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Changes
Peritoneal
Mast
Cells
By Yuzuru
Two
in Numbers
and Types
Cavity
of Mice After
Kanakura,
different
produce
cell
Kuriu,
types
of cells
in the
cell
colonies
colonies
precursors
cells
(IP)
eration
was
process
between
injection
CFU-Mast
then
M-CFU-Mast
and
few
peritoneal
mast
cells,35
mast
proliferation
cells
by
using
x C57BL/6)F,-
mice
as
genetically
differentiation
single
of
the in vivo
identifiable
mast
(hereafter
A
for
rela-
cell-deficient
WBB6F,-
peritoneal
W/WT)
mast
cell
was
+ I +
of
inhibit
the
1988
marrow
Grune
cells
syndrome)
On
appeared
the
colony
other
hand,
formation
by
confirmed
the
both
that
result
5% of the
Nakahata
3 (IL
for clonal
tiation
type
that
produced
cells
but
light
(L-CFU-Mast)
the
the
microscopy.’
Although
In the present
of
the eradication
L-CFU-Mast
ship.
cell
lymphoid
et al’
colonymast
cells
the
suggesting
When
first.
L-CFU-Mast
of differentiated
did
L-CFU-Mast
from
that
had
been
Blood,
Vol 71,
mice
cells
mast
two days
were
injected
the bloodstream.
No 3 (March),
irradiated
1988:
mast
pp 573-580
fly.3I4
Mice
were
Radiation
used
METHODS
/
+
between
) and
+
were
mice.
laminar
flow
bocyte
chimerism
(BMT)
according
2 to 4 months
WBB6F,injected
with
chimeras.
(850 rad) and
C57BL/6-bg/bg
The
2
/
+
+
C57BL/6-(bg’/bg,
months
mice
were
were
bone
method
reported
Cancer
Pathology.
X-irradiated
were
marrow
Survivors
after
of age.
mice
bone
recipient
enclosure.
to the
with
cells
(10’)
of
kept
within
a
checked
marrow
for granu-
transplantation
by Murphy
et al.’5
Mice
the
mice
by
of
Second
Medical
Laboratory
Animal
Department
School,
May
Supported
by grantsfrom
Culture.
Foundation,
the
and
Address
reprint
sity
8. 1 987;
Ministry
Takeda
Foundation,
the
Biomedical
Internal
Osaka,
Hamamatsu,
accepted
the
Asahi
School,
Science
Welfare,
the
Mochida
Science
and
MD,
Institute,
4-3-57.
and
Mitsubishi
Memorial
Culture.
Kitamura,
Research
Nakanoshima
Shizuoka
7, 1987.
ofEducation.
to Yukihiko
Biomedical
Osaka
and
Japan.
Ministry
Fundfor
Research
Medicine,
Japan;
October
of Health
and
Science
Foundation,
requests
Pathology.
Medical
Kita-Ku.
Center,
Submitted
of
Division
Osaka
Kita-Ku,
of
Univer-
Osaka,
530
Japan.
purified
injection,
Division
and
University
Cancer
relation-
the
Institute
cell
that the presence
the recruitment
of
rescued
AND
) were raised in our laboratory.
From
S-CFU-Mast
In WBB6F,-+/+
and
to M-CFU-Mast.
by
the number
medium
not increase,
suggesting
mast cells may suppress
lethally
cells,
the water
type, whereas
type. Since
of +/+
The giant granules of C57BL/
mice
were used as markers to identify the origin of mast
cells.”2
The original stocks of mutant mice were derived from The
Jackson Laboratory,
Bar Harbor, ME, but W” and bg’ mutant genes
have been maintained
in C57BL/6
mice of our own inbred cob-
formation,
of a hierarchic
after
to
Ch#{233}diak-l-Iigashi
ofbg/bg
were
Mice of WBB6F,-(W/W’,
Mice.
water.’#{176}The
and
presence
WBB6F,-+/+
peritoneal
Then
(M-CFU-Mast)
units
the
and
demonstrated
of distilled
mast
suppress
to M-CFU-Mast.
(beige,
were
MATERIALS
filter-air
and small mast cell
has not been clarified.
peritoneal
mast cells by
ofdifferentiated
increased
colony-forming
appeared,
the
process
relationship
After
mast
differentiated
for colony
injection
In
of mast cells was investigated
to clarify
between
L-CFU-Mast
and S-CFU-Mast.
regeneration
the
(IP)
were
(CFU-Mast)
Nakahata
L-CFU-Mast
units (S-CFU-Mast)
study we eradicated
intraperitoneal
4)
cells.9
contained
IL 3 alone
between
colony-forming
the
large
resembling
required
relationship
of mice
not
We
by differen-
units
are
precursors
L-CFU-Mast
that
produced
colony-forming
colonies.8
The
larger
are
4 (IL
mast
cell
vitro
cells.
demonstrated
interleukin
other
units
and
of differentiated
tiated
in
mast
develop-
S-CFU-Mast.
Inc.
