scatter characteristics. Then, the second gate was set on CD34+ cells. The expressions of c-kit and CD13 on CD34+ cells were examined. The proportion of positive cells was determined by comparison to cells stained with FITC-, PE-, or PC5-conjugated mouse isotype-matched Ig.
Immunocytochemical staining
The cultured cells were spread on glass slides using a Cytospin II (Shandon Southern, Sewickly, PA) and stained with May-Grünwald-Giemsa or peroxidase. Reactions with mouse mAbs against tryptase, chymase, CD2, CD11b, CD15, CD19, CD41, and GPA were detected using the alkaline phosphatase-anti-alkaline phosphatase (APAAP) method (Dako APAAP Kit System; Dako, Carpinteria, CA), as described previously (19). The isotype mouse mAb was also used as a control. Briefly, cytocentrifuged samples were fixed with Carnoy’s fluid, washed with PBS, and preincubated with normal rabbit serum to saturate the Fc receptors on the cell surface. After being washed with PBS three times, the samples were reacted with each of the mouse mAbs for 30 min at room temperature in a humidified chamber. After three more washes with PBS, the samples were incubated with rabbit anti-mouse IgG Ab, washed three times, and successively reacted with the calf intestinal alkaline phosphatase-mouse monoclonal anti-alkaline phosphatase complex. Finally, alkaline phosphatase activity was detected with naphthol AS-MX phosphate, Fast Red TR, and levamisole to inhibit nonspecific alkaline phosphatase activity. The specimens were counterstained with hematoxylin. Three hundred cells were examined.
Assay of histamine and cytokine levels
Histamine concentrations in the cell lysates obtained by the treatment of 6-wk cultured cells (5 x 104) grown with SCF or SCF+TPO with 0.5 ml of 1% Triton X-100 containing 0.5 M KCl were measured with the Histamine Enzyme Immunoassay Kit (Immunotech). The detection limit was 1 nM. All assays were conducted in triplicate.
Tryptase and chymase enzymatic assay
Tryptase and chymase enzymatic activities were measured according to the procedure described by Xia et al. (20). The cultured cells (5 x 104) grown with SCF or SCF+TPO were lysed with 0.5 ml of 1% Triton X-100 containing 0.5 M KCl, and sonicated. Aliquots (20 µl) of the samples were incubated with 0.2 mM tosyl-Gly-Pro-Lys-p-nitroanilide (Sigma), 50 mM HEPES (pH 7.6) containing 0.12 M NaCl, 100 µg/ml of a soybean trypsin inhibitor (Sigma), and 1 µg/ml of heparin sulfate proteoglycan (Sigma) in a total volume of 180 µl at 37°C for 1 h. The release of p-nitroaniline was determined spectrophotometrically. As a control, we used p-nitroaniline purchased from Sigma. The addition of PMSF (Nacalai Tesque) at 1 x 10-3 M reduced the levels of tryptase enzymatic activity by 87.3%. For the assay of chymase enzymatic activity, aliquots of the samples (20 µl) were incubated with 0.2 mM succinyl-Ala-Ala-Pro-Phe-MCA (Peptide Institute, Osaka, Japan), 100 mM Tris (pH 7.8) containing 2 M NaCl, and 150 µg/ml of aprotinin (Sigma) in a total volume of 180 µl at 37°C for 1 h. Reactions were stopped by the addition of 200 µl of 10% SDS (Sigma) and 2 ml of 100 mM Tris (pH 9.0). The release of MCA was measured spectrofluorometrically. As a control, we used MCA obtained from Peptide Institute. The addition of chymostatin (Sigma) at 3.3 x 10-8 M to 3.3 x 10-4 M almost completely suppressed the release of MCA.
