Book - Uterus And Embryo - Rabbit (1889)

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Minot CS. Uterus And Embryo - I. Rabbit II. Man. (1889) J Morphol. 2:

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This historic paper by Minot published in 1889 shows the development of mammalian animal models to study embryonic development.
Also bu this author:

Minot Links: Harvard Collection | 1889 Uterus And Embryo - Rabbit | 1905 Harvard Embryological Collection |1897 Human Embryology | 1903 A Laboratory Text-Book of Embryology | 1905 Normal Plates of Rabbit Embryo Development | Category:Charles Minot

See also his later volume in the series on normal rabbit plates in this series:

Normal Plates Series: 1897 Pig | 1900 Chicken | 1901 Lungfish | 1904 Sand Lizard | 1905 Rabbit | 1906 Deer | 1907 Tarsiers | 1908 Human | 1909 Northern Lapwing | 1909 South American and African Lungfish | 1910 Salamander | Franz Keibel | Embryology History

Modern Notes:

Rabbit Links: 2009 Student Project | Category:Rabbit | Animal Development
Historic Embryology - Rabbit 
1889 Uterus and Embryo | 1905 Normal Plates | 1905 limb veins | 1908 Pancreas | 1908 Pharyngeal Pouches | 1908 intestinal diverticula | 1909 Lymph glands | 1918 Pituitary | 1929 ovulation | 1931 prochordal plate | 1935 Oocyte | 1935 Somites | 1964 Placentation
Historic Disclaimer - information about historic embryology pages 
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Pages where the terms "Historic" (textbooks, papers, people, recommendations) appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms, interpretations and recommendations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)

Rabbit Uterus And Embryo

The observations here recorded were made upon pregnant uteri of the rabbit at various intervals from the sixth to the fifteenth day of gestation, both inclusive. The uteri were cut out carefully, stretched very slightly, and the ends of each uterus tied to an iron rod ; the specimens were then hardened in Kleinenberg's picrosulphuric acid, according to the directions given in Foster and Balfour's Embryology, 2d ed. pp. 425, 426. Although this reagent worked fairly well, and preserved the histological elements of the uterus and of the older embryos satisfactorily, it failed to preserve the blastodermic vesicles in uteri of six and seven days ; and in the older specimens, after hardening, the extra-embryonic foetal membranes were somewhat rumpled. Owing to the great difficulty of obtaining doe-rabbits in Boston, and their consequent high price, I have been unable to experiment with other methods of hardening. The specimens after hardening were for the most part stained in toto with alum cochineal and eosine, imbedded in paraffine and cut into serial sections with an automatic microtome, made by Herr G. Baltzar of Leipzig.

Uterus at six days and three hours

The position of the ova is recognizable externally, being marked by a very slight protuberance on the free side of the tubular uterus. Transverse sections show that there is a considerable dilatation of the uterine cavity, corresponding to the swelling ; the walls are considerably thinned out by stretching. The glands are much altered, otherwise there is no striking change in the uterine structure. The shape of the glands varies, but everywhere their cavities are very much expanded, and the epithelial linings of adjacent glands are separated only by very thin connective tissue partitions ; on the side of the mesentery the glands are distinctly tubular, and grouped on folds of the mucosa ; the relations of these folds are described in the next section. On the opposite side of the uterus, that is, away from the mesentery, the glands are short, with wide cavities, constituting a series of irregular ampullae with wide mouths. The epithelium is thickened everywhere ; it stains deeply, and has enlarged nuclei ; it has many intercellular vertical fissures, and therefore a good many of the cells are separated from their neighbors ; adjacent cells project unequally, rendering the surface of the epithelium irregular. The change in the epithelium is greatest opposite and least near the mesentery, but is everywhere similar in kind, though varying in degree.

I am unfortunately unable to state anything in regard to the relations of the ovum, owing to the failure of its attempted preservation in my specimens.