S-CFU-Mast
of L-CFU-Mast
+ I +
6-bg/bg
sites.’
reported
et al’
to small mast cell colonies
mast cells, the peritoneal
cavity
forming
al’
peritoneal
3) and
growth
of mast
injection
et
purified
of Nakahata
interleukin
necessary
addition
at about
and
the injection
of distilled
water into the peritoneal
cavity
of
the radiation
chimeras
resulted
in the development
of bg/
bg-type
M-CFU-Mast
and then S-CFU-Mast,
the presence
of differentiated
mast cells appeared
to inhibit
the differen-
under the phase contrast
microscope,
picked
up
micromanipulator,
and injected
into the skin of
WBB6F,-W/W”
mice. Mast cell colonies
comprising
-2,000
cells
of
mice,
bloodstream
of L-CFU-Mast
L-CFU-Mast
and
been
cells
in the
to
the
the
of distilled
then
appeared
of C57BL/6-bg/bg
M-CFU-Mast
had
injection
and
from
& Stratton,
mice,
that
but
The
the
In
marrow
resulted
cells
L-CFU-Mast
differentiation
by
type.
chimeras
mast
increase.
bone
M-CFU-Mast
of
not
M-CFU-Mast
bg/bg
of
presence
after
type,
of
radiation
purified
days
syndrome)
were
of bg/bg’-type
When
two
mice
by
Kitamura
Ch#{233}diak-Higashi
were
recruitment
+ I +
rescued
S-CFU-Mast
the
did
WBB6F1-
and
L-CFU-Mast
identified
with
the
mast
of
Yukihiko
injected
L-CFU-Mast
(beige,
to
and
relationship.
were
the
C57BL/6-bg/bg
S
used
recently
we demonstrated
morphologically
W/W’
recipients.6”
suggesting
widely
on the
and
Yonezawa,
cells
irradiated
The
S-
Precursors
a hierarchic
cavity
lethally
ment
and
Until
done
but
of
potential
(WB
are
of
mast
injection.
water
S-CFU-Mast.
appeared.
functions.”2
been
regen-
increased,
CELLS
cell
had
studies
and
S-CFU-Mast
by
relationship
M-CFU-Mast
L-CFU-Mast
MAST
mast
In the
Takeshi
presence
peritoneal
cell
mast
The
the
Asai,
peritoneal
cells
water.
water,
but
ERITONEAL
tively
mast
to clarify
M-CFU-Mast,
distilled
disappeared,
of
microscopy
mast
of distilled
investigated
of
studies
light
respectively).
the
Cells in the
Evidence
That
Marrow-Derived
Hidekazu
water
“small”
peritoneal
injection
of mice
“Large”
identifiable
S-CFU-Mast.
L-CFU-Mast,
After
by
and
eradicated
intraperitoneal
P
lymphoid
Nakano,
marrow-derived
by morphologically
we
Toru
cavity
bone
Cell Colony-Forming
of Distilled
Water:
of Bone
methylcellulose.
by
and
study
Waki,
peritoneal
in
“medium”
produced
(M-CFU-Mast
present
Noriko
produced
whereas
are
cells
are
resembling
(L-CFU-Mast),
colonies
Differentiation
Akira
mast
mast
Suppress
of Mast
Injection
bone
The
charge
publication
costs
ofthis
article
payment.
This
article
must
“advertisement”
indicate
this fact.
© I 988
by Grune
in
accordance
& Stratton,
with
were
defrayed
therefore
18 U.S.C.
be
in part
hereby
§1734
by page
marked
solely
to
Inc.
0006-4971/88/7103-0124$3.0o/o
573
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574
KANAKURA
that
were
bg/bg
shown
granulocytes
were used as
+ chimeras.
Cell suspensions.
25 g, were
injected
3 mL
saline.
of
bg’/bg-type
to have only
+1
-+
Mice
of either
IP with
At
3 mL
various
weighing
sex,
ofdistilled
times
water.
after
the
approximately
Controls
received
injection,
mice
were
(Sigma),
60 ;g of human
moL/L
FeCl3 (Wako
soybean
lecithin
(Sigma)
per milliliter
Clonal
cell
transferrin
(Sigma)
Pure Chemicals,
(Sigma)
per
per
Osaka,
milliliter,
and
ET AL
milliliter,
0.45
Japan),
9.6
16 j.g of
zg of cholesterol
for five days.
cultures.
Methylcellulose
culture
was
carried
out
anesthetized
by ether and were killed by decapitation;
3 mL of
a-medium
(Flow Laboratories,
Rockville,
MD) containing
10 IU/
mL heparin and 0.1% bovine serum albumin (BSA) was injected
into the peritoneal cavity;
the abdomen was gently massaged for 30
seconds. The peritoneal cavity was opened, and the fluid containing
peritoneal cells was aspirated with a Pasteur pipette. Peritoneal cells
according
were
plated in 35-mm Lux standard
nontissue culture dishes (Flow).
Dishes were incubated at 37#{176}C
in a humidified
atmosphere
flushed
with 5% CO2 in air. Mast cell colonies were counted on day 14 and
were
classified by their size into three types: small (four to 3 1 cells),
washed
and
suspended
in a-medium.
cells were suspended in a-medium
Blood samples
were collected
mononuclear
cells were separated
by B#{216}yum.” Two
equal
volume
milliliters
( I .077
the
and
retro-orbital
according
and were
g/mL;
marrow
spleen
as described.”
from
blood
carefully
Pharmacia
sinus.
to the method
of heparinized
of saline
Ficoll-Paque
Sweden).
Bone
were
mixed
layered
Fine
The
described
Uppsala,
and suspended
in
uous
and dense
gradient
centrifugation
density
according
to
the
methods
described by B#{216}yum”and Yurt et al,” respectively.
Peritoneal cells
from ten mice were collected by peritoneal
lavage of each mouse
with 3 mL of Tyrode’s
buffer containing
0.1% gelatin
(Sigma
Chemical
Co. St Louis). The cells were sedimented at 400 g for 15
minutes
at room
temperature
and
washed
twice
with
the buffer.
10 cells in I mL of Tyrode’s
buffer were layered on 2 mL of 22.5% wt/vol Metrizamide
(1.120
g/mL,
Nyegaard
& Co, Oslo, Norway)
and centrifuged
at room
temperature
for 15 minutes
at 400 g. The cells remaining
at the
To obtain
interface
in
dense
were
the
fractions,
collected
pellet
were
3 x 10 to
and used to obtain
washed
and
light
resuspended
fractions.
in
1 mL
The
of
cells
Tyrode’s
buffer. The above-mentioned
procedure was repeated by using the
cells resuspended from the pellet to obtain dense fractions in which
purity
of mast cells was 99%.
