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Quantitative studies of lymphocytes and other cell populations in the bone marrow of neonatally thymectomized C3H mice.

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Quantitative Studies of Lymphocytes and Other Cell
Populations in the Bone Marrow of NeonatallyThymectomized C3H Mice
s. C . MILLER A N D D. G . OSMOND
Department o f Anatomy, McGill University, P . 0. Box 6070,Station A,
Montreal, Quebec, Canada H3C 3G1
ABSTRACT
The effects of neonatal thymectomy on the development of the
lymphoid, erythroid and granulocytic cell populations in mouse bone marrow
have been assessed by quantitative techniques. The numbers per unit volume of
bone marrow of 17 cell types were determined in neonatally thymectomized and
sham thymectomized C3H mice a t two, four and eight weeks of age, and compared with those of normal C3H mice. After neonatal thymectomy the numbers
of small lymphocytes, large and medium-sized lymphoid cells, and erythroid cells
reached normal levels at two weeks but fell progressively to 1 8 % , 22% and 42%
of normal, respectively, by eight weeks. In sham thymectomized mice these cell
populations did not differ significantly from normal. Immature and mature
granulocytes were elevated in numbers two weeks after either neonatal thymectomy or sham thymectomy, suggesting a transient non-specific stimulation of
granulocytopoiesis. During continuous infusion of 3H-thymidine for ten days in
neonatally thymectomized mice aged four weeks and eight weeks many bone
marrow small lymphocytes remained unlabeled. The results demonstrate that
early postnatal development of bone marrow lymphoid and erythroid cells proceeds normally in the absence of the thymus, in accord with the concept of the
bone marrow as a primary site of lymphocyte production and differentiation. In
addition, some slowly-renewing small lymphocytes in bone marrow appear to be
thymus-independent cells.
Large numbers of small lymphocytes are
produced continuously in mammalian bone
marrow (Osmond and Everett, '64; Miller
and Osmond, '73; Osmond, '75) from
which they migrate to peripheral lymphoid
tissues, notably the spleen and lymph
nodes (Brahim and Osmond, '70). Soon
after their production, many bone marrow
small lymphocytes show immunoglobulin
molecules on their surface (Osmond and
Nossal, '74), suggesting that this process
represents a primary genesis and dissemination of B lymphocytes, i.e. cells with
readily detectable surface immunoglobulin mediating humoral immune responses.
Functional assays of antibody-forming cell
precursors in bone marrow are consistent
with this view (Stocker et al., '74). Of importance to such a concept of the bone
marrow as a primary lymphoid organ is
the question whether the development of
intense lymphocytopoiesis is an intrinsic
ANAT. REC., 184: 325-334.
property of the marrow or is secondary to
extramyeloid influences.
The possibility that thymic factors may
influence cell production in other lymphoid
tissues has been suggested by the activity
of thymic extracts in vitro (Stutman et al.,
'70) and by the effects of either thymic
grafts or diffusion chamber implants on
neonatally thymectomized animals in vivo
(Miller and Osoba, '67). However, these
studies have been concerned only with
lymphocytes in the lymph nodes, spleen
and blood. While the effects of neonatal
thymectomy on peripheral lymphoid populations are well known (Miller and Osoba,
'67), there appear to have been no quantitative studies of the effects on marrow
lymphocytes. A relationship between the
thymus and the production of erythrocytes
in the marrow has been suggested by the
observations that neonatal thymectomy is
Received May 30, '75. Accepted Aug. 21, '75.
325
326
S. C. MILLER AND D. G . OSMOND
(Coulter Electronics, Model B). The marrow was centrifuged, smeared in serum,
and stained with MacNeal's tetrachrome.
The total cellularity and absolute numbers
of various marrow cell types per mm3 were
determined by the method of Wller and
Osmond ('74). Approximately 2,500 nucleated cells were examined along the
middle third of each smear and classified
as detaiIed elsewhere (Miller and Osmond,
'74).