Uterus of seven days and three hours

The placental swellings are well marked as smooth, rounded bulbs only a little larger in diameter than the unaltered uterus between the swellings, and not projecting at all on the mesenterial side of the uterus. Transverse sections show at once the changes which have taken place. As is well known, the rabbit's uterus has six longitudinal folds, symmetrically disposed ; the line of insertion of the mesentery (mesometrium or broad ligament) corresponds to the space between two folds, which alone participate in the formation of the placenta; accordingly we may designate them as the placental folds. In the region of the swellings the placental folds are already hypertrophied, and form a marked contrast to the opposite side, where the folds have completely disappeared, and their glands have become shorter and somewhat contorted ; the two lateral folds are intermediate in appearance. In the placental folds there is a great increase in the connective tissue, which consists solely of anastomosing cells, forming a loose meshwork of very granular protoplasm, of which only a small amount is accumulated around each nucleus. Described in other words, the cells are small, granular, with long processes continuous with those of adjacent cells. The glands extend only a short and nearly uniform distance down from the surface of the folds ; the glands themselves are somewhat dilated ; their epithelium stains deeply ; its free surface is quite irregular; the nuclei are greatly increased in number, and lie crowded throughout the whole thickness of the layer ; the nuclei are round or oval in outline, with a well-marked reticulum densest superficially. In many places the nuclei are grouped, three, four, or five together, and sometimes one can distinguish a distinct outline around the group. These appearances I interpret as evidence that the nucleus of each cell proliferates, rendering the cell multinucleate. The blood-vessels are likewise hypertrophied in the placental folds, and to a less extent in the adjacent folds, but not at all in the folds opposite the placenta. In the placental folds there are larger blood-vessels running for the most part longitudinally, and all situated in the zone next the muscularis ; between this zone and the glandular layer, the blood-vessels are, on the contrary, all of small calibre, most of them taking a more or less radial course, and lying approximately in the plane of the transverse sections. All the blood-vessels of the mucosa have, so far as I have observed, the character of capillaries, for they consist of merely an endothelium without adventitial or muscular envelope, although some of them are many times the diameter of ordinary capillaries. The blood-vessels of the placenta of the Guinea pig are stated by Creighton, 77a, p. 544, to have the same character. There is a single layer of connective tissue cells condensed around the vessels, and representing the commencement of the perivascular decidual cells, though the cells themselves scarcely differ yet from the ordinary connective tissue cells between the vessels.

We find at this stage all the regions of the placental swellings, to be found in later stages, already definitely marked out.

These regions are as follows : —

1, Placental : subdivided into

A, glandular zone.
B, sub-glandular vascular zone with (a), sub-glandular zone with small vessels (b), outer zone with large vessels.

2, Peri-placental.

3, Ob-placental.

Each of these regions comprises two folds of the mucosa, viz. : the placental, the two folds next the mesentery[1]; the periplacental, the two lateral folds ; and the ob-placental region, the two folds opposite the mesentery. The three zones of the placental area persist and become much more marked in later stages, owing to the great divergence of the processes of histological differentiation in each zone. Of the two vascular zones, the sub-glandular is characterized later by its very large multinucleate cells, while the outer zone is characterized by its crowded uninucleate decidual cells. All the regions and their subdivisions will be perhaps better understood by the descriptions and figures of the nine days' uterus. (See below.)

In my specimens, although the uterus seemed to be very well preserved, the blastodermic vesicles were completely shrivelled up ; hence I could make no observations as to the relations of the embryo to the uterine wall.

Uterus of eight days and three hours

It is unnecessary to describe the appearances at this age in detail, as they have been described already with admirable clearness and exactitude by Masquelin and Swaen, 114, 25-30. I have therefore only to confirm their account and refer to certain points on which my observations extend or differ from theirs ; it is also necessary to describe the extra-placental structures, which are left out of consideration by Masquelin and Swaen.

The connective tissue is but little altered from the condition at seven days ; it has the same adenoid character; the cells are elongated in directions more or less parallel to one another, and the appearance of the protoplasmic reticulum therefore varies according as the section passes at right angles or parallel with the long axes of the cells ; in the former case the meshes are smaller, in the latter larger and longer. The perivascular cells have grown ; Masquelin and Swaen trace their origin to a metamorphosis of the connective tissue cells, in doing which I entirely agree with them ; these authors likewise describe fibrillae in the connective tissue, but in my preparation I can find none, nor from what we know of the structure of the mammalian uterus is it probable that any are present ; in regard to this point I think that Masquelin and Swaen's account needs rectification.