To obtain light fractions the cells remaining
at Tyrode’s
bufferMetrizamide
interface
were washed and resuspended
in Tyrode’s
buffer. Five milliliters
of the suspension
was layered on 3 mL
Ficoll-Paque
and centrifuged
at room temperature
for 20 minutes at
400 g; the cells at the interface
were washed and resuspended
in
5 mL
of Tyrode’s
Ficoll-Paque
buffer;
the
cell
suspension
and was centrifuged.
was
The interface
again
layered
on
was used as light
HyClone,
in either
methylcellubose.
cals)
method
method
described
by Nakahata
et al.#{176}
After
being
washed
dilution
of
PWM
a-thioglycerol
sodium
selenite
(GIBCO,
(Sigma),
(Sigma),
Grand
25 mmoL/L
1% of
Island,
HEPES
deionized
NY),
(Sigma),
bovine
0.1
mmoL/L
0.1 ,moL/L
serum
albumin
UT),
1%
and
and
30%
deionized
10%
large
fetal
(500
cells,
bovine
BSA,
(vol/vol)
serum
10
moL/L
PWM-SCM
cells)
mast
cultured
or peritoneal
mast
was
cell colonies,
cells.’2
concentration
of hydroxyurea
bromodeoxyuridine
(BrdUrd;
Wako
was used as an index for cell proliferation
described
previously.2’
Briefly,
50 ,g/g
N NaOH
three times with a-medium,
spleen cells were incubated at 2 x 106
cells/mL
in a 1:1 mixture
of a-medium
and modified
Ham’s F,2
medium (Flow Laboratories,
Rockville,
MD), containing
a 1/300
This
incorporated
The
by the
(Sigma),
cells
that
Cell counts.
Number
of cells
was determined
with standard
hemocytometer.
Mast cells were identified
either by staining with
neutral red (0.02% in 0.9% NaCI) or by the phase contrast microscope. These methods gave similar
results. However,
when the
proportion
of mast cells in the examined
cell suspension
was low, i05
Southern,
peritoneal
for
previously.’
Shandon
nucleated
was suitable
after
(Cytospin,
I0
al.2#{176}
One
killing cells in S phase, as reported by Kanamaru
et al.’3
Incorporation
of bromodeoxyuridine.
Proportion
of mast
was
in a cytocentrifuge
containing
et
Hydroxyurea
treatment.
Bone marrow cells and peritoneal
cells
were washed twice in serum-free a-medium
and then incubated for
60 minutes at 37#{176}C
in prewarmed
serum-free
a-medium
with or
without 200 jzg/mL hydroxyurea
(Sigma) at a concentration
of 106
cells/mL.
After incubation
cells were washed three times in amedium
supplemented
with 2% fetal calfserum
(FCS)
and plated in
minutes
spun
Nakahata
cells, or 3 x 10’ bone marrow
(Sigma),
aminoglycans
BrdUrd
were
by
Staining
ofcultured
cells.
Individual
colonies
were lifted
from
the methylcellubose
medium by using 3-L Eppendorf
pipette under
direct microscopic
visualization
and were collected
in Eppendorf
microcentrifuge
tubes containing
0.5 mL of Eagle’s medium.
After
washing two times with the medium, the samples were immediately
spun in a cytocentrifuge
at 600 rpm for five minutes. The slides were
stained with alcian blue’9 or berberine sulfate.2’
Specimens
stained with berberine
sulfate were examined
with
Olympus epifluorescence
microscope.
Enerb#{228}ckdemonstrated
that
berberine sulfate specifically
stains heparin-containing
granules of
connective tissue-type mast cells (CTMC)
by cytofluorometry.2’
We
recently confirmed
this by showing that the fluorescence
disappeared after the heparinase digestion.’6
Moreover,
the staining with
berberine sulfate is consistent with the chemical analysis of glycos-
In one experiment
the fractionation
was done after removal of
phagocytes
by carbonyl
iron (GAF Co. New York) as described
Elliot, IL) at 600 rpm for five minutes; mast cells were counted after
staining cytocentrifuged
specimens with alcian blue.”
Conditioned
medium.
Serum-free
pokeweed
mitogen
stimulated spleen cell conditioned
medium (PWM-SCM)
was prepared
Logan,
(32 to 499 cells),
fractions.
cells
mixture
mononuclear
2-mercaptoethanol
respectively.
Peritoneal
cells were separated
(a 1 . I 20) fractions
on discontin-
centrifugation.
I .077 g/mL)
(FBS;
described
1% methylcellulose
medium
gradient
(
light
a-medium,
of
Chemicals,
method
of a culture
an
were washed
the
l0 blood
with
The cells at the interface
Density
milliliter
cells,
on 3 mL
a-medium.
into
to
peritoneal
injected
the
cells
specimens
intravenously
injection,
(IV);
and
were
fixed
in chilled
were
first stained
for denaturation
the
were
with
alcian
blue,
neutralized
killed
60
preparations
(4#{176}C)70% ethanol
of DNA,25
Chemi-
according
to the
body
weight of
mice
cytocentrifuge
Pure
of
for 12 hours.
treated
with
with
0.1
0.07
moL/L
borate buffer (pH 8.5), and then incubated with mouse anti-BrdUrd
monoclonal
antibody
(MoAb;
Becton Dickinson,
Mountain
View,
CA).
