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History of the decidual plasmodia or giant cells of Citellus townsendi.

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HISTORY O F THE DECIDUAL PLASMODIA OR GIANT
CELLS O F CITELLUS TOWNSENDI
ROBERT H. KREHBIEL
Zoulogical Laboratory, State College of Washington
FIVE FIQURES
IXTRODUCTION
During the time of gestation certain changes take place in
the uterine mucosa which are distinctly characteristic of the
period. Included among the many changes is found one
phenomenon which is outstanding in that it is restricted to
only a few species of mammals, and is in a true sense of the
word an isolated occurrence. This phenomenon, which is
found in the decidua of the uterus and with certain reservations in the trophoblastic cells of the embryo, is the formation of giant cells. Due to differences observed in their
structure, different names, origins, and functions have been
assigned to them, until to-day the accumulated data make it
impossible to draw any general conclusions regarding their
true nature. The origin and also the structure are subjects
of controversy. While there are a few objections, the generally accepted theory of their function is one of phagocytosis.
The giant cells have been described in the mouse, rabbit,
hedgehog, and man, the most extensively in the mouse. In
the different species of the latter animal variations are found
as to the structure and origin of these enlarged cells. Duval
('91) states that they are derived from the foetal ectodermal
wall, and is supported by Sobotta ( ' 0 3 ) , who finds the giant
cells undoubtedly arising from foetal tissue. Jenkinson ( '02)
attributes the origin to foetal tissue, saying that they are
enlarged trophoblastic cells which migrate into the decidua.
275
THE ANATOXICAL RECORD, VOL. 5 0 , NO. 3
276
ROBERT H. KREHBIEL
I n absolute contradiction to this, Kolster (’03) and Disse
(’06) find that the growth of decidual cells gives rise to the
giant cells. There is a marked resemblance in the structure
of the cells described by Jenkinson and by Disse. I n the
rabbit, Chipman (’03) finds the giant cells to be transformed
epithelial cells of the glands of the uterus, whereas Sansom
(’27) attributes the origin to the trophoblastic cells. I n the
hedgehog, Hubrecht (’89) attributes the origin to maternal
tissue. I n man, Bryce and Teacher (’08) state that the
decidua is the probable source of the giant cells. I n every
case it is to be noted that a giant cell is regarded as the
resultant of the enlargement of a single cell.
This described variation of origin would seem to suggest a
possible difference in structure and function. On the other
hand, variations in structure other than size are very slightin fact, so slight that they do not hinder the investigators in
the acceptance of a general theory as to their function. Thus
it may be said that the ‘megalokarocytes’ of Jenkinson, the
‘Riesenzellen’ of Sobotta and Disse, and the ‘giant cells’ of
Hubrecht, Chipman, Sansom, and Bryce and Teacher are all
f o r the purpose of bringing about changes in the uterine wall,
which will facilitate implantation and placentation. Allow me
to repeat that in all cases the investigators have come to the
conclusion that they are phagocytes. Having done so, they
apparently have interpreted the decidual and blood cells contained in the cytoplasm of the giant cell in such a manner as
t o substantiate their theory of the function of these structures.
Should such a conception be accepted, it would necessitate
the isolation of these cells as distinct in nature from all other
known cells. I n all of the cellular transformations which are
found in any organism it is impossible to find a comparable
enlargement or similar origin of phagocytes. They exceed
in size any other single cell of metazoan bodies known; the
only cells which may be compared in this respect are the large
phagocytic cells of the blood stream. Also, it would be without precedent to assign hemopoietic activity to the trophoblast or to an unmodified mucosa.
GIANT C,ELLS O F CITELLUS TOWNSENDI
277
Evidence that contradicts the above accounts has been
found in the Townsend ground squirrel (Citellus townsendi).
From a purely structural viewpoint I have found that these
structures are not single hypertrophied cells, but are the
result of the fusion of a group of cells, being purely a passive
product, rather than an active structure as previous investigators have concluded. They resemble a plasmodia1 structure
greatly, and due t o the fact that this is contradictory to previous findings, I shall use the term plasmodium rather than put
forth a definite name or use the existing term of ‘giant cell’
in this paper. Should these bodies found in Citellus townsendi be of an entirely different nature than those found in
other species, and should the other structures be true phagocytes, it seems highly important to assign a name to them
which will distinguish them from the giant cells found in
the blood stream. The knowledge concerning these ‘cells’
is not complete enough at the present time to give them a
definite name. However, it seems that a term such as decidual
gialzt cells or decidual plasmodia would serve the purpose
until further research has provided a basis for different
nomenclature.