The placental blood-vessels have increased in size, and, I think, in number ; their epithelium, particularly in the larger vessels, is decidedly thickened.

The uterine epithelium has entered upon its complex degenerative metamorphosis — most of the changes have been seen and correctly described by Masquelin and Swaen for the placental area. They conclude that the changes lead to a new formation of blood corpuscles out of the substance of the epithelium. My own observations oblige me to regard the changes as phases of a hyaline degeneration with hyperplasia of the degenerating elements, and having nothing to do, therefore, with blood formation. In all parts of the uterine dilatations the epithelium is considerably thickened (Plate XXVI., Fig. i). The thickening is due to the enlargement and fusion of the epithelial cells, and this enlargement of the cells is due to the proliferation of the nuclei and to the growth of the protoplasm, which begins later and continues longer (as later stages show) than the multiplication of the nuclei. That the nuclei multiply within each cell can be distinctly seen in my specimens of this age ; the same fact has been observed by Masquelin and Swaen. The growth of the protoplasm is more properly described as an enlargement, due to degenerative metamorphosis. As to the nature of this metamorphosis I am unable to speak with much precision. The substance presents a very granular appearance, and possesses a slightly greater affinity for coloring-matters than the unaltered protoplasm. Examination with an apochromatic oil immersion shows in some parts of the degenerated epithelium a distinct network, the threads of which are rather coarse and hyaline in appearance. In default of chemical and further microscopic examination we may accept the hypothesis that the degeneration consists in direct change of the protoplasmic reticulum into hyaline substance, accompanied by thickening of the reticular threads. The degeneration of the epithelium has progressed much further over the non-placental area than elsewhere, and much less over the placental area: the peri-placental regions are in an intermediate stage.

It is also important to note that the deep portions of the glands are nowhere degenerated. The glandular layer may be divided accordingly into an upper degenerated zone and a lower riot degenerated zone.

In the placental area there is no stretching of the tissues, and accordingly the glands retain their tubular character. The nuclei fill up most of the epithelial layer ; there are three, four, or even five, in each cell in the upper part of the gland ; the cells of the fundi are but slightly altered from their usual appearance. The embryo is attached to the maternal placental surface only by the ectoderm, without any participation of the other germ layers, direct or indirect, so far as I can observe. That portion of the ectoderm which is soldered to the uterus is very much thickened, in marked contrast to all other parts of the layer. As shown in Fig. i., PI. XXVL, the placental ectoderm runs over the surface only of the placenta, and stretches straight across the mouths of the glands, shutting them completely ; it does not dip down into the glands at all, and possesses no villi whatsoever. On the surface, between the glandular orifices, the uterine epithelium, already degenerated, is clearly distinguishable.

In the other regions the stretching of the walls stretches the glands also, and of course proportionately to the extent of the strain ; hence, in the non-placental area the glands become slits running parallel to the surface, and in the peri-placental part become wide cavities. The upper zone of the peri-placental glandular layer has its epithelium changed into a very thick layer, and beginning to undergo resorption, as evidenced by the presence of cavities. As we follow round towards the non-placental area, the evidences of resorption are greater, and over the area itself a large part of the upper glandular zone has disappeared altogether. Similar relations are found in the uterus of nine days, from which the drawings have been taken. For the sake of greater clearness, and to avoid repetition, we pass at once to the next stage. The fact that I have found the uterus at eight days so much nearer in its stage of development to that of nine than to that of seven days, may be attributed to accidental variations.

Uterus at nine days and three hours

Fig. 2, PI. XXVI., represents a transverse section through a swelling. The attenuation of the walls everywhere, except in the placenta, is very marked, and affects both the outer and inner muscular layers, Im^ cm, and the mucosa, mttc. In the placental region, PI, on the contrary, the walls are thickened ; the placenta itself is formed chiefly by the hypertrophy of the connective tissue of the two longitudinal folds nearest the mesentery, mes : the superficial glandular layer, gl, owing to its deeper staining, is readily distinguished even by the naked eye ; each lobe of the placenta is imperfectly subdivided into two lobules ; the embryo, in the specimen figured, appears in transverse section over the right-hand lobe, directly above the furrow separating its lobules ; the actual disposition is shown in Cut i ; in Fig, 2 the embryonic structures are purposely omitted on account of the small scale ; to the consideration of the foetal membranes the next section (§ 5) is devoted.