The
specimens
were
washed,
incubated
with
a
biotin-
conjugated
horse antimouse
antibody
(Vector
Laboratory,
Inc,
Burlingame,
CA), and incubated
with an avidin-biotin-peroxidase
complex (Vector Laboratory).
Visualization
of the reaction product
was achieved with the diaminobenzidine-H,02
reaction, as previously described.’6 Mast cells were identified by the presence of alcian
blue-positive
granules in the cytoplasm,
and the incorporation
of
BrdUrd was recognized by the presence of dark brown granules on
the nucleus.
RESULTS
Mast
cell colony-forming
cell (CFU-Mast)
in the intact
peritoneal
cavity.
Peritoneal
cells of intact WBB6F,+ / +
mice were cultured
in methylcellubose
with
PWM-SCM.
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DIFFERENTIATION
OF MAST
575
CELLS
-s--.-
I
‘-M-----
L
-
180
:
1111_1_
4
8
16 32 64 128
No of Mast Cells
Colony
per
Fig 1 .
Number
of mast cell colonies
that contained
different
numbers
of cells 14 days after
plating
1O peritoneal
cells of
WBB6F,+ I + mice. Each bar represents
the mean of seven mice.
Mast
cell colonies
were
arbitrarily
divided
into three
groups
according
to their size: (1 ) small colonies
(S; four to 31 cells). (2)
medium
colonies
(M; 32 to 499 cells), and (3) large colonies
(L;
>500 cells).
When
colonies
were
scored
most colonies
culture,
previously.”
colonies
different
histogram
shows
individual
colonies,
into
groups
to 31 cells),
colonies
the
divided
to their
colonies
(32
Mast
cells
mast
Fig 2.
Cytocentrifuge
preparations
of cells in dense (panels
A
and C) and light (panels
B and D) fractions
separated
from
peritoneal
cells of WBB6F,+ I + mice.
The fractionation
was
done after removal
of phagocytes.
The same number
of cells (3 x
1 O) from
dense and light fractions
was applied
to the cytocentrifuge. Panels A and B. stained
with alcian blue; original
magnification x 60. Alcian blue-positive
cells were scarcely
observed
in the
light
fraction
(panel
B). Panels
C and D, stained
with
MayGr#{252}nwald-Giemsa;
original
magnification
x470.
Most of cells in
the dense fraction
were mast cells (panel C). and most of cells in
the light fraction
were cells that resembled
lymphoid
cells by light
microscopy
(panel D).
numbers
mast
cell
colonies
size: small colonies
to 499 cells),
and
in colonies
cell
the
in
Although
of cell
spectrum
we arbitrarily
cells).
of the
of
of cells.
according
(500
initiation
number
numbers
a continuous
medium
after
only mast cells, as described
1 depicts
Figure
containing
three
14 days
comprised
(four
large
of each size were
sulfate;
about
35% cells in small
colonies
and about 7% cells in medium
colonies
were stained
with
berberine
sulfate,
but cells in large
colonies
were
stained
with
scarcely
berberine
stained
sulfate-positive
cells,
were
colonies
ment.
Each
I .077)
(
colony
(Fig
and dense
(a I . 120)
dye
(Table
I).
2), and
were
differentiated
mast
cell
cells
small
originate
and
the
purcursors
as described
Table
Type
of
CFU-Mast
tAlthough
L-CFU-Mast
mast
cell colonies
mast
cell
mast
by
scarcely
cells
Nakahata
1 . Classification
Number)
500
32-499
and
samples.
light fractions
were considered
cells,
large
lymphoid
et al’
of CFU-Mast
mast
to
tion
by
produced
I).
Recovered
From
Proportion
of Berberine
Sulfate-Positive
Cells
in Colonies (%)
<
of
Numbers
counted.
cell
cells
(Table
not significantly
the
IP
0. 1
7.2
35.0
cells and macrophages,
resembling
lymphoid
were
collected,
affect
cells.
and
-
cells
distilled
of
No
the
the
number
distilled
mast
number
of
of peritoneal
water
cells
water and increased
1 1% of the value
harvested
water
were
resulted
in
detectable
in
gradually.
observed
by peritoneal
Cavity
at various
were
ofsmall,
medium,
Before the injection
the Peritoneal
was
mice;
after
the
cavity
24 hours after the injection
of distilled
cells first appeared
at I week after
the IP
cells
times
cultured
in
and large
ofdistilled
were
of WBB6F1-
The mast
in control
injection
3).
after
and
the injec-
methylcellulose.
mast cell colonies
were
water most colonies
mast
small
cell
colonies.
+ I + Mice
Density
Morphology
Light
Resembling
Dense
Mast cell
Dense
Cells from ten to 20 small colonies and cells from three to ten medium
contained
lymphoid
to be the precursors
saline
the proportion
of differentiated
Although
the IP injection
injection
of mast
Peritoneal
in methylcelappeared
of distilled
or
saline-injected
mice at 1 2 weeks after the water
reached
the preinjection
level at 20 weeks (Fig
chiefly
cells
(Fig 2). Since
4-32
22
mast
cells
cells and
determined.
injection
ofdistilled
cell number
was
in
water
peritoneal
The
the peritoneal
water.
