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(Received for publication, September 12,
1994; and in revised form, November 3, 1994) From the
We have demonstrated for the first time that a conditioned
medium from a human cell strain can induce morphologically mature mast
cells that express Fc Despite the substantial progress that has been made in deriving
phenotypically distinct populations of non-transformed mouse mast
cells, less progress has been made in inducing human progenitor cells
to preferentially differentiate in vitro into cells that
resemble mature cutaneous mast cells. Kit ligand
(KL), One of the characteristics of all
known in vivo differentiated mast cells is that they bind IgE
with high affinity via the Fc Using a coculture approach, Levi-Schaffer and co-workers found that
mouse 3T3 fibroblasts can maintain the viability and phenotype of rat
serosal (38) and human lung (39) mast cells ex vivo and can induce immature IL-3-dependent mast cells to mature,
increasing their carboxypeptidase content
The HBM-M cell is a cell derived from the
bone marrow of a patient with diffuse cutaneous
mastocytosis(44, 45, 46) . In the present
study we show that conditioned media from this cell strain will induce
bone marrow progenitor cells from normal subjects to preferentially
differentiate into mast cells that express tryptase, chymase,
carboxypeptidase, and Fc
At different times during culture,
cytocentrifuge preparations of bone marrow cells were examined for
their expression of tryptase, chymase, carboxypeptidase, and Fc To
analyze immunochemically for the expression of mast cell-specific
proteases, cytocentrifuge preparations of the cultured cells were
air-dried, placed in Carnoy's fixative for 15 min at room
temperature, incubated for 30 min at room temperature with the relevant
monoclonal antibody, and then incubated with alkaline
phosphatase-labeled rabbit anti-mouse IgG (1:50 dilution, Dakopatts)
and alkaline phosphatase anti-alkaline phosphatase complex (1:50
dilution, Dakopatts) for 30 min at room temperature. Slides were
developed for 20 min in 0.1 M Tris-HCl, pH 8.2, buffer
containing 0.2 mg/ml naphthol AS-MX phosphate (Sigma) and 1 mg/ml fast
red. Indirect immunofluorescence was used to detect IgE receptors
and Bsp-1 epitopes. For these analyses, cells were fixed for 10 min in
acetone, washed in PBS, and then incubated for 60 min at 37 °C with
purified human myeloma IgE in PBS, pH 7.4, or with human IgG as a
control. Fluorescein isothiocyanate-conjugated rabbit anti-human IgE
(Dakopatts) was used as a second antibody to detect IgE binding.
Fluorescein isothiocyanate-conjugated rabbit (Fab`) anti-mouse IgM
(Caltag Laboratories, South San Francisco, CA) was used to detect
anti-Bsp-1 binding.
The oligonucleotide primers for analysis of the tryptase,
chymase, and N-Ras transcripts were synthesized on a PCR-MATE DNA
synthesizer (Applied Biosystems Inc). Oligonucleotide primers for
analysis of the Fc
Figure 1:
Comparison of the
number of cells in the culture (A) and the development of mast
cells when bone marrow cells were cultured with 50% HBM-M-CM alone
(
With HBM-M-CM alone, the percentage of cells
that could be stained by toluidine blue reached a maximum of 18
± 3% (mean ± S.D., n = 3) at day 21 (Fig. 1B). In the presence of rhKL alone, only a few
toluidine blue cells were detected in the culture at day 21 or 30, but
56 ± 6% (mean ± S.D., n = 3) of these
cells were toluidine blue-positive by day 48 (Fig. 1B and Fig. 2B). In enriched media with both rhKL and
HBM-M-CM, 12 ± 2.8% and 50 ± 3% (mean ± S.D., n = 3) of cells were toluidine blue-positive at day 21
and day 48, respectively ( Fig. 1and Fig. 2).
Metachromatic staining cells in the cultures derived with both rhKL and
HBM-M-CM appeared as large cells with prominent metachromatic granules (Fig. 3G). The intensity of granule staining was
similar in cells cultured with rhKL with or without HBM-M-CM at day 48 (Fig. 3, D and G).
Figure 2:
Cytochemical and immunochemical
characteristics of mast cells derived by culturing human bone marrow
cells from normal donors for 21 days (A) or 48 days (B) in 100% enriched media, 50% enriched media/50% HBM-M-CM,
enriched media supplemented with rhKL, or 50% enriched media/50%
HBM-M-CM supplemented with rhKL.