The connective tissue of the placenta is already far advanced in its metamorphosis, which progresses as described by Masquelin and Swaen. It consists of a rich cellular network. Fig. 3, conn, of which the cell bodies are much larger than in previous stages ; these bodies are for the most part elongated, with very irregular surfaces, and are, therefore, perhaps best characterized as roughly spindle-shaped ; their long axes are more or less parallel with the blood-vessels ; the nuclei are round, oval, or elliptical, granular, but with a clearer cortical layer, as is usually the case in young connective tissue cells : compare Rollett's Figs. 4 and 5 in Strieker's Handbuck der Lehre von den Geweben, I., pp. 63 and 65. The processes of the cells are numerous and very fine, forming a meshwork, between the cells, of such delicacy that it can be followed out only with high powers (400-500 diams.). The observation of the threads of this network has led certain investigators to assume the presence of connective tissue fibrillae. Scattered about in the connective tissue are a not inconsiderable number of leucocytes, /, /, /, easily recognized by their size and shape, their granular appearance, deep staining and characteristic nuclei. Around the blood-vessels is the perivascular layer of decidual cells, per v, which have already been amply described by Masquelin and Swaen, Ercolani, Godet, Creighton, and others. Ercolani's descriptions, of which the most important to us is that of the rabbit at fifteen days,[2]89, p. 278, is far from sufficient. Godet's paper I know only from an unsatisfactory abstract. Creighton's account of the perivascular layer in the Guinea pig, 77a, 544, is also good, and he agrees with the Belgian authors in tracing the origin of the cells to the metamorphosis of the connective tissue. Ercolani opposed this view and maintained that the uterine mucosa is completely destroyed, leaving the whole placental tissue of the mother to arise as a new formation. My preparations render it impossible to agree with Ercolani, since they show all the phases of the metamorphosis. It is only necessary to follow, in Fig. 3, the three series of cells numbered I, 2, 3, 4, each, and to find in all parts of the placenta the same appearances ; to see the perivascular layer at six and seven days, before it is much differentiated ; and finally to see the perivascular accretions at later stages, to render inevitable the conviction that the perivascular layer is modified connective tissue. Neither at this stage nor at any earlier or later one have I been able to detect any evidence whatsoever of the resorption of the connective tissue affirmed by Ercolani, 89. Masquelin and Swaen describe multinucleate cells, but I fail to find them until later stages.

The blood-vessels have their endothelial lining considerably thickened, each cell for itself, and to its individual degree, Fig. 3, Endo ; they are stained by alum-cochineal and cosine more deeply than the adjacent decidual cells, from which they are sharply distinguished. I am unable to recognize any cells which might be interpreted as intermediate stages between the endothelial and decidual cells, as we should anticipate, were Ercolani's suggestion correct that the decidual cells arise from the blood-vessels. The contents of the blood-vessels are blood corpuscles and coagulum ; the blood corpuscles resemble the ordinary red globules of the rabbit, a point deserving notice in view of the change occurring later. There are occasional leucocytes, but they are nowhere numerous.

The two layers of the vascular zone are now distinguishable not only by the size of the vessels (not well illustrated in the section drawn as Fig. 2), but also by the much greater development of the perivascular cells in the outer zone ; in the subglandular zone the cells are now not far from their maximum development, forming a coat one or two cells thick around the vessels ; on the outer zone, on the contrary, the number of layers of cells has still to increase very much ; consequently as development progresses, the difference between the subglandular and outer zone becomes more conspicuous.

The epithelium and glands repay careful study at this stage. The degenerative processes are similar in certain essential respects in all parts of the uterine swelling. The likeness concerns five chief points : 1°, the deep portions of the glands show little change in the epithelium ; 2°, the upper portions are very far degenerated ; 3°, the protoplasm of the degenerated epithelial cells is fused into a continuous thick hyaline mass, the growth of which ultimately obliterates the cavity of the glands ; 4°, the nuclei of the degenerated epithelium multiply enormously ; 5°, the degenerated tissue is absorbed by progressive vacuolization.