RH-thymidine infusion and radioautography. Two further groups of ten neonatally thymectomized mice were infused
subcutaneously at four weeks and eight
weeks with 3H-thymidine (spec. act.: 6.7
Ci,/mM; New England Nuclear Corp.,
Boston, Mass.) at a rate of 2 clCi in 0.04
ml sterile water/gm body weight/day as
described elsewhere (Miller and Osmond,
'75). Animals were killed at 12 hours and
at daily intervals from one to ten days
MATERIALS AND METHODS
after beginning isotope infusion. Smears
Animals. Male C3H/HeJ mice (Jack- of femoral marrow were fixed in methanol
son Laboratories, Bar Harbor, Me. ) were and prepared for radioautography by coating with Kodak NTB, liquid emulsion, exused.
Operative procedures. Thymectomy and posing for 21 days, processing and staining
sham thymectomy were performed under with MacNeal's tetrachrome. From each
ether anesthesia within 16 hours of birth. animal, 2,000 nucleated bone marrow cells
Through a midline incision the cervical were counted through the middle third of
strap muscles were displaced laterally, the the smears and the proportion of small
sternum was separated from the fmt two lymphocytes (< 8.0 p nuclear diameter),
ribs and pulled forward. The thymus was identified as described elsewhere (Osmond
ablated by gentle suction. The skin was and Everett, '64; Osmond, '67; Osmond
sutured and sealed with aerosol plastic et al., '73; Miller and Osmond, '73), was
dressing. Sham thymectomized mice were determined, From 1,000 small lymphocytes
subjected to the same anesthesia and oper- in each animal the percentage of labeled
ative exposure. All thymectomized animals cells was noted. In each experiment three
used in the experiments showed an ab- or more radioautographic grains indicated
sence of thymic tissue in the mediastinum positive labeling of small lymphocytes by
when examined under a stereomicroscope comparison with counts of background
grains over 500 erythrocytes.
(X 18).
Bone marrow sampling. Groups of ten
RESULTS
thymectomized and ten sham thymectomized mice were sampled at two, four and
All neonatally thymectomized C3H mice
eight weeks of age. A further group of showed a reduced growth rate from two
ten normal, aged mice were sampled at weeks and the appearance of a progressive
78 weeks. To avoid diurnal variation in runting syndrome from three weeks oncell populations all animals were sampled ward. These features did not appear after
at the same time of day (3 PM). Bone mar- neonatal sham thymectomy.
row was gently flushed from femoral shaft
Total cellularity o f the bone marrow.
segments with fresh rat serum plus 3.8% In both neonatally thymectomized and
sodium citrate (3: 1) and suspended by sham thymectomized mice the total numaspiration. Nucleated cells were enumer- ber of nucleated cells per unit volume of
ated with an electronic particle counter femoral marrow was higher than normal
followed by an apparent erythroid maturation arrest in opossums (Miller et al., '65)
and anemia in mice (Metcalf, '66), and
that thymus suspensions exert a beneficial
effect on erythropoiesis when injected with
bone marrow cells into lethally irradiated
allogeneic mice (Goodman and Grubbs,
'70; Lord and Schofield, '73).
The present studies aimed to determine
the effects of thymic ablation on the postnatal development of lymphoid, erythroid
and myeloid (granulocytic) cell populations in mouse bone marrow. Quantitative techniques, developed previously to
study murine bone marrow during normal
growth and development (Miller and
Osmond, '74), were used to enumerate
cells at each morphologically distinguishable stage of differentiation at early intervals after either neonatal thymectomy or
neonatal sham thymectomy.
BONE MARROW OF NEONATALLY THYMECTOMIZED C3H MICE
at two weeks of age ( p < 0.001 j but fell to
normal by four weeks (fig. 1). Subsequently, in thymectomized mice the marrow cellularity continued to fall while
sham thymectomized mice maintained normal values (fig, 1 ) .
Bone m a r r w cell populations. Neonatal thymectomy resulted in selective
changes in the major groups of nucleated
cells in the bone marrow, as shown in
figures 2 and 3.