Figure 3:
Cytocentrifuge preparations of bone marrow
cells cultured in the presence of HBM-M-CM (50%) on day 21 (A-C) and rhKL (100 ng/ml) on day 48 (D-F) and HBM-M-CM (50%) and rhKL on day 48 (G-I) stained with toluidine blue (D and G), anti-tryptase Ig (A, E, and H),
anti-chymase Ig (B, F, and I), or
anti-carboxypeptidase Ig (C). Magnification,
Figure 4:
Electrophoretic analysis of the products
of the RT-PCR amplification from RNA obtained from mast cells derived
in enriched medium supplemented with HBM-M-CM (A), rhKL (B), or both HBM-M-CM and rhKL (C) using
oligonucleotide primers of N-Ras (1), Fc
Human mast cells, derived by culturing normal
bone marrow cells in the presence of HBM-M-CM with or without rhKL,
specifically bound IgE. At day 21, 27 ± 2.3% (mean ±
S.D., n = 3) of the cells in the culture derived with
HBM-M-CM alone specifically bound IgE (Fig. 2A). After
culture for 21 and 48 days in the presence of both HBM-M-CM and rhKL,
12 ± 2% and 26 ± 2.4%, respectively, of the cells bound
IgE (Fig. 2, A and B). None of the mast cells
in the cultures that were derived with only rhKL bound IgE. By RT-PCR,
the transcript that encodes the
Figure 5:
Ultrastructural appearance of mast cells
derived by culturing bone marrow cells for day 48 in the presence of
rhKL alone (B and D) or in the presence of both HBM-M-CM (50%) and rhKL
(A and C). Magnification,
We have examined the consequences of culturing normal human
bone marrow cells for up to 50 days in a conditioned medium derived
from a cell strain obtained from a patient with bullous mastocytosis.
Conditioned medium from the HBM-M cells promoted the development from
bone marrow precursors of morphologically mature mast cells that
expressed Fc Although HBM-M-CM could induce human cells to differentiate into a
mast cell lineage after only 1 week of culture, rhKL was required to
maintain the long term survival of the mast cells. HBM-M-CM-derived
mast cells express tryptase, chymase, and carboxypeptidase. In addition
these cells possessed multilobed nuclei. This observation has important
implications for categorizing metachromatic cells as basophils or mast
cells based on nuclear morphological criteria. While maintaining the
viability, rhKL suppressed the ability of HBM-M-CM to induce the
expression of cells that contained carboxypeptidase and Fc The in vitro development of mature mast cells both in humans and
rodents has been achieved using hematopoietic progenitor cells from a
variety of sources cocultured with
fibroblasts(36, 42) . Fibroblasts (43) and
stromal cells (49) express both membrane and soluble forms of
KL in addition to other cytokines. Human mast cells derived from
progenitors of cord blood mononuclear cells cocultured with 3T3
fibroblasts are ultrastructurally quite mature and express both
tryptase and chymase(42) . In contrast, Irani et
al.(50) , using the same fibroblast coculture system and
dispersed human fetal liver cells as a source of progenitors, obtained
human mast cells that expressed tryptase but not chymase. This implies
either that the progenitors from the two sources were different or that
there were other cells in the cord blood culture providing accessory
mast cell regulatory cytokines which induced chymase expression. Our
results suggest that rhKL induces mast cells that are tryptase-positive
and that supplementation with HBM-M-CM induces chymase in the cells.
The synergy between rhKL and HBM-M-CM in increasing the total number of
mast cells has also been demonstrated in human and rodent systems where
bone marrow is cultured with KL and IL-3(51, 52) . The
factor in HBM-M-CM remains to be determined, but HBM-M-CM does not
contain detectable levels of IL-3, IL-5, granulocyte/macrophage
colony-stimulating factor, or KL(46) . Mast cells derived
from human bone marrow using rhKL do not bind fluoresceinated human
IgE, in contrast to the cells that were grown in HBM-M-CM. The addition
of rhKL to HBM-M-CM resulted in a down-regulation of IgE binding at
both day 21 and day 48 of culture. In both culture systems, RT-PCR
analysis revealed the presence of the transcript that encodes the Human mast cells derived from cord blood
progenitors cocultured with 3T3 fibroblasts bind human IgE but with an
intensity of fluorescence less than that of human lung mast cells
sensitized with IgE(42) . Moreover, IgE binding was
demonstrated only after 74 days of coculture of cord blood mononuclear
cells with 3T3 fibroblasts, when less than 10% of cells were identified
as mast cells(42, 54) . In contrast to our study,
Valent and co-workers (22) induced differentiation of human
mast cells from bone marrow using rhKL in long term cultures and
reported that these cells bound human IgE. This difference may be due
to the fact that we have used a total bone marrow cell preparation and
not a mononuclear fraction as Valent and co-workers have done. Nilsson
and co-workers (53) were unable to induce the expression of
Fc
Volume 270,
Number 5,
Issue of February 3, 1995 pp. 2258-2263
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
RI and three mast cell-specific proteases
from normal bone marrow progenitor cells. In contrast, recombinant
human Kit ligand induced the differentiation of mast cells that were
tryptase-positive but negative for chymase, carboxypeptidase, and
Fc
RI. This data indicates that factors other than Kit ligand are
critical for inducing the differentiation and maturation of mast cells
in the human. The HBM-M cell was originally derived from a patient with
mastocytosis. As mastocytosis is thought to represent a reactive
hyperplasia rather than a mast cell malignancy, the factor secreted by
the HBM-M cell strain could well be responsible for the mast cell
hyperplasia seen in some patients with mastocytosis.