But although these resemblances are dominant, each of the three principal regions, the placental, peri-placental, and ob-placental, presents now a very distinctive appearance, and has its distinctive further history.

In the peri-placental region, with which we begin, because the relations are more obvious there than elsewhere, we find the appearances shown in Fig. 4. The line of demarcation from the placenta, though not definite or sharp, can be approximately determined, but the passage into the ob-placental region is very gradual. The most striking feature of the section is the degenerated and enormously thickened epithelium, h.ep, deeply tinctured by the eosine, and remarkable for the crowded band of nuclei. Within the area of the degeneration the former gland cavities are closed ; the diameter of the glands has enormously increased, and in some places two adjacent glands have swollen until they have come in contact and fused, the glands then forming a network ; in the placental region the conversion of the glands into a network goes very far. The distribution of the nuclei as at a and b preserves in some parts the original grouping in opposite walls of the gland tube ; at other points they lie in irregular patches. Secondary cavities, vac, appear at various points ; they are irregular in size, shape, and position, and arise by the resorption of the degenerated tissue. There is probably a certain amount of resorption carried on upon the surface against the connective tissue, for that surface becomes jagged and irregular, presenting a corroded appearance, as can be seen at various parts of Fig. 4. The vacuolization is, however, the principal factor of destruction. As to the manner in which the spaces are produced in the heart of the very compact layer, my observations give no satisfactory information. There are no accumulations of leucocytes either in the epithelial layer nor even in the connective tissue (see Fig. 4), in which all the cells are copied with approximately entire accuracy from the preparation. The only material I have ever noticed in the vacuoles is broken-down fragments of the surrounding hyaline tissue (epithelium) itself. The hypothesis may be suggested that the resorption vacuoles are produced by liquefaction, but the suggestion calls for no further discussion since there 'are no direct observations to test the validity of the hypothesis.

The deep portions of the peri-placental glands. Fig. 4,^/, are dilated transversely to an extent which has converted them from tubes into wide vesicles. Towards the ob-placental region the transverse stretching gradually increases. The epithelium differs but little from that of the resting utricular glands; it is composed of cylinder cells with basally placed oval nuclei.

In the ob-placental region the mucosa is much thinner than elsewhere. As we proceed from the edge of the peri-placental region towards the pole furthest from the placenta we find that the layer thins out and is more advanced in its degeneration. Near the peri-placental thickening there is a wide superficial layer of degenerated epithelium with the characteristic central band of nuclei, but the prolongations corresponding to the degenerated gland ducts are short ; the deep portions of the glands are oval slits parallel with the muscularis, Fig. 5, gl. A little further along, the resorptive vacuolization begins, producing a curious irregular layer, Fig. 5. The degeneration and vacuolization is found still further along to have involved the inner adjacent wall of the gland vesicles, thus producing the appearances shown in the left-hand part of Fig. 5, where there are shallow cups, gl, of epithelium, each entirely separate from its fellows, and all overlaid by the hyaline stratum, Ji.ep. There is usually a dome-like hollow in the degenerated stratum above each cup. Since the processes described vary in rapidity, there is not a uniform,' but only a general, progression of stages towards the centre of the ob-placental region. Moreover, the variability is great, and the images from different sections and different parts of the same section are correspondingly multifarious, but the general succession of changes is everywhere the same; hence it would be profitless to expand the descriptions.