The increased marrow cellularity at two
weeks was attributable entirely to significantly increased nunibers ( p < 0.001) of
myeloid cells in both the neonatally
thymectomized and sham thymectomized
mice (fig. 2 ) . The myeloid cells fell to
normal values by four to eight weeks in
sham thymectomized mice. These values
also fell in neonatally thymectomized mice
at two to four weeks, but they failed to return completely to normal. The numbers
of nucleated erythroid cells per unit volume of bone marrow were unaffected by
neonatal thymectomy, except that they did
not show the usual pubertal rise at eight
weeks (fig. 2). The numbers of small lym-
phocytes in the bone marrow of neonatally
thymectomized mice attained normal high
levels at two weeks (fig. 3 j . Thereafter,
the sham thymectomized mice continued
to follow normal levels but the values in
neonatally thymectomized mice fell progressively to 18% of those in the sham
operated mice by eight weeks. The large
and medium-sized lymphoid cells fell simultaneously to 30% of sham operated
values by eight weeks.
Subpopulations of bone marrow cells
are detailed in tables 1 and 2, as reported
previously for normal C3H mice (Miller
and Osmond, ’74). Fluctuations in the
lymphoid, erythroid and myeloid cell lines
affected cells at each stage of differentiation in a proportionate manner. In particular, the ratios of late, non-dividing forms
in each cell line (small lymphocytes; late
erythroblast s ; met amyelocytes plus band
cells and polymorphonuclear leucocytes )
to the earlier, proliferative stages remained
closely comparable in neonatally thymectomized, sham thymectomized and normal
mice at all ages studied.
Small numbers of plasma cells were
3.0
r,
E
E
\
2.5
“0
x
-B 2 . 0
el
3
e
1.5
m
0
n
v
g 1.0 -
m
0
z
0
0
I
2
3
4
5
6
7
8
Age (weeks)
Fig. 1
Total numbers of nucleated cells per unit volume of femoral marrow in normal
neonatally thymectomized (- -)
and sham thymetomized ( - - - - - )
C3H
mice of various ages.
(-),
327
328
S . C. MILLER AND D. G . OSMOND
1600 I400
11.
-
MYELOID
CELLS
1200 -
-
nE 1000
-
E
\
n
-o
aoo-
X
v)
600 -
0"
400
-
200
-
01
0
1
I
2
3
4
5
Age (weeks)
6
7
8
Total numbers of myeloid and erythroid cells per unit volume of femoral marrow
(-),
neonatally thymectomized (- -), and sham thymectomized ( - - - - - )
C3H mice of various ages.
Fig. 2
in normal
aoo
SMALL LYMPHOCYTES
T
700
600
E
E
500
\
"
--
0 400
\
x
v)
2 300
200
\
\
\
\\
\\
MEDIUM AND LARGE
LYMPHOID CELLS
100
C
I
2
3
4
5
A g e (weeks)
6
7
8
Total numbers of lymphoid cells per unit volume of femoral marrow in normal
neonatally thymectomized (- -)
and sham thymectomized (- - - --) C3H
mice of various ages.