Statistical analysis
The results are expressed as means ± SD. To determine the significance of difference between two independent groups, we used the unpaired t test or Mann-Whitney U test when or if the data were not normally distributed. To compare the size of mast cell colonies, the unpaired t test was performed on logarithms of the cell numbers of individual colonies. One-way ANOVA, followed by post hoc contrasts with the Bonferroni limitation, was used for more than three independent groups.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We examined the effects of SCF (10 ng/ml), TPO (10 ng/ml), IL-3
(100 U/ml), and IL-6 (50 ng/ml), alone or in combination, on the
generation of mast cells from CD34+ PB cells
mobilized with G-CSF in serum-deprived liquid cultures. Half of the
culture medium was replaced weekly with fresh medium containing the
factor(s). As presented in Fig. 1
, SCF
alone induced the production of significant numbers of progeny from
CD34+ PB cells, with a peak of 3 times the
input quantity at 6 wk. The number of viable cells decreased at 8 wk.
In the presence of TPO, IL-3, and IL-6 alone, the total cell number in
a well estimated at 2 wk was 6400 ± 800, 3500 ± 900, and
1200 ± 200, respectively. Subsequently, the cell numbers were not
measurable. The addition of IL-6 significantly reduced the number of
progeny grown with SCF, consistent with the previous result
(17). In the presence of SCF and IL-3, the total cell
number was maintained from 2 to 6 wk. Two-thirds of 6-wk cultured cells
reacted with anti-tryptase mAb, and some of the remaining cells
were positive for peroxidase. In contrast, the addition of TPO caused a
significant enhancement of the SCF-dependent cell generation from
CD34+ PB cells. The number of viable cells
reached maximal at 6 wk, and was 5- to 6-fold that at the beginning of
the culture. There was a decline in the number of viable cells at
8 wk.
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70% of the cultured cells became
positive for tryptase at 2 wk. A large portion of the cultured cells
reacted with anti-tryptase mAb after 4 wk. Although the frequency
of chymase+ cells was at a negligible or very low
level at 2 wk, the percentage of the cells positive for chymase
increased to 80–90% at 4 wk. It is of interest that the relative
numbers of both tryptase+ cells and
chymase+ cells in the cultured cells generated by
stimulation with SCF+TPO increased in parallel with the values in the
cells grown with SCF alone during 8 wk. At 6 wk of the culture with SCF
alone or SCF+TPO, the cells with other lineage-specific markers (CD2,
CD19, CD11b, CD15, CD41, or GPA) were at negligible levels. Asthmatic patients have more circulating hemopoietic progenitors with a potential to differentiate into mast cell lineage than normal controls
The combination of SCF and TPO was the most favorable stimulus for
mast cell growth from CD34+ PB cells of asthmatic
patients as well as from those mobilized with G-CSF. The numbers of
tryptase+ cells grown at 4 wk by 1 x
104 CD34+ PB cells were
20,700 ± 2,000 in SCF alone; 61,400 ± 9,000 in SCF+TPO;
17,700 ± 2,100 in SCF+IL-6; and 23,800 ± 3,100 in SCF+IL-3.
Then, we compared the ability of CD34+ PB cells
to generate mast cells between asthmatic children in a stable condition
and controls. The results are presented in Fig. 2. CD34+ PB cells
(2 x 104) from healthy children generated
12,500 ± 6,300 cells at 6 wk of the culture with SCF+TPO. The
numbers of the cultured cells from nonallergic patients with lower
respiratory tract infection were 8300 ± 8100, being similar to
the values obtained by healthy subjects. In contrast,
CD34+ PB cells of asthmatic patients had a
significantly higher potential to generate the progeny than did those
of nonallergic controls (p < 0.01). A
substantial difference was also observed in the culture containing SCF
alone (84,000 ± 6,500 cells from 2 x
104 CD34+ PB cells of three
asthmatic children, and 3500 ± 1600 cells in three healthy
subjects). Furthermore, in the presence of TPO,
CD34+ PB cells from asthmatic children responded
to a suboptimal concentration of SCF (1 ng/ml) to a greater extent than
those from normal controls (Fig. 3). In
both asthmatic individuals and nonallergic control subjects, >99% of
6-wk cultured cells were positive for tryptase, and >95% of them
positive for chymase. However, an increase in the generation of mast
cells from CD34+ PB cells was found in a part of
patients with other allergic disorders (Fig. 2).