The placental glands have preserved their tubular character ; they are less degenerated than the uterine glands of the nonplacental parts ; their walls are less thickened and in most parts the glandular cavity is still present. The deep portion of the glands are tubes lined by columnar epithelium. For the rest, I may refer to the satisfactory description of Masquelin and Swaen, 114, 30-31, except as to one point. As shown in Cut i, p. 355, the ectoderm of the embryo is firmly soldered to the placental surface over certain areas. The nature of this connection and the accompanying structural changes in the uterus are illustrated in Fig. 7, which has been copied with great care from one of the sections. For the sake of clearness, only the nuclei of the connective tissue have been drawn in; the perivascular cells are represented by their nuclei and outlines, and the nuclei and cells of the foetal ectoderm are given in outline ; but there is nothing diagrammatic in the drawing; of course in the figure the distinction between the foetal and maternal tissues is more marked, though not more real than in the section ; in fact there is scarcely a cell even on the line of junction of the ectoderm with the uterus about the assignment of which one could have any doubt, so distinct is the texture and the staining of the foetal and maternal tissues. This is a matter of importance, as it renders it possible to ascertain beyond question that there are no villi ; nevertheless their presence has been assumed not infrequently. To pass on : where the ectoderm, Fig. 7, Ecto, touches the placenta, the active resorption of the degenerated glands is going on (see the part of Fig. 7, above bracket C) ; whereas in other parts the glands present the appearance shown in Fig. 7, A, gz, and described by Masquelin and Swaen. There is also an intermediate zone shown in Fig. 7, above bracket B, where the transition phases between the two states are found; the zone of transition lies immediately underneath the point where the ectoderm, Ecto, joins the uterine epithelium, k.ep; here the glands are thickened and hypertrophied ; the lumen is obliterated, but the cylindrical shape is irregularly preserved ; where the distal end of the ectoderm leaves the placenta, there is again a similar transition : in other words, the resorption is less advanced around the periphery than in the centre of the area of ectodermal attachment. The resorptive process is essentially the same as outside the placenta, — superficial corrosion and internal vacuolization, — but the vacuoles formed are relatively small and consequently more numerous : moreover, the space left by the disappearing epithelium is at once occupied by connective tissue cells, so that there are no cavities. The resorption goes on principally in the superficial layers of the placenta, where it results, as later stages show, in the complete disappearance of the glands immediately underneath the ectoderm ; deeper down the glands at the present age are hypertrophied and without lumina, but even in the region of bracket C of Fig. 7 (PL XXVII.) most of the glands show very few or no vacuoles.

Embryo at nine days and three hours

It is not proposed to consider here anything but a few points bearing on the relations of the embryo to the uterine walls.

First, as to the positioji of the embryo: the dorsal surface of the embryo is turned towards the placenta ; the embryo may be situated over one or the other lobe of the placenta or across both ; its long axis may be either parallel or oblique or at right angles, to the long axis of the uterus. In the specimen represented in Cut I, both the uterus and embryo appear in transverse section. Similar variability appears in my specimens of uteri of eight days, and of nine days and seventeen hours. The statements of Van Beneden and Julin, 44, and other authors[3], lead rather to the supposition that the embryo normally lies across the uterus; but this is true in my experience only of the later stages after the embryo is suspended more freely.

Minot1889 fig01.jpg

Cut 1. - Transverse section of a rabbit embry, in situ, of nine days and three hours. d, wall of yolk-sack composed of ectoderm and endoderm only; vt, vena terminals; mrs, mesoderm; sol, splanchnopleure; coe, coelom; nch, notochord; Md, medullary groove; my, myotome; Endo, endoderm; Ecto, ectoderm; gl, glands; v, blood-vessels; he, hyaline uterine epithelium.