Fig. 3
(-),
BONE MARROW OF NEONATALLY THYMECTOMIZED C3H MICE
329
TABLE 1
Absolute numbers of cells in femoral marrow of neonatally thymectomized C 3 H
mice of various ages ( x 103/mm3)
Cell type
Small lymphocyte
Medium-sized lymphoid cell
Large lymphoid cell
Total lymphoid
Proerythroblast
Early erythroblast
Intermediate erythroblast
Late erythroblast
Total erythroid
Myeloblast
Promyelocyte
Myelocyte
Metamyelocyte
Band
Polymorphonuclear
Total myeloid
Unclassified blast
Unclassified mitotic figures
Other
Damaged forms
1
2wkl
4wkl
8wkl
656.62 36.4
90.6 2 7.2
17.0-C 0.9
764.2 2 38.7
4 . 0 i 0.9
15.5-C 4.1
5 7 . 9 i 15.2
244.7542.0
322.1 i60.7
24.3rl: 2.2
112.7rl: 3.9
823.8-C 53.9
298.6-C 18.2
224.62 19.8
11.92 0.8
1495.9 % 76.6
7.2% 1.2
28.92 4.3
9 . 6 i 0.7
234.7 2 30.9
452.9 rl: 45.2
64.8% 7.1
1 8 . 9 2 3.3
536.6251.3
4 . 0 2 1.0
10.12 1.5
50.0% 8.0
146.52 19.7
210.7226.4
23.0% 2.6
84.62 7.1
564.0 i26.8
224.4 2 17.3
181.3 1: 17.0
21.8-e 2.8
1099.0 i52.7
13.2-e 2.5
13.6f 1.9
11.22 1.5
174.62 17.6
87.2 2 17.0
18.42 5.1
8.1-C 2.3
113.8223.7
6.0C 1.06
18.12 3.2
38.2-C 5.4
94.9 2 12.8
157.2221.7
19.3C 1.8
94.42 8.2
627.2 2 36.4
208.72 17.2
181.22 15.6
3 4 . 7 r 3.4
1165.5265.5
2 . 4 2 0.4
13.72 1.1
4 . 9 2 0.9
132.2k 13.9
Mean 4 standard error; ten mice.
TABLE 2
Absolute numbers of cells in femoral marrow of neonatally sham thymectomized
C3H mice of various ages ( x 103/mm3)
Cell type
Small lymphocyte
Medium-sized lymphoid cell
Large lymphoid cell
Total lymphoid
Proerythroblast
Early erythroblast
Intermediate erythroblast
Late erythroblast
Total erythroid
Myeloblast
Promyelocyte
Myelocyte
Metainyelocyte
Band
Polymorphonuclear
Total myeloid
Unclassified blast
Unclassified mitotic figures
Other
Damaged forms
1
Mean
+-
2wkl
699.52 53.1
119.4" 11.8
29.6& 5.0
848.5 2 63.9
6 . 8 2 1.4
20.82 2.4
87.72 14.3
277.1 rl: 19.6
392.4 2 35.6
28.3C 3.6
102.42 9.4
876.1 C 87.3
266.5 C 26.5
263.8 i32.6
30.12 7.4
1567.1t 136.3
12.6C 2.9
26.0 2 3.3
11.12 1.1
225.4 C 19.3
4wkl
8wkl
661.7C34.8
101.12 9.6
20.22 2.5
783.0 C 40.2
4 . 6 2 1.0
14.3% 2.6
38.02 7.5
144.0 2 28.5
200.92 38.5
12.7C 0.9
51.5C 4.8
516.7 i37.2
193.5 2 19.5
136.12 19.3
18.52 2.8
929.1 & 56.1
6 . 6 2 0.9
15.7k 1.5
10.2, 1.3
177.0 C 19.6
471.1 227.2
72.4) 5.0
17.22 1.3
560.7 2 30.2
6 . 7 2 1.5
18.42 2.1
59.62 7.6
226.8 2 31.9
311.4538.2
1 8 . 0 i 1.4
59.6) 5.4
527.1 i26.4
226.22 10.8
207.9 2 18.6
31.62 3.1
1070.4 2 43.8
4 . 7 2 0.9
13.72 1.6
8 . 6 2 1.5
170.92 19.7
standard error; ten mice.
found in normal bone marrow, increasing
in incidence with age (table 3). In neonatally thymectomized mice the bone marrow plasma cells were greatly reduced in
numbers but still appeared to increase with
age (table 3).
Labeling of bone marrow small Eymphocytes by "-thymidine. During continuous infusion of "-thymidine into neo-
natally thymectomized mice many bone
marrow small lymphocytes remained unlabeled, in contrast to the high labeling
indices reached in normal animals (Miller
and Osmond, '75). From four to ten days
after beginning infusion the labeling of
bone marrow small lymphocytes fluctuated
from 8.0% to 32.0% in 4-week mice and
from 24.0% to 46.0% in 8-week mice.