(1, 2, 3, 4, 5, 6) ,
interleukin (IL) 3(7, 8) ,
IL-4(9, 10) , IL-9(11, 12) ,
IL-10(13, 14, 15) , granulocyte macrophage
colony stimulating factor(16, 17) , and nerve growth
factor (18) can each regulate the growth, differentiation,
and/or granule maturation of mouse mast cells in vitro. While
neither IL-3 nor IL-4 by themselves induces human hematopoietic
progenitor cells to differentiate into mast
cells(19, 20) , morphologically immature populations
of human mast cells are obtained when hematopoietic progenitor cells
from normal bone marrow, peripheral blood, fetal liver, or umbilical
cord blood are cultured in the presence of recombinant human KL
(rhKL)(21, 22, 23) .
Chymase(24, 25, 26) ,
tryptase(27, 28, 29, 30) , and
carboxypeptidase (31, 32, 33, 34, 35) are
granule proteases that are specifically expressed by cutaneous human
mast cells. While the majority of the KL-derived human mast cells
express tryptase, they do not express
chymase(21, 36) .
RI receptor. This receptor also is
expressed in vivo on basophils and recently has been
identified on Langerhans cells(37) . It consists of an
,
, and two chains. Although the
chain binds IgE, it
requires the and chains for cell surface expression.
100-fold(40, 41) . Furitsu and co-workers (42) reported that mature,
chymase
/tryptase
mast cells were
obtained when human cord blood mononuclear cells were cocultured with
mouse 3T3 fibroblasts. In subsequent studies, these investigators found
that fibroblast conditioned media containing soluble KL could induce
stem cells from human cord blood to differentiate into a population of
immature mast cells that expresses tryptase but not
chymase(21, 36) . Two KL transcripts have been
detected that result from differential exon splicing of the KL gene (43) . One transcript encodes a protein that is retained in the
plasma membrane, whereas the other encodes a protein that is
constitutively secreted. Because neither recombinant nor purified KL
alone will induce human or mouse progenitor cells to fully
differentiate into mature mast cells, the fibroblast-induced
differentiation and maturation process of cord blood progenitor cells
into mast cells is dependent on either membrane-bound KL or another
fibroblast-derived factor.
RI.
Preparation of HBM-M Conditioned Medium
HBM-M
cells were maintained in 75-cm
tissue culture flasks
(Corning) containing 20 ml of enriched medium ( minimal essential
medium (Life Technologies, Inc.) supplemented with 20% heat-inactivated
fetal calf serum (Flow Laboratories), 2 mML-glutamine (Life Technologies, Inc.), and 100 units/ml
penicillin-streptomycin (Life Technologies, Inc.)) at 37 °C in a
humidified atmosphere of 5% CO. Conditioned medium
(HBM-M-CM) was prepared by collecting spent supernatant from growing
cells every 2-3 days, centrifuging at 1500 
g for
10 min and filtering through 0.2-µm low protein binding Millex GV
filters (Millipore Corp., Bedford, MA).Cultures of Human Bone Marrow Cells
Following
informed consent, 10 ± 1 ml (mean ± S.D., n = 8) of bone marrow from normal donors was collected in
heparinized tubes. The cells were suspended in Dulbecco's
phosphate-buffered saline (PBS, Life Technologies, Inc.) and then
centrifuged at 700 g for 10 min. Erythrocytes were
lysed by hypotonic treatment in 0.5% ammonium chloride. The remaining
cells were washed in enriched media, and then replicate aliquots were
resuspended at 1 to 3 10
cells/ml in enriched media
alone, enriched media supplemented with 100 ng/ml rhKL (Amgen Inc.,
Thousand Oaks, CA) alone, 50% enriched medium/50% HBM-M-CM, or 50%
HBM-M-CM and 100 ng/ml rhKL. The biological activity of the rhKL was
assessed in a proliferation assay using the MO7e cell
line(47) . The cells were cultured at 37 °C in a 5%
CO humidified atmosphere with the medium being changed
every 2-3 days. The adherent cell population was separated from
the nonadherent cells when the adherent cells reached confluence. As
the adherent cells in the cultures were negative for tryptase, chymase,
and FcRI (data not shown), these cells were not examined further.