Mast
con-
IP injection
injection.
did
small
after
distilled
the peritoneal
cavity
of WBB6F,-+/+
mice were killed
at various
times
saline
cells
cultured
colonies
resembling
(Cell
S-CFU-Mast
of six to
produced
of
injected
into
the recipient
destruction
in the
mast
cells
of
Three
of total peritoneal
mast cells were
from
cells
were
fraction
Size of Colonies
L-CFU-Mast
M-CFU-Mast
‘Mean
cells
they
the light
large
medium
differentiated
from
colonies
from
light microscopy
mast
when
mast cells and comprised
cells by light microscopy
produced
obtained
all
identifiable
colonies
In contrast,
tamed
differentiated
resembling
lymphoid
lulose,
were
almost
morphologically
these
methylcellulose.
the light
cells,
mast
milliliters
Regeneration
water.
of berberine
When
light
entirely
cells.
fractions
peritoneal
fraction
medium
and
fluorescent
and no colonies
consisted
or sulfate-negative
phagocyte-free
dense
this
cells from individual
small or medium
with berberine
sulfate
in one expericontained
a mixture
of positive
and
stained
negative
cells,
sulfate-positive
the
with
it was necessary
to pool three
to 20 small
or
colonies
to determine
the percentage
of berberine
Although
medium
Mast
colonies
were
lymphoid
cellt
cell
pooled
to prepare
a sample.
removal
of macrophages
increased
the concentration
of L-CFU-Mast.
cells by light microscopy
(Fig 2) as described
by Nakahata
et al.
Thus
From www.bloodjournal.org by guest on March 1, 2016. For personal use only.
576
KANAKURA
ET AL
108
1O
(
§
Total
v
.
Cells
foe
10
>.
c1o5
lO
,
;<;;_
Mast
Cells
a
io
15
20
Weeks after Water Wijection
Fig
3.
Numbers
of total nucleated
cells and morphologically
identifiable
mast cells in the peritoneal
cavity
of WBB6F,+ I +
mice at various
times after the IP injection
of distilled
water.
Each
point represents
the mean
±
SE of five to eight mice. The SE of
total nucleated
cells was too small to be shown.
The points on the
left side represent
the value
observed
at one day after
the
injection.
Hatched
areas
represent
the mean
±
SE observed
in
intact
WBB6F1+ I + mice.
Fig 4.
Numbers
of L-CFUMast,
M-CFU-Mast,
and
S-CFUMast
in the peritoneal
cavity
of
WBB6F,-+
I +
mice
at various
times after the IP injection
of distilled water.
Each point represents
the mean
±
SE of five to eight
mice.
The points
on the left side
represent
the value
observed
at
one
day
after
the
injection.
Hatched
areas
represent
the
mean
±
SE observed
in intact
WBB6F1+ I + mice.
row
cells
to analyze
Neither
small
nor
the peritoneal
of distilled
The
medium
cells
harvested
water,
number
at I week
mast
cell
at 24 hours
but only large
of L-CFU-Mast
after
week
injection
(Fig
developed
after
the preinjection
increase
+
developed.
and continued
4). The
injection
from
the injection
mast cell colonies
exceeded
the water
up to the third
colonies
to increase
of M-CFU-Mast
identifiable
mast
Peritoneal
cells
recovered
which
had been injected
with
from
dense
and
into
the
used
for separation
+
I+
light
distilled
water.
Thus
and the light
L-CFU-Mast,
distilled
fractions
which
water,
fractions
occurred
(Figs
with
cells
the
from
intact
the
whole
in the light
fraction
(Table
the number
of L-CFU-Mast
in the light fraction
cantly
larger
than the number
of morphologically
able
tion
mast
cells,
L-CFU-Mast,
Recruitment
of CFU-Mast
diation
chimeras
produced
Table
2.
Presence
in the peritoneal
by transplantation
of L-CFU-Mast
in the Light
20 weeks
identifiable
Mast and
cells
of
of
cavity.
of bone
No
Mice
Intact
1 wk after
injection
Peritoneal
cells
of ten
of five replicate
of light
cells,
cultures.
1 .077
in
the
but
mast
were
small
and
cells
in the
3). In other
words,
of bg’/bg-’
and
cells
/
+
then
+ radiation
appeared
chimeras;
again.
and CFU-Mast
When
were
mast
types
water increased
in the peritoneal
the number
of
cavity
of bg/
chimeras.
We investigated
whether
the injection
water induced
the proliferation
of CFU-Mast
of
in the peritoneal
cavity.
from WBB6F,-+/+
injection
were divided
incubated
with
or
without
Peritoneal
cells
that
were
mice at various
times after
into two aliquots;
each was
hydroxyurea.
The
number
Ra-
in the bone marrow,
which was used as a control,
after the hydroxyurea
treatment
(Table
4). Numof L-CFU-Mast
in the bone marrow
and the peritoneal
bers
of Peritoneal
Cells
Removed
of Distilled
from
WBB6F1-
+ I + Mice
at Various
Times
After
CelIst
No. per 10’ Light
Mast Cell
114.0
1620.0
L-CFU-Mast
Cellst*
S-CFU-Mast
2.8
Mast
2.8
Cell
19.0
4.0
22.0
0.3
17.0
0.8
1.5
7.2
29.0
29.0
0.8
3.0
g/mL.
tenths
of cells
were
the
Water
16.0
nine
of
GM-CFU
decreased
1.0
pooled;
at
after
the water
injection,
most morphologically
mast cells and S-CFU-Mast
and all M-CFUL-CFU-Mast
were of bg/bg
type (Table
3).
0.3
were
of
determined
12.0
treatment.
Density
type
S-CFU-Mast
4.0
mice
BMT.
chimeras
(Table
type
peritoneal
after
+
cells
type
+
/
of bg/bg
mast
bg-’+/+
harvested
the water
mar-
Unfractionated
+
/
IP
bg/bg-.’
whereas
2 months
+
used
after
14.0
wk after injection
tMean
per 1O
1.4
3wkafterinjection
5
.