330
S. C. MILLER AND D. G. OSMOND
TABLE 3
Incidence of plasma cells in femoral marrow of
normal and neonatalLy thymectonzized C 3 H
mice o f various ages ( p e r
1,000 nucleated cells)
Normal mice
Neonat ally
thymectoniized mice
4wk
8wk
16wk
0.1
0.6
4.2
0.006
0.02
3
Approximately 5,000 nucleated cclls counted at
each age (1,000 cells i n each of 5 mice).
2 Approximately 15,000 nucleated cells counted at
each age (3,000 cells i n each of 5 mice).
3 No neonatally thymectomized mice survived to 16
weeks.
1
Bone marrow cell populations in old
mice. Because the changes in bone marrow cell populations throughout the first
eight weeks in neonatally thymectomized
mice appeared to resemble normal age
changes proceeding at an accelerated pace,
a further group of aged (78-week old)
normal C3H mice was examined. The
number of nucleated cells in the femoral
shaft (13.6 -t. 0 . 7 x 106,'femur) resembled closely the value in normal young
adults (13.5 -C 0.7 X 1Oe/femur at 16
weeks. The relative incidence of the main
marrow cell groups in aged mice were:
small lymphocytes, 12.0
1 . 3 % ; erythroid cells, 7.0 e 1.0%; myeloid cells,
68.0 -r- 1 . 9 % , generally similar to the
cell distribution in the 8-week neonatally
thymectomized mice : small lymphocytes,
5.3 -t. 0.9%; erythroid cells, 10.4 5 1.7%
and myeloid cells, 73.2 2 1.8%.
DISCUSSION
In normal C3H mice the bone marrow
small lymphocytes reach maximal numbers at two to four weeks of age and are
predominately rapidly renewed (Miller and
Osmond, '74, '75). With increasing age
the numbers and renewal rate of these
cells decline (Miller and Osmond, '75).
Recent radioautographic studies in mice
confirm that, as in other rodents, the
rapidly renewing bone marrow small lymphocytes are produced locally within the
bone marrow by the proliferation of large
and medium-sized lymphoid cells (M. Z.
Kaiserman, S. C. Miller and D. G . Osmond,
unpublished). The present quantitative
studies in neonatally thymectomized C3H
mice indicate that the bone marrow lymphocyte population can undergo a normal
early postnatal development even in the
absence of the thymus, previously noted
only in percentage terms (Kalpaktsoglou
et al., '69). Furthermore, bone marrow
small lymphocyte renewal has been shown
radioautographically to occur at a normal
rapid rate in young congenitally athymic
(nu/nu) mice (Osmond and Miller, '75;
Ropke et al., '75). These results are in
keeping with the concept that the production and maturation of lymphocytes in the
bone marrow is thymus-independent.
The cause of the delayed decline in marrow lymphocyte numbers after neonatal
thymectomy is not clear. Since the large
and medium-sized lymphoid cells fall in
numbers as well as the small lymphocytes,
and the labeling indices of the latter during 3H-thymidine infusion are lower than
usual, a secondary reduction in marrow
lymphocyte production seems to be the
case. This might be due to a deficiency of
a thymic lymphocytopoietic factor. If so,
the post thymectomy delay in the effect
wouId indicate either that such a thymic
factor remains active for a prolonged
period after release from the thymus or
that it acts neonatally at a very primitive
stage of marrow lymphocytopoiesis. Alternatively, the secondary decline in marrow
lymphocyte numbers may well be an indirect effect of neonatal thymectomy secondary to the endocrine and other abnormalities of the runting syndrome. Neonatally
thymectomized or congenitally athymic
mice show adrenal cortical enlargement,
reversible by implantation of a normal
thymus (Pierpaoli and Sorkin, '72). Elevated circulatory levels of corticosteroids
and hypersecretion in response to stress
or infection could be responsible for a secondary decline in the cortisone-sensitive marrow lymphocytes (Fruhman and
Gordon, '55; Harris, '61; Morrison and
Toepfer, '67; Esteban, '68; Bennett, '70).
Other contributory factors may be reduced
endocrine secretion by the anterior pituitary, thyroid gland and gonads (Law et al.,
'64; Bianchi et al., '71; Fabris et al., '71a,b;
Sakakura and Nishizuka, '72).