Histochemistry and
Immunocytochemistry
Cytocentrifuge preparations of bone marrow
cells were stained with May-Grunwald Giemsa reagent for assessment of
morphology and trypan blue to assess viability. Metachromatic
granule-containing cells were identified by staining with 1% toluidine
blue in methanol, pH 2.5.RI
by immunocytochemistry and immunofluorescence. The following reagents
were used: mouse anti-human mast cell tryptase and chymase monoclonal
antibodies (Chemicon International Inc., Temecula, CA), mouse
monoclonal anti-human carboxypeptidase antibody (Sigma), purified human
myeloma IgE, and Bsp-1 (a basophil-specific monoclonal antibody).
RNA Analysis by RT-PCR
Total RNA was purified from
3 10
non-adherent cells by the method of
Chomczynski (48) in order to determine by RT-PCR if any of the
cultures contained the transcripts that encode the -chain of
FcRI, mast cell tryptase, or mast cell chymase. Since the N-Ras
transcript is ubiquitous in cells, the presence or absence of this
N-Ras transcript was used to assess integrity of the RNA preparations.
Oligonucleotides used in the RT-PCR were as
follows.
RI
-chain transcripts were synthesized and
HPLC-purified by DNA Express (Macromolecular Resources, Fort Collins,
CO). The isolated total RNA was reverse transcribed in a total volume
of 20 µl in a buffer containing 50 mM potassium chloride,
3 mM magnesium, 0.01% gelatin, and 10 mM Tris, pH
8.3. 500 mM dNTPs (Pharmacia Biotech Inc.), 20 pM random hexamer, 20 units of recombinant RNasin® ribonuclease
inhibitor (Promega Corp.), and 100 units of Moloney murine leukemia
virus reverse transcriptase (Life Technologies, Inc.). Double-stranded
DNA was obtained following the addition of 1 unit of Taq DNA
polymerase (Boehringer Mannheim) and the appropriate oligonucleotide
primers. Denaturing, annealing, and extension reactions were carried
out each at 94, 58, and 72 °C, respectively, for 30 cycles on a
Hybaid thermocycler.Transmission Electron Microscopy
The nonadherent
cells in the bone marrow culture were processed for electron
microscopy. Cells were fixed in 1.25% glutaraldehyde and 2%
paraformaldehyde in 0.1 M cacodylate buffer, pH 7.4, for
2-4 h at 4 °C. Fixed cells were washed three times in 0.1 M cacodylate buffer, postfixed in 1% osmium tetroxide at 4
°C for 1 h, dehydrated in graded ethanol, and then embedded in
Spurr's resin. Sections (60-80 nm), were cut on an
ultramicrotome (Reichert-Jung Ultracut E) and examined using a Hitachi
7000 electron microscope.
Development of Metachromatic Human Mast Cells in Vitro
from Bone Marrow Cells
One ml of normal bone marrow yielded 1.7
10 ± 0.64 (mean ± S.D., n = 8) nucleated cells. The viability of the dispersed cells
was greater than 96 ± 2% (mean ± S.D.). At the start of
each experiment, none of the cells could be stained by toluidine blue
or by anti-tryptase, chymase, or carboxypeptidase antibodies. Cells
were divided into aliquots, and the effects of different culture
conditions on cell numbers and viability were assessed over time (Fig. 1). rhKL maintained cell viability and increased total
cell number by 41 ± 1.5% (mean ± S.D., n = 4) at day 14 (Fig. 1A). Although slightly
decreased at day 30, cell number was maintained for 50 days. Total
number of cells in the cultures maintained with a combination of rhKL
and HBM-M-CM was similar to that obtained with rhKL alone. However, the
total number of cells in those cultures maintained in media alone or
HBM-M-CM alone decreased significantly over time (p < 0.005
by Student's t test). At day 21, total cell number had
decreased by 10-fold.
), 50% HBM-M-CM and 100 ng/ml rhKL (
), 100 ng/ml rhKL
alone (
), or enriched media alone (
). The percentages of
cells staining positive for toluidine blue (B), tryptase (C), and chymase (D) are shown. For all time points, n = 3.
2000 (A-D, and G-I) and
1000 (E and F).
Expression of Mast Cell Granule Proteases and the High
Affinity IgE Receptor in Cultured Mast Cells
rhKL and HBM-M-CM
alone or in combination had differential effects on the expression of
mast cell-specific proteases (Fig. 1Fig. 2Fig. 3).