L-CFU-Mast
type,
mast
The IP injection
ofdistilled
bg’/bg-type
L-CFU-Mast
each
injecthe
IP Injection
were
process of CFU-Mast
Neutrophils
of the
bg/bg
of
irradiated
changed
cavity
of distilled
2). Since
after
were
disappeared
WBB6F,-
to have
Fraction
colonies
L-CFU-Mast
peritoneal
was signifiidentifi-
which
increased
not considered
of distilled
water,
were
morphology
of mast cells.
large
were
to
chimera),
methylcellulose,
only
differentiated
The increase
the injection
of
were
colonies
technique
peritoneal
in methylcellulose.
was observed
after
the recruitment
of distilled
water.
in
cells
numbers
of cells were not recovered
up to 5 weeks after the injection
of
we cultured
mice
to the donor type in the peritoneal cavity of bg/bg-.’
+ / + chimeras.
Three
milliliters
of distilled
water
was injected
into the
3 and 4).
same
Weeks after Water Injection
C57BL/6-bg/bg
mice (bg’/bg-’+/+
chimeras
medium
WBB6F,+ / +
mice,
water, were separated
distilled
of peritoneal
mice. Significant
dense fraction
in the
cells
I
cells remained
of +1+
type
peritoneal
cells of bg/bg-..
cultured
followed
the increase
of L-CFU-Mast
and reached
the
preinjection
level at 3 weeks after the injection.
Then the
number
ofS-CFU-Mast
started
to increase
with the increase
of morphologically
I+
mast
When
level
from
WBB6F,-+/+
_________
10
.
fractionated;
the
remaining
one
tenth
of cells
4.0
were
cultured
without
any
From www.bloodjournal.org by guest on March 1, 2016. For personal use only.
DIFFERENTIATION
Table
OF
3.
MAST
Numbers
CELLS
577
and Types
of CFU-Mast
and Morphologically
Radiation
Chimeras
Identifiable
Before
and After
No. per 1 0’ Peritoneal
Number
bg/bg-
+1+
1 wk after
injection
chimeras
Cells
Cells and Proportion
Proportion
of
Mast
bg/bg-type
Mast
0.5
100%
3.5
0%
34.0
0%
9.0
100%
4.8
95%
0.3
ND
injection
3.2
100%
7.8
100%
1 1.0
96%
injection
1.0
100%
6.5
100%
31.0
98%
after
four
4.
Effect
of Hydroxyurea
due to paucity
Treatment
of mast
on the Number
of Mast
Cell
Colonies
Percent
Organ
Mice
Intact
after
injection
3 wk after
injection
5
injection
wk after
Percent
a
tNA.
decrease
significant
CFU-Mast,
most
peritoneal
of
and Granulocyte-Macrophage
the proportion
of Colonies
Decrease
Colony
0
NAt
Peritoneal cavity
NAt
15
0
NAt
Peritoneal
cavity
NAt
14
0
0
Peritoneal
cavity
+
not
NAt
decreased
by the
of M-CFU-Mast
and
(Table
4). The injection
of distilled
proportions
of L-CFU-Mast,
Min S-phase
and
27
cells/No.
(Table
4).
S-CFU-Mast
in
the
of differentiated
that incorporated
5, the proportion
WBB6F,+ / +
mast
BrdUrd
was
I%
mice,
and
by the injection
of distilled
The
number
comparable
cell
did
ofCFU-Mast
in the blood
S-CFU-Mast
were
not
present
was a possibility
that the increase
peritoneal
cavity
reflected
the
in the blood,
the IP injection
of
not increase
deficient
5.
Cavity
the number
of L-CFU-Mast
Proportion
of Mast
Cells
Injection
in S-Phase
at Various
of Distilled
Mice
Intact
3 wk
after
Mast.
mast
injection
Cells
of cells that incorporated
significant
SE; number
differences
0.2
±
0.3
(6)
±
0.1
(5)
±
0.2
(7)
in parentheses.
mice of different
experimental
cells
on
Numbers
of morphologically
cell colony-forming
units
the water
injection.
such
as the simple
invasion
of
L-CFU-
identifiable
to induce
cavity,
there
the invasion
is a possibil-
cells may inhibit
the invasion.
IP injection
ofwater,
and then
two
groups.
injected
group
of
smaller
in
mice (Table
morphologically
appeared
into
were
mast
number
did not increase
mice even after
process,
of
of mast
received
the other
the increase
control mice.
(7)
mast
injection
divided
(2 x l0)
of morphologically
into
of mice
Purified
peritoneal
the peritoneal
cavity
was used as a control.
identifiable
mast cells and mast
were determined
I and 3 weeks
As shown
identifiable
of L-CFU-Mast,
in Table
7, the presence
mast cells significantly
which was observed
inhibin the
DISCUSSION
BrdUrd. The results are shown
of mice is shown
between
IP
ited
±
0.9
±
the
S-Phase (%)
0.8
12 wk after
injection
in
0.6
1.0
Proportion
Peritoneal
After
a passive
of
to be
the increase
in the concentrato be an active process,
such
into the peritoneal
were
is known
genetically
of L-CFU-Mast
of WBB6F,-W/W”
water,
appeared
ity that the presence
WBB6F,-+/+
mice
cells
mice,2’
eradication
by water
of L-CFU-Mast
mice
and
much
effect
Since
cells
in the blood
in the peritoneal
cavity
was
mice than in WBB6F,-+/+
as invasion,
rather than
leak from capillaries.
after
7wkafterinjection
the mean
in the
Times
Water
Mast
100.
the
the injection
ofdistilled
tion of L-CFU-Mast
mast
+ I + Mice
x
but
6). Since the concentration
in the peritoneal
cavity
the
6).
of WBB6F,-
cells)
WBB6F,-+/+
WBB6F,-W/W”
of one group;
Table
6
by control
of L-CFU-Mast
Inhibitory
(Table
produced
between
L-CFU-Mast
WBB6F,-W/W”
water.
the concentration
0
of colonies
appear.
also
numbers
was not increased
water
Colony
Cell
NAt
/
and
Small Mast
0
were
M-CFU-Mast
Mast
Cell Colony
29
by hydroxyurea-treated
and
Treatment
Medium
29
+
(Table
6). Although
there
of L-CFU-Mast
in the
increase
of L-CFU-Mast
by Hydroxyurea
Large Mast
Cell Colony
37
had the morphology
We measured
in Intact
NAt
cavity
marrow
did
but
Colonies
Peritoneal
the proportion
of mast cells
was measured.