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. In the presence
of SCF+TPO, significantly greater numbers of colonies were formed in
the cultures containing CD34+ PB cells from
patients with asthma, as compared with the values obtained by normal
controls. A prominent difference was also noted in the culture with SCF
alone. A majority of the constituent cells of pooled colonies were
positive for tryptase under stimulation with SCF alone or SCF+TPO in
children with or without asthma. There was no significant difference in
the size of mast cell colonies formed in the presence of SCF+TPO
between asthmatic children and normal controls. The mean number of
constituent cells in mast cell colonies was 70 ± 84 (20–312) in
patient 1, 89 ± 129 (20–500) in patient 2, 28 ± 7 (23–48)
in patient 3, 110 ± 258 (20–1300) in patient 4, and 66 ±
89 (20–400) in the controls. As it has been demonstrated that most of
the human mast cells originate from
CD34+c-kit+ cells or
from
CD34+c-kit+CD13+
cells (6, 9), we investigated whether relative numbers of
these particular CD34+ cell subsets were also
increased in CD34+ PB cells of patients with
asthma. The results are presented in Table II. There was no significant difference
in the proportion of c-kit+ cells or
c-kit+CD13+ cells in
CD34+ cells between asthmatic children and normal
controls.
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Finally, we compared intracellular levels of histamine and proteases of 6-wk-old cultured cells between asthmatic subjects and normal individuals. To estimate the cellular amounts of tryptase and chymase protein, we measured protease enzymatic activity in a total of 5 x 104 cells, as described by Xia et al. (20). In addition, we used the cultured mast cells derived from G-CSF-mobilized CD34+ PB cells of nonasthmatic individuals as controls, because of the paucity of mast cells grown from normal steady-state CD34+ PB cells. There were no significant differences in intracellular histamine content and tryptase/chymase enzymatic activities between the two groups. The histamine concentration of 5 x 104 6-wk cultured cells grown with SCF (10 ng/ml) + TPO (10 ng/ml) from CD34+ PB cells was 1508 ± 532 nM (826–2197 nM) in asthmatic patients, and 2097 ± 1079 nM (739–3667 nM) in controls. Tryptase enzymatic activity of them was 5284 ± 2124 µM (3434–9336 µM) in asthmatic patients, and 3519 ± 1439 µM (1634–5631 µM) in controls. Chymase enzymatic activity of them was 16.0 ± 8.8 µM (7.5–28.8 µM) in asthmatic patients, and 28.5 ± 23.8 µM (3.7–62.1 µM) in controls.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Rottem et al. (7) demonstrated that IL-3 substantially increases the numbers of mast cells grown with SCF from CD34+ PB cells. In contrast, Valent et al. (12) found IL-3-mediated down-regulation of SCF-dependent mast cell formation in long-term cultures. In this study, the addition of IL-3 to the culture containing SCF failed to augment the generation of mast cells both from G-CSF-mobilized CD34+ PB cells and from CD34+ PB cells obtained without G-CSF. In contrast, a combination of SCF and TPO exerted a prominent synergism on the production of mast cells from CD34+ PB cells obtained with or without G-CSF treatment. The time course study of the culture containing mobilized CD34+ PB cells showed that relative numbers of both tryptase+ cells and chymase+ cells in the cultured cells grown under stimulation with SCF+TPO increased in parallel with the values in the cells grown with SCF alone. These results suggest that TPO can expand the SCF-dependent growth of mast cells from mobilized CD34+ PB cells without influencing the differentiation into the mast cell lineage.