Next as to the extra-embryonic portions of the germ layers : my observations compel me to differ as to the composition of the walls of the blastodermic vesicle or yolk sack. Sections through the middle region of the embryo, Cut 1, show an open medullary groove, Md, the thickened notochordal band, nch, of the entoderm ; the mesoderm of the Staminsone is undivided ; that of the parietal zone is split to form the coelom, Coe, which may be followed a considerable distance from the axis of the embryo, when the two leaves of the mesoderm again unite into a single distal plate, vies, in which the two layers can be distinguished for a certain distance ; the distal edge of the mesoderm is sharply marked ; the mesoderm is thickened around its margin. Beyond the margin the ectoderm and entoderm come into contact, a ; the former is the thicker layer, being composed of cubical cells, while the entoderm consists of very thin broad cells ; the two layers continue outwards until, having passed over the periplacental thickening, they reach the region of transition from the peri-placental to the ob-placental area, where the ectoderm changing to a thin flat-celled membrane is intimately conjoined to the degenerated epithelium of the uterus. Where the concrescence takes place, the union of the two layers becomes very intimate, so that it is difficult to satisfy one's self how much farther the ectoderm extends, but apparently it goes completely around, forming a closed vesicle, as is generally stated and as is found later. Apparently the ectoderm is not involved in the resorption of the uterine epithelium, which disappears — but further investigation is required. The entoderm of the other hand is readily followed, and although somewhat crumpled and torn in the obplacental region of my specimens, there is to my mind very little doubt that it forms a closed sack, corresponding to the entodermic lining of the yolk sack of other mammals. From the observations above recorded it is evident that two germ layers are readily traced for some distance from the embryo, but that beyond a certain line only one layer, the entoderm, is readily followed. Now this fact is carefully represented in van Beneden's and Julin's diagram, 44, PL XXIV., but the membrane which stops is there given as entoderm, which, as seen in my specimens, is continued around. It is probable that when embryos of nine days are removed, that a portion of the ectoderm remains attached to the uterine wall, and consequently the inferior portion of the vesicle is without any ectoderm. Being unaware of such a possibility, van Beneden and Julin have perhaps represented the single layer left as ectoderm on account of the theoretical necessity of an ectodermal covering on the external or apparently external surface of the ovum. The question, therefore, is to be posed : Have not observers found two layers up to a certain limit beyond the ve7ta terminalis, and only one layer over the remaining inferior portion of the embryonic vesicle, and assumed the single layer to be ectoderm, whereas it is entoderm, and the true ectoderm is left upon the uterus, to which it is indissolubly attached. The view I advocate brings the further question whether a portion of the embryonic ectoderm disappears by being involved in the resorption of the ob-placental uterine epithelium. This I think is not the case. The intimate adherence of the extra-embryonic portions of the germ layers to the uterine walls has been carefully recorded by Bischoff, Entwickeliings gesch. Kaninchens, p. 131, Vom dem Umkreise der Vena terminalis an ist das Ei [of ten days] in die in dieser Lage, etc. . . . und von hier an sind auch alle Eihaute so innig unter einander und durch den Uterus vereinigt, dass es nicht gelingt sie zu l5sen.

The attachment of the embryo takes place as described by van Beneden and Julin, p. 402, 403, by an area of thickened ectoderm ; the general arrangement is well shown in Cut i, while the fitting together of the foetal and maternal surface is better illustrated by Fig. 7, PI. XXVII. The foetal mesoderm does not participate even indirectly in this attachment, but runs along free from the outer germ layer. The ectoderm, as it nears its attachment (see Fig. 7), gradually thickens. Just where it joins the uterine surface there are several large cells with very large nuclei ; appearances which are probably connected with the growth of the layer, for beyond the line of the large cells the ectoderm is very much thicker. Extremely distended nuclei also occur very strikingly in the developing supra-renal capsules, and are also there connected presumably with cell proliferation. If these suppositions are correct, there is a modified form of cell division characterized by dilatation of the nuclei and which deserves special study. Over the area of attachment the uterine epithelium, Fig. 7, h.ep, is degenerated as before described, its surface is extremely irregular, but the ectoderm, Ecto, is perfectly fitted to every irregularity, but the free surface (towards the mesoderm) is comparatively smooth ; the layer consists of two, three, or four strata of cells. Beyond the area of attachment the ectoderm again thins out.

As to how the tissues are held together, my observations afford no explanation. It seems to me possible that the two tissues actually grow together as a grafting unites with a bough ; but for aught we know it may be by some other process, perhaps simple agglutination. The thickening of the ectoderm I am inclined to regard as degenerative, and therefore somewhat comparable to the degenerative thickening of the uterine epithelium. I am brought to this view by no conclusive observations, but chiefly by two facts : 1, that in later stages the ectoderm seems to have disappeared over the greater part of the placenta (see § 7. Uterus of eleven days) ; 2, hyperplasia is often the commencement of degeneration, as is familiarly known to pathologists. To this evidence may be added the appearance of the ectoderm at nine days and seventeen hours, which I interpret as indicative of degeneration.

Uterus of nine days and seventeen hours

In my specimen there are not many changes from the previous stage last described, but of these changes the following deserve special mention : 1°, the commencing formation of perivascular decidual cells in the peri-placenta ; 2°, the reconstitution of the ob-placental epithelium ; 3°, the formation of the true chorion ; 4°, changes in the extra-embryonic ectoderm ; 5°, the contents of the placental blood-vessels.