As shown in Table
in the peritoneal
cavity
of intact
in the blood
90%
NAt
cells,
distilled
89%
NAt
M-CFU-Mast
cavity
in which
72.0
570.0
13
and S-CFU-Mast
Since
NDt
33
of colonies
WBB6F,-
were not
not increase
Macrophage
No. of colonies produced
(1 -
=
treatment,
hydroxyurea
S-CFU-Mast
water
did
0%
2.0
Bone marrow
Bone
numbers
of intact
cavity
1,040.0
+ I + Mice
WBB6F1-
Granulocyte-
wk
Proportionf
cells.
Water-Injected
1
Cells
Number
to six mice.
tTvpe of mast cells in the colony.
tND, proportion could not be determined
Table
+ I +
-‘
Cells
Proportion
Number
12 wk after
wk
of bg/bg
S-CFU-Mast
Proportion
Number
Cavity
Water
20
Mean of
as
in the Peritoneal
of Distilled
M-CFU-Mast
L-CFU-Mast
Mice
Mast
Injection
There
‘oups.
are no
CFU-Mast
of colonies
L-CFU-Mast
were divided
into three
as a criterion;
S-CFU-Mast,
produced
small,
medium,
types by using
M-CFU-Mast,
and
large
the size
and
mast
cell
From www.bloodjournal.org by guest on March 1, 2016. For personal use only.
578
Table
6.
Number
of C FU-Mast
of Various
Types
in Blood
and Peritoneal
lnj action
Cavity
of Distilled
I + and -W/W
of WBB6F1-+
Mice
Blood
+
/
+
L-CFU-Mastt
+1+
Intact
1 wk
,
after
injection
IntactW/W’
1 wk after injection
+1+
WIW’.
Peritoneal
cavity
Intact
w/wv,
Blood
a
mononuclear
tMean
of
colonies,
cells
five replicate
mast
Mast.
The
cells
S-CFU-Mast
was
and
morphology
CFU-Mast
were
with
The
tiated
IP injection
mast
cells.
also
eradicated
mast
mast
cells
sensitive
by
this
cells
with
were
colonies
were
not
0
0
0
0
0
C)
1.8
0
0
0
2. 1
0
0
0
14.5
was attributable
rather
than
0.2
0
0
0
0.2
0
0
0
sulfatefrom
not
only
potential
eradicated,
preinjection
level at 1 week
water.
Since
the proportion
the injection
of morphologically
without
proliferation
from
within
identifiable
of L-CFU-Mast
of distilled
water.
(with
we
(Fig
when
Table
7.
numbers
Effect
of M-CFU-Mast
of IP Injection
of Purified
mast cells
that was
1 wk
3 wk
Purified
tThe
P
<
after water
after
water
peritoneal
injection
injection
mast
cells
(2
x
10)
were
study’
numbers
blood
+
since
S-CFU-Mast
low
Peritoneal
Mast
not
identifiable
mast
may
suppress
potential)
to M-CFU-Mast
mononuclear
enter
cells
the
and
peritoneal
in
part
L-CFU-Mast,
produce
mast
as
cell clusters
of L-CFU-Mast
discussed
but
by
cells
of
above.
and
0.2
No
6
1 8.2
±
2.2
Yes
5
5.7
±
0.6t
No
6
1 2.0
±
1 .0
Yes
5
3.7
±
1.0
after
were
However,
S-CFU-Mast
in the
mast
simply
Cavity
the
not
injection
injected
of distilled
with
purified
cavity
of Water-Injected
Cellsf
Mast
2,620
2,720
2 1
3,000
mast
cells
by
t
test.
Cells
±
7
water.
peritoneal
W/W’
cells at the
reflect
the
peritoneal
L-CFU-Mast
2.5
sites of
We conof mast
in the skin of WBB6F,-
in the Peritoneal
±
that
peritoneal
M-CFU-Mast,
No. per 1O Nucleated
mice
the
5). In
mast
of L-CFU-Mast
proportion
No. of Mice
days
(Fig
of
cells
cavity
that
contained
cells. This explana-
of differentiated
of
IP two
were
I + Mice
5
injected
to
we carried
out a similar
experiment,
and types of mast cell precursors
be correct
all
on Number
No
results
are shown
as the mean
± SE.
.01 , when compared
with the value of the control
5-
but
L-CFU-Mast
mice,’
the low proportion
of bg/bg-type
injection
sites of the peritoneal
cells may
Cells
and
I+
number
may
tion
Mast Cells
Intact
proliferation
of L-CFU-Mast
measured
not
and S-CFU-Mast
that the presence
of morphobogically
or without
cells did
sufficient
the
and
.
chimeras,
M-CFU-Mast
is a possibility
mast cells, whereas
only one of 48 injection
peritoneal
cells contained
bg’/bg’-type
mast cells.
sidered
at that time that the circulating
precursors
may
.
did
bg-type
cavity.
disappearance
to peritoneal
Injection
propor-
radiation
chimeras
into the skin of WBB6F,w/wv mice. All 32 mast cell clusters that appeared
at
injection
sites of blood
mononuclear
cells contained
bg’/
WBB6F1-+
Mice
water,
in S-phase
with the low proportion
of mormast
cells
that
incorporated
whereas
There
number
bg/bg’-”
5).