It is of interest that CD34+ PB cells from stable asthmatic children generated substantially greater numbers of mast cells in response to SCF alone or SCF+TPO than did steady-state CD34+ PB cells from controls. However, such an increase in the generation of mast cells from CD34+ PB cells is unlikely observed in all types of allergic disorders. Based on the results of the flow cytometric and immunocytochemical analyses, the discrepancy does not appear to result from the difference in the percentages of the particular subsets in CD34+ PB cells and from the distinct maturation stage of the progeny between asthmatic patients and normal subjects. The single-cell culture experiments clearly demonstrated that significantly greater numbers of mast cell colonies were formed by SCF alone in the cultures containing CD34+ PB cells from patients with asthma, as compared with the values obtained by normal controls. A prominent discrepancy was also noted in the SCF+TPO-responsive mast cell progenitors. Additionally, in the presence of TPO, CD34+ PB cells of asthmatic children generated apparently higher numbers of progeny under stimulation with a suboptimal concentration of SCF than did those of normal subjects. Thus, in patients with allergic asthma, greater numbers of CD34+ PB cells appear committed to the mast cell lineage. Moreover, it is suggested that mast cell progenitors have a hypersensitivity to SCF in this disorder.
Denburg and coworkers (1, 2, 3, 4, 5) have proposed that activation
of specific hemopoietic pathways in the BM contribute to the allergic
diathesis through increased production and traffic of
lineage-committed inflammatory progenitors such as those of
eosinophils. Moreover, significant changes are observed in the
expression of hemopoietic cytokine receptors on
CD34+ cells. In particular, increased expression
of IL-5 receptor on CD34+ cells favors
eosinophilopoiesis, and may thus contribute to the subsequent
development of blood and tissue eosinophilia. In vivo
allergen-stimulated products of cytokines may account for the increases
in CFU for eosinophils and/or basophils. Actually, detectable serum
IL-5 concentrations are found in a proportion of patients with acute
severe asthma, but not in the same patients following oral
glucocorticoid therapy or in normal controls (21). Hence,
there were significant falls in circulating eosinophil/basophil
progenitor counts with resolution of the asthma exacerbation on
beclomethasone therapy (22). In contrast, an increase in
the number of mast cell progenitors in CD34+ PB
cells was observed in stable asthmatic patients. Additionally, the
concentrations of SCF and TPO in venous plasma were not elevated in
asthmatic children compared with the values in normal subjects (the
values of SCF and TPO were 1271 ± 233 pg/ml and <0.20–0.39
fmol/ml, respectively, in asthmatic children; 1047 ± 277
pg/ml and 0.26–0.74 fmol/ml, respectively, in normal controls).
Therefore, it is likely that a raised level of mast cell progenitors in
CD34+ PB cells from asthmatic children is
mediated through a mechanism different from hemopoietic progenitors
differentiating into eosinophils or basophils.
It is demonstrated that mast cell numbers are increased in bronchoalveolar lavage fluid in relatively stable asthmatic patients (23). The active recruitment of mast cell progenitors from the circulation into the tissue may contribute to ongoing airway inflammation during asymptomatic periods.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kenichi Koike, Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, 390-8621, Japan.
3 Abbreviations used in this paper: BM, bone marrow; PB, peripheral blood; SCF, stem cell factor; TPO, thrombopoietin; GPA, glycophorin A.
Received for publication July 3, 2000. Accepted for publication January 19, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit expression on bone marrow-derived CD34+ cells from asthmatic subjects: a novel marker of progenitor cell commitment towards eosinophilic differentiation. J. Clin. Invest. 100:2466.[Medline]
RI- cell population. Blood 84:2489. receptor type I expression in recombinant human stem cell factor-dependent fetal liver-derived human mast cells. J. Immunol. 159:2911.[Abstract]
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,
Asthmatic children; 
, normal controls. *, Significantly different
from the values obtained by normal controls (p <
0.02).