Whereas 40 ± 11% of the cells in day 48 cultures derived with
rhKL alone expressed tryptase, only 5 ± 1% of the cells
expressed chymase (Fig. 1, C and D;
2B; and 3, E and F) and no cells were
detected that expressed carboxypeptidase. As assessed
immunohistochemically, after 21 days of culture with HBM-M-CM alone, 17
± 5%, 8 ± 5%, and 9 ± 4% (mean ± S.D., n = 6) of the cells expressed tryptase, chymase, and
carboxypeptidase, respectively (Fig. 1, C and D; 2A; and 3, A-C). However, in
cultures supplemented with both HBM-M-CM and rhKL at day 21, there were
fewer cells that expressed carboxypeptidase (Fig. 2A).
In the day 48 cultures, 40 ± 9% of the cells in the culture
derived with both HBM-M-CM and rhKL expressed tryptase, 30 ± 3%
expressed chymase, and there were no cells detected that expressed
carboxypeptidase (mean ± S.D., n = 3) (Fig. 2B and Fig. 3, H and I).
Numerous cells in the cultures supplemented with HBM-M-CM possessed a
segmented or lobulated nucleus (Fig. 3). By RT-PCR, transcripts
that encode mast cell tryptase and chymase were present in cultures in
which progenitor cells were cultured in the presence of HBM-M-CM or
rhKL (Fig. 4).
RI (2),
tryptase (3), and chymase (4). The 248-bp N-Ras,
338-bp Fc
RI, 440-bp tryptase, and 296-bp chymase DNA products and
the molecular weight markers (M) were visualized by ethidium
bromide staining.
chain of FcRI was present in
only one of three cultures with rhKL-derived human mast cells (Fig. 4). However, this transcript was present in all cultures
in which progenitor cells were cultured in the presence of HBM-M-CM.
Ultrastructural Analysis
At day 48, many of the
cells that arose in the cultures with both HBM-M-CM and rhKL were
morphologically mature mast cells. The cells had electron-dense
membrane-bound granules of variable number and size (Fig. 5A). A scroll or a crystalline granule morphology
was seen occasionally (Fig. 5C). Non-membrane-bound
lipids were also observed but were less frequent. Approximately 50% of
the mast cells in each HBM-M-CM/rhKL treated culture exhibited the
morphology of the cells depicted in Fig. 5(A and C). In contrast, the mast cells that were obtained by
culturing bone marrow cells for 48 days in the presence of rhKL alone
contained a large nucleus with a prominent nucleolus and condensed
chromatin. These cells had blunt folds on their surface and had
membrane-bound cytoplasmic secretary granules that were less well
filled than HBM-M-CM/rhKL-derived mast cells. Crystal or scroll-pattern
granules generally were not seen (Fig. 5, B and D).
9200 (A and B) and
45,500 (C and D).
RI, chymase, tryptase, and carboxypeptidase.
RI. In
the BALB/c mouse, IL-9 and IL-10 induce expression of certain
proteases, whereas IL-3 and IL-4 each suppress the expression of these
proteases (12, 14, 15) . While rhKL induces
mouse bone marrow-derived mast cells to express mMCP-4, it
does not suppress the steady state level of the carboxypeptidase and
the Fc
RI transcripts. The demonstration that rhKL prevents the
induction of these two transcripts has not previously been reported in
any other in vitro system. As carboxypeptidase is a granule
protease of mature cutaneous mast cells, this supports previous
findings that in the human rhKL induced immature mast cells.
chain of FcRI (Fig. 4). Mast cells derived by culturing
human fetal liver cells in the presence of rhKL alone also do not bind
human IgE but occasionally in some cultures have the Fc
RI
transcript(53) . The expression of FcRI without IgE
binding could be due to lack of transcription of the
and
genes or a failure of the
, , and transcripts to be
translated or the receptor complex to be properly assembled in the
endoplasmic reticulum.
RI in cultures of fetal liver cells with rhKL supplemented with
conditioned medium from a human T cell line. Other workers have used
human hematopoietic progenitor cells from a variety of sources,
co-cultured with a range of human stromal/fibroblast cell lines, but
have been unable to induce the development of cells that exhibit the
phenotype of cutaneous mast cells(36) .
))
We thank A. Coleman for excellent secretarial
assistance; Dr. G. Layton, Medical Innovations, Queensland, Australia
for kindly providing purified myeloma IgE; and Dr. M. Bodger
Christchurch Hospital, Christchurch, New Zealand, for gift of Bsp-1
monoclonal antibody.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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