Even
+ type.
+1
injecting
identifiable
mast cells (with or
potential)
appears
to suppress
the
effective
invasion
of L-CFU-Mast,
and their
may enhance
the invasion
from the bloodstream
of distilled
and S-CFU-Mast
radiation
type,
the previous
L-
after
of
Therefore,
the injection
is consistent
identifiable
differentiation
the bloodstream
the peritoneal
after
This
a certain
the
L-
of
number
of M-CFU-Mast
In bg/bg’-”+/+
to be
with
cells,
increasing
tions
of bg’/bg’
were of
but
appeared
the
and
to the invasion
presence
cavity
4.5
BrdUrd.
Therefore
the increased
of M-CFU-Mast
CFU-Mast
may not be attributable
to their division
recruitment
from L-CFU-Mast
(Fig 5).
terminal
potential
were
increase.
phologically
eradicated
differenand
M-CFU-Mast
pressure.
In contrast
identifiable
mast
to the proliferation
after
1,470
0.9
from L-CFUdense cells with
proliferation
The IP injection
of morphologically
significantly
inhibited
the increase
observed
1 18
7.2
L-CFU-Mast
in S-phase
was not augmented
by the water
injection,
the increase
of L-CFU-Mast
in the peritoneal
cavity
Differentiated
Mast Cells
S-CFU-Mastt
pooled.
derived
derived
were
treatment,
proliferation
exceeded
the
of distilled
injection
mice
of berberine
in
without
to the low osmotic
of morphologically
eradication
CFU-Mast
CFU-Mast
the
proportion
highest
of distilled
water
Since
S-CFU-Mast
differentiated
also
of five
Cells
2. 1
of differentiated
mast cells,
whereas
Llight cells that were not granulated.
This is
the report of Nakahata
et al.8
consistent
were
cells
lowest in colonies
and M-CFU-Mast
S-CFU-Mast
the
and peritoneal
injection
the
cultures.
respectively.
positive
1 wk after
W ith or Without
2.0
15.2
W/W’
Intact
M-CFU-Mastt
2.3
1 wkafterinjection
+/+.
ET AL
Water
No. per 10’ Nucleated
Organ
Mice
KANAKURA
±
230
1
±
570
±
4
±
740
of
From www.bloodjournal.org by guest on March 1, 2016. For personal use only.
DIFFERENTIATION
OF MAST CELLS
579
into four stages
of stage 1 mast
stages
with
cells
2 to 3 mast
safranin
cells
increased;
in-positive
alcian blue-safranin
were stained
only
the number
stage
granules.
4 mast
of granules
cells
of
figures
granules
blue; in
stained
contained
Incorporation
of mitotic
identification
staining:
with alcian
only
with
safran-
[3H]thymidine
indicated
that
and
mast
cells
in
stages I and 2 comprised
a mitotic
pool, whereas
those in
stages 3 and 4 were mitotically
inactive.28
In mice, stage 4
mast cells of Combs
et al28 are few, even in the adult
5.
A scheme
for differentiation
of peritoneal
mast cells. L,
L-CFU-Mast;
M, M-CFU-Mast;
S. S-CFU-Mast;
T represents
a
differentiated
mast cell that lacks proliferation
potential.
M, 5, and
T cannot
be distinguished
by morphological
methods.
The presence of differentiated
mast cells (with
or without
proliferation
potential)
appears
to suppress
the invasion
of L-CFU-Mast
from
the
bloodstream
to the peritoneal
cavity
(arrow
1 ) and the
differentiation
of L-CFU-Mast
to M-CFU-Mast
(arrow
2).
Fig
peritoneal
cavity,
and this
sulfate
instead
of safranin.”
is the reason
Although
direction
proposed
of differentiation
that
claim
necessarily
berberine
lack
of
mean
the lack
B cells,
radiation
chimeras.
method
is more
kinetic
The
other
suitable
words,
than
the
the previous
with
consistent
who
investigated
embryos.
in
the model
differentiation
for
in Fig 5 is
proposed
of
vitro
method
presented
differentiation
classified
They
present
in vivo
analysis
of mast cell precursors.
model of mast cell differentiation
principally
al,”
In
by Combs
mast
cells
process
et
in
rat
of mast
cells
mast
cells
cells,
does
potential.
may
to originate
finally
bone marrow.
Some macrophages,
proliferate
after differentiation.36’3’
either
in
Langerhans
are known
and to differentiate
not
In fact,
proliferate
macrophages,”
and T cells34”5
the bone marrow
et al,28 we
incorporation
of proliferation
sulfate-positive
berberine
with the
by Combs
[‘H]thymidine
vivo2’ or in vitro.30
In addition
to mast
cells’2’33
we used
we agree
after
from
leaving
the
B cells, and T cells
Moreover,
the same
may
mol-
ecules,
ie, IL 4, are used to stimulate
the proliferation
of
differentiated
mast cells, B cells, and T cells.’38’39 The model
described
in Fig 5 explains
the differentiation
of mast cells in
the peritoneal
cavity of mice, but it may be applicable
at least
in part
to differentiation
of the above-mentioned
cell types.
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From www.bloodjournal.org by guest on March 1, 2016. For personal use only.
1988 71: 573-580
Changes in numbers and types of mast cell colony-forming cells in the
peritoneal cavity of mice after injection of distilled water: evidence that
mast cells suppress differentiation of bone marrow-derived precursors
Y Kanakura, A Kuriu, N Waki, T Nakano, H Asai, T Yonezawa and Y Kitamura
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