MATERIAL AND METHODS
The uteri were taken from tlie animals immediately after
they were shot and fixed in Zenker’s bichromate solution. The
enlarged areas, the sites of implantation, were sectioned in
series at 6 and 7 v. The sections were stained very lightly
in Delafield’s haematoxylin before being stained in Giemsa ’s
modification of azur-eosin stain (Grubler ’s prepared solution). Mallory’s triple stain of acid fuchsin, anilin blue, and
orange G, and iron haematoxylin were also used.
ORIGIN AND F A T E O F DECIDUAL PLASMODIA
The plasmodia originate in close approximation to the epithelium and spend their life in the same region. They are
generally confined to the antimesometrial end of the lumen.
Here they occupy the greater part of the decidual region,
278
ROBERT H. HREHBIEL
being from two to five rows in thickness. Decidual cells may
be seen to be distributed among them as well a s connective
tissue. I n general, the epithelium is intact until a general
.. .
.' .
.-
.r
@ Q'
,
P'
I
Fig. 1 Drawing showing tho distribution of the plasmodia. a, mesometriuni;
a', antimesometrial end of lumen; bl, blood in lumen; p , plasmodia; p', region
X 38.
Fig. 2 Section of plasmodia1 region. A, formative stage; B, nuclear stage;
C, late nucleolar stage. n, wall of nuclear structure; n', remains of nucleolar
formation ; T , reticulum formed by disintegration of individual nuclei ; o, vacuolar
remains of a single deteriorated cell; ue, uterine epithelium. X 650.
of placentation.
sloughing off of the plasmodia takes place. At the mesometrial end of the lumen the decidua is destroyed in such a
manner as t o allow the blood t o flow from the opened capillaries into the lumen. This is distinctly a different type of
GIANT CELLS O F CITELLUS TOWNSENDI
279
necrosis from that found in the antimesometrial end (fig. 1).
As soon as the egg has come to rest in the lumen at the site
of implantation, the below-mentioned changes start. The
period through which the plasmodia1 structures are found
persist up to that time when the placental formation is well
under way. A few may be found at the stage in which the
chorionic vesicle has completely filled the lumen and started
to stretch the uterine wall.
The metamorphoses which take place in the plasmodia
necessitate a description of the different stages of their life
history. It seems advisable to divide the span of their existence into four stages, namely: 1) formative, 2) nuclear,
3) nucleolar, and, 4) vacuolar stages. It is to be understood,
however, that at no time is there an abrupt change which
would allow one to divide the life history into four distinct
stages. I n fact, the different cells, which go to make up a
single plasmodium, may be in very different stages of deterioration.
1.
Formative stage
I n the very early periods of gestation the mucosa of the
uterus, throughout most of its extent, is apparently normal
and is lined on the lumen surface by a normal epithelium. I n
a few places, however, marked changes can be seen in the
cells that are located in close approximation to the epithelial
cells of either the lumen or the glands. This alteration consists of the loss of the cytoplasmic contour of the individual
cells. The breaking of the cell wall brings about the liberation of the cytoplasm and allows the several cells to fuse. At
first, definite areas of cytoplasm can be seen to inclose several
nuclei, but as the formation of the plasmodium continues, it
can be seen that there is a marked tendency of the cytoplasm
to become a homogeneous mass (fig. 2, A).
Not only is there a general fusion of the cytoplasm, but
also of the nuclei. When the nuclei are liberated by the
breaking of the cytoplasmic boundaries, they assume a central position. At first, this action can only be detected by the
presence of several nuclei in contact with each other. This
280
ROBERT H. KREHBIEL
nuclear clumping continues until there is a large nuclear
aggregate in the center of each plasmodium. Occasionally
several such aggregates will be formed, and, in some cases,
there is practically no clumping (fig. 2, B).
The deterioration of the cells in a plasmodia1 region is not
regular. There may be found, in the same region of formation, cells which have lost every trace of cytoplasmic integrity.
At the edge of these regions individual nuclei can be seen
Fig. 3 Plasmodium in nuclear stage. a, nuclei being taken into the plasmodia1
structure ; d, decidual cells ; i, individual nucleus with its chromatic material
clumped in the center of the vacuole formation; TL, nuclear formation; n',
resultant nucleolar formation of a few aggregated disintegrated nuclei;
2), vacuole with the limiting membrane gone; v', vacuole still retaining a portion
of the membrane. X 650.
which are apparently entering the decidual formation (fig.