Regardless of its cause, the decline in
numbers of marrow lymphocytes implies
that neonatally thymectomized mice suffer
indirectly from a reduction in production
of virgin B lymphocytes as well as an ab-
BONE MARROW OF NEONATALLY THYMECTOMIZED C3H MICE
sence of thymus-derived ( T ) lymphocytes.
Small lymphocytes in normal mouse bone
marrow develop readily detectable surf ace
immunoglobulin as they mature (Osmond
and Nossal, '74) and migrate to peripheral
lymphoid tissues (Brahim and Osmond,
'73) where they appear to form progenitors
of antibody producing cells in the primary
immune responses (Stocker et al., '74;
Osmond, '75). The immunological defects
of neonatally thymectomized mice during
the runting syndrome may thus be due to
deficiencies in both T and B lymphocytes.
The reduction in numbers of bone marrow
plasma cells noted in the present study
may be due to both the lack of virgin antibody producing cell precursors themselves
as well as of the T helper cells necessary
for the activation of such precursor cells
by many antigens.
Bone marrow of normal mice contains
a small population of long-lived small lymphocytes (Ropke and Everett, '73; Miller
and Osmond, '75) which increases in
numbers with age. Many are recirculating
cells entering the marrow from the blood
stream (Ropke and Everett, '74). While
some of these cells normally are recirculating thymus-derived (T) lymphocytes
(Howard and Scott, '72) the substantial
proportions of small lymphocytes which
remained unlabeled during 3H-thymidine
infusion in the bone marrow of neonatalIy
thymectomized mice in the present study
suggests that some long-lived small lymphocytes in bone marrow are independent
of the thymus in origin. They may be
either indigenous, cy tokinetic ally resting
marrow cells, as described in the rat
(Haas et al., '71), or recirculating marrow-derived (B) cells.
The maintenance of normal bone marrow erythroid cell populations for four
weeks after neonatal thymectomy argues
strongly against a direct dependence on
thymic erythropoietic factors. The secondary disturbance in erythropoiesis seen in
pubertal animals after neonatal thymectomy may be attributed to a generalized
endocrine deficiency. Several hormones including growth hormone (Peschle et al.,
'72), thyroid hormone (Shalet et al., '66;
Peschle et al., '71b), testosterone (Gurney
and Fried, '65), cortisol and ACTH (Peschle
et al., '71a), stimulate erythropoiesis in
331
normal and endocrine-deficient animals,
while a marked atrophy of all the major
endocrine glands occurs during severe
runting in athymic animals (Law et al.,
'64; Bianchi et al., '71; Fabris et al., '71a,b;
Sakakura and Nishizuka, '72).
Granulocytic cells in the bone marrow
are increased in numbers at two weeks
after either neonatal thymectomy or sham
thymectomy, in each case maintaining a
normal ratio of proliferating to non-dividing forms. This is therefore a non-specific
stimulation of granulocytopoiesis, probably occurring in response to tissue damage at operation. The slight elevation in
numbers of bone marrow granulocytic cells
persisting at four and eight weeks after
neonatal thymectomy accords with previous observations in the blood and histological sections of bone marrow (Parrott,
'62; Law et al., '64), and is probably secondary to infection and abnormal levels
of hormones such as corticosteroids (Morrison and Toepfer, '67).
The sequence of cellular changes in the
bone marrow after neonatal thymectomy
resembles normal ageing, greatly accelerated. By eight weeks after neonatal thymectomy the bone marrow resembles that of
78-week old normal mice. These features
complement hematologic (Good et al., '62),
immunologic (Metcalf et al., '67) and endocrine (Pierpaoli and Sorkin, '72) similarities between runting athymic and aged
animals.
ACKNOWLEDGMENTS
The authors thank Mrs. E. D. Watson
for technical assistance. This work was
supported by the Medical Research CounciI of Canada.
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population, marrow, thymectomized, c3h, mice, neonatal, studies, lymphocytes, bones, quantitative, cells
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