3, a ) by the flowing of the cytoplasm out around them. The
nuclei show a similar variation of deterioration. The
chromatin material is generally in the form of small granules,
the majority of them being located at the periphery of the
nucleus. Even in the very early stages there is a lack of
oxychromatic material in all the nuclei, and a few of them
consist of nothing more than a deeply staining broken wall
and a single, central body of chromatin (fig. 2, r ) .
GIANT CELLS O F CITELLUS TOWNSENDI
281
2. Nuclear stage
The nuclei, which have been in different stages of deterioration up to this time, now reach the same point of disintegration in which they consist of nothing more than small
vacuoles with chromatic central masses (fig. 3, i). As the
nuclei become contiguous their adjacent walls disintegrate,
so that a simple fusion of material forms the large nucleus.
The outer part of the membrane of the nuclei at the periphery
of the mass remains and becomes the wall of the fusion
nucleus. Extending from this wall can be seen parts of the
nuclear wall of the individual nuclei which have gone t o make
up the plasmodium. The remainder of the walls of the nuclei
go to form a broken reticulum of the late nuclear and the
early nucleolar stage. The chromatic material, upon the disintegration of the walls of the individual nuclei, may become
scattered throughout the nuclear structure or aggregated
into one or more large masses. The latter is more frequently
found.
3. Nucleolar stage
The assumption of a central position by the chromatic material causes the plasmodium to have the appearance of a
typical, large, single cell (fig. 4). The large nucleolar structure found in this stage, judging from staining quality, undoubtedly arises as a result of a fusion of the chromatic
material of the individual nuclei of the first two stages. At
times, much in the same manner as the nuclei were aggregated
to form the nucleus, the chromatic material forms more than
one nucleolus. The nucleus still retains its wall, which
becomes somewhat more even in outline than it was previously. Vestiges of an incomplete reticulum, formed by the
broken walls of the individual nuclei, can still be seen. Up
until the very late periods of this stage a few independent
nuclei may be detected, as shown at a in figure 4.
282
ROBERT H. IiREHBIEL
4. Vacuolar stage
The destruction of nuclear material leads to the disappearance of the nucleolus and the broken reticulum, leaving the
irregular nuclear wall to surround the vacuole thus formed.
First the nucleolar structure disintegrates, then the reticulum
surrounding it, and finally the nuclear wall itself. There is no
dispersion of material in the process of its final disintegration, but merely a very gradual fading from view of all the
nuclear constituents. The nuclear wall gone, a vacuole is
Fig. 4 Plasmodium in nucleolar stage. a , individual nucleus contained in
nuclear structure; n, nuclear wall; n', nucleolar formation ; ue, uterine epithelium.
X 650.
the only indication, in the very late stages of the plasmodium,
of a previous clumping of nuclei (fig. 5, v).
The cytoplasm, which was assuming a homogeneity in the
formative stage, attains that condition in the nuclear stage.
It remains as such until the nuclear structures have disappeared. However, it contains within it vacuoles of varying size which were undoubtedly formed by independent
small groups of nuclei going through the process of disintegration.
A very fine fibrillation can be detected in the cytoplasm
throughout most of its existence. This characteristic does
GIANT CELLS OF CITELLUS TOWNSENDI
283
not carry over into the final stages, in which the cytoplasm
assumes an extremely coarse fibrous character. The boundaries of the cytoplasm are not distinct. It can be seen to
pass into the surrounding tissue in many places, thus engulfing nuclei (fig. 3, u ) . Connective tissue is found between
the plasmodia, and often there are only a few strands
separating two adjacent ones.
After the nuclear structure has become merely a vacuole,
the cytoplasms of the contiguous plasmodia fuse, and thus
Fig. 5 Plasmodium in vacuolar stage. d, decidual cells; ue, uterine epithelium; w, vacuole without membrane ; w', vacuole still retaining membrane.
X 650.
in the very last stages one finds a wall of cytoplasm, containing connective tissue and vacuoles, lining the lumen of
the uterus. Upon reaching this condition, which has required
the destruction of the decidual cells, and leaving only connective tissue to replace it, the cytoplasm, in turn, deteriorates. The deterioration of the latter consists of a loss of
its compactness (fig. 5) and ends in it being passed off into
the lumen in small portions of much the same size as the
original individual plasmodia, there to become converted into
a finely fibrous structure, and finally disappear.
284
ROBERT H. K R E H B I E L
The destruction of the mucosa by the formation and disintegration of the plasmodia quite naturally leaves the
uterine wall much thinner at the site of implantation than
it is elsewhere, since little more than the muscular wall
remains.
DISCUSSION
From the foregoing description there can be no doubt that
the plasmodia are of decidual origin, and that they arise as
a result of the fusion of a large number of mucosal cells.
If the conclusions drawn by previous investigators are right,
the plasmodia herein described must be regarded as structures which have no likeness to the giant cells they described.
However, when a structural comparison is made, such does
not seem to be the case. The interpretation of past investigators has accounted for the decidual and blood cells contained in the large ‘cells’ on a basis of supposed phagocytic
action of the giant cell. On the other hand, the present
account, it seems to me, makes that interpretation wholly
untenable.
The ‘megalokarocytes’ of Jenkinson ( ’02) and the ‘Riesenzellen’ of Disse (’06) show an inclosure of decidual cells
which are undoubtedly deteriorating, but to ascribe the function of phagocytosis on this basis alone, without accurately
determining their origin, seems rather unjustifiable. In the
‘megalokarocytes one finds a structure which resembles the
plasmodia in every phase other than in their supposed origin
and disappearance. I n his illustrations Jenkinson has shown
individual nuclei inclosed in the cytoplasm of the ‘megalokarocytes’ and also groups of several nuclei clumped as a
result of their deterioration. Disse ( ’06), on the other hand,
did not account for the inactivity of the ‘Riesenzellen’ as they
pass through the capillaries from the base of the decidua,
the site of the origin, to the implantation cavity, where they
supposedly resume phagocytic activity. I am inclined t o
believe that a restudy of Jenkinson’s and Disse’s material
would lead to a classification of these giant cells as plasmodia
of the same type as those found in Citellus townsendi.
GIANT CELLS OF CITELLUS TOWNSENDI
285
The striking resemblance of the ‘cells’ found in the mouse
to the plasmodia is overshadowed by the resemblance of the
latter to the ‘cells’ found in the rabbit, as described by
Sansom ( ’27). This admirably illustrated paper shows giant
cells located under the uterine epithelium in the same manner
as in CItellus townsendi. It is very hard to associate the
structures which he has shown as giant cells with phagocytic
activity. The improbability of such structures coming from
foetal tissue seems great at the present time. Had Sansom
not failed to correlate his findings with those of the other
investigators working with the same animal, he would have
noted resemblances. It seems highly probable that the structures shown in his figure 12, plate 23, are, for the most part,
plasmodia in the later nucleolar stage. Also, it seems rather
inconceivable to attribute the power of division and growth
to such a protoplasmic formation. However, it must be kept
in mind that his giant cells appear at a much later date
than the plasmodia of Citellus townsendi.
Sobotta’s ‘Riesenzellen’ are decidedly smaller than the
other giant cells. They are distinctly part of the chorion and
are merely enlarged cells, the enlargement not being great
enough to set them aside as distinct structures. I n man the
giant cells appear at a much later date and are clearly a part
of placentation; I believe that it may be said with safety
that these cells are, as Sobotta’s cells, entirely of a different
nature.
With the close resemblance of the plasmodia to several
of the previously described structures the question arises :
What should our interpretation of the significance of these
structures be if they are not to be regarded as phagocytes?
It would seem that they serve no purpose other than to
bring about a thinning of the uterine wall in the site of
implantation, and, as such, may correspond very closely t o
the vacuolization found in the higher forms of implantation,
in so far as function is concerned.
An explanation of the formation of the plasmodia upon a
purely microscopical basis is comparatively simple and com-
286
ROBERT H. XREHBIEL
plete; an ascertation of the cause of this phenomenon is by
no means so easy. Since the nature and source of the factors
which bring about this change are unknown, an explanation
of this alteration must be purely hypothetical. I n view of
the present theory, which attributes the changes that are
brought about in the decidual area of the uterus during
implantation and early placentation to the action of the
blastodermic vesicle, the first thought would be, of course,
that the blastodermic vesicle is the instigator of the formation of the plasmodia. The distribution of the plasmodia,
and the different type of necrosis found in the mesometrial
end of the lumen, however, make this conception appear
unsound. On the other hand, there is no positive evidence
to show that it is the maternal system which brings about
the change, although there is less to refute such a supposition. It can readily be seen that this question is but a part
of the general problem of the mechanics of implantation and
the activity of the blastodermic vesicle and maternal system
in effecting it, of which a comprehensive discussion at the
present time is unwarranted.
The formation of the plasmodia suggests some very interesting problems in the field of physical chemistry. It would
seem that the process is perhaps somewhat related to fertilization, in its physical aspects. A solution of these problems
is absolutely essential to a complete understanding of the
phenomena associated with implantation, at least in Citellus
townsendi. An explanation at this time cannot be advanced
didactically, but rather as a suggestive interpretation of the
physical actions involved, which may be supported or rejected by future research. The intrinsic value of such a
hypothesis is, naturally, slight, but it may be of great value
by way of suggesting possible lines of research designed to
isolate and elucidate the factors of implantation.
The first assumption necessary in an explanation of the
phenomena is that the destructive force is acting from two
or more localized points, with the areas of activity located
in a central position in a group of cells. The force acting
GIANT CELLS O F CITELLUS TOWNSENDI
287
from these points attacks the surrounding cells, and brings
about a lowering of surface tension. Thus, the portion of
the cell next to the point of action will be attacked first and
there will be, upon the lowering of the surface tension, a
flow of the cytoplasm of the cell in the direction of the attack,
due to the fact that each molecule of the cytoplasm has a
tendency to disrupt the interfacial membrane of the cell.
Once the restrictive forces of like molecules are withdrawn,
they can migrate out into clear space. With this happening,
the area of activity will become filled with cytoplasm and,
due to the greater flow in this direction, the nuclei of that
area will be drawn closer together.
As the destructive force continues to spread out from the
point of origin it gradually brings about a lowering of the
surface tension in the entire region. However, the surface
of an area which lies in close approximation to another such
area will have a lower tension than the rest of the surface
of that area, due to the fact that the force from another
area is also acting there. Thus there will be a general flow
of the cytoplasm in that direction and the nuclear groups
in turn will be carried closer to each other. The like attraction of nuclear material will, in turn, draw the same into
the form of a large nuclear structure. I n the same manner
the chromatic material will assume the form of a nucleolar
formation after the walls of the individual nuclei break.
This theoretical explanation of the physical factors involved in the formation of decidual plasmodia in Citellus
townsendi is more in harmony with our knowledge of the
behavior of protoplasmic masses than any other which I can
devise. Now, if we go one step further and try to see the
ultimate source of the destructive force, it would be very
difficult to conceive of the trophoblastic vesicle producing
the destructive force in the localized manner assumed. Thus,
I am led to suggest that we should seek for the factors of
implantation within the maternal system.
288
ROBERT H. KREHBIEL
SUMMARY
1. Previous investigators have regarded the ‘giant cells ’
as merely large phagocytic cells originating from single
hypertrophied trophoblastic or mucosal cells.
2. I n Citellus townsendi the decidual plasmodia originate
from the decidual cells, by a process of fusion of deteriorating tissue. The nuclei of the contributory cells fuse, causing
the plasmodium to resemble a very large single cell, All of
the chromatin becomes collected in masses which have the
appearance of giant nucleoli.
3. Complete disintegration of nuclear material leaves only
the cytoplasm with its vacuole. These vacuolar structures
line the lumen of the uterus.
4. There is a striking resemblance between the plasmodia
and the cells described by Jenkinson, Disse, and Sansom.
5. Contrary to previous interpretations, the decidual
plasmodia are regarded as passive products of uterine
necrosis whose formation and dissolution serve no purpose
other than to contribute to the process of enlarging the lumen
of the uterus.
6. It is suggested that the factors underlying this process
should be sought within the maternal system.
I wish t o acknowledge the criticism received from
Dr. J. McA. Kater during the course of this work.
BIBLIOGRAPHY
BRYCE,T. H., AND J. H. TEACHER1908 Contributions to the study of early
development and embedding of the human ovum. GIasgow.
DISSE, J. 1906 Die Vergrosserung der Eikammer bei der Feldmaus. Arch. f .
mikr. Anat., Bd. 68.
DCVAL,M. 1891 Le placenta des rongeurs. Jour. de I’Anat. et de la Phys.,
T. 27.
HUBRECHT,
A. A. W. 1889 The placentation of Eriiiaeeus europaeus. Quar.
Jour. Micr. Science, vol. 30.
KOLSTER,R. 1903 Zur Kenntiiis der Embryotrophe.
Anatomische Hefte,
Bd. 68.
sax so^, G. S. 1927 Giant cells in placenta of rabbit. Proe. of Roy. Soe.
of London, vol. 101B.
SOBOTTA,
J. 1903 Die Eiitwicklutig des Eies der Maus vom Sclilusse der
Furchungsperiode bis zum Auf treten der Amniosfalten. Arch. f . mikr.
Anat., Bd. 61.
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