  1. The peri-placenta is still only a small bolster at the side of the placenta ; its glands are still recognizable and its blood-vessels are more conspicuous ; the connective tissue cells are enlarged and have begun to form more or less distinct coats around the blood-vessels. I feel assured that the decidual cells arise here in the same way as those of the outer zone of the placenta ; the cells in the two parts appear to me identical in character as soon as they attain their full development, and to differ only in the period during which their development takes place ; later on, Fig. 8, PI. XXVIII., the peri-placenta forms, together with the outer zone of the placenta, a continuous layer of uninucleate decidual cells, extending over half the uterus.
  2. In the ob-placental region the degenerated portion of the uterine epithelium is almost completely resorbed around the pole opposite the placenta, (compare Figs. 4, 5, and 6). Fig. 6, taken from an older stage, in which the phase existing at nine days and seventeen hours at the pole is found near the peri-placenta, illustrates the manner in which the patches of unaltered epithelium, gl, of Fig. 5, grew together by the union of their edges into a continuous sheet of epithelium, Fig. 6, gl, forming a series of shallow cups, widely open.
  3. The chorion of mammals, as I have defined it elsewhere, is " the whole of that portion of the extra-embryonic somatopleure which is not concerned in the formation of the amnion.[4] The term is not applicable until the mesoderm has united with the ectoderm in the region outside the embryo to form a single membrane : such a union has now taken place ; the thickened placental ectoderm is coated by a thin layer of flat cells, epithelial in character and with bulging nuclei. These cells represent the lining of the body cavity, or, as this lining is conveniently called, mesothelium. The mesothelium, and consequently the coelom, extend a slight distance beyond the edge of the placenta; the mesothelium then bends over onto the yolk sack, of which it becomes the vascular coat, and then runs towards the embryo ; the vascular coat has a large vessel, sinus terminalis, near the end of the coelomatic space, and the mesoderm stretches a short distance beyond away from the embryo. The ectoderm, on the contrary, extends beyond the end of the mesoderm away from the embryo over the rest of the yolk sack. Thus the yolk sack, as is well known, comprises two parts, one near the embryo with walls composed of entoderm covered by mesoderm, and away from or opposite the embryo, with walls composed of entoderm covered by ectoderm ; compare the clearly expressed summary of the relations in the rabbit given by Balfour in his Comparative Embryology, II. , 199, 200.
  4. The ectoderm of the embryo presents the same general arrangement as at nine days. The area of thickened entoderm, however, which is attached to the placenta has changed in appearance ; at nine days and three hours each cell outline was distinct, and the protoplasm around each nucleus dense and finely granular ; now the cell outlines are hard to follow and the picture is confused by broader lines of hyaline matter, which is colored by the eosine ; the nuclei are enlarged, the protoplasm is more coarsely and more irregularly granular, and somewhat vacuolated. The characteristics enumerated concord with the idea that degeneration is going on, — an idea suggested, also, as before stated, by the failure to find this part of the ectoderm in later stages.
  5. The blood-vessels show increased hypertrophy of their epithelium, and the perivascular cells form two or three layers around them ; they are especially remarkable for containing a very large number of multinucleate leucocytes and comparatively few red corpuscles. The excessive abundance of white globules continues up to the oldest stage I have examined (sixteenth day). The predominance of nucleated corpuscles causes the contents of the maternal vessels to resemble foetal blood when examined with a low power; with high magnifications the difference is evident. To the foetal blood in the placenta we shall have to recur.

Uterus at eleven days and three hours

Very great changes have taken place — so great that they cannot be understood completely until some of the intermediate phases are studied. Want of suitable material has hitherto prevented my doing this. At the present stage — the beginning of the twelfth day — the placenta is distinctly pedunculate, and there is consequently a circular cleft between its sides and the closely adjacent peri-placenta; in the middle of the placenta a deep fissure corresponds, of course, to the space between the two folds of the uterus, out of which the placenta is developed, and therefore runs lengthwise of the uterus. The allantois has acquired considerable size and is attached to the surface of the placenta, from which the ectoderm has disappeared. The glands of the placenta are very far degenerated and altered ; in the sub-glandular zone the multinucleate cells have appeared, and in the outer zone the perivascular cells have increased so as to occupy nearly all the space between the vessels. In the periplacental and ob-placental regions, the modifications are equally noteworthy. Such, in brief, are the more striking changes. Let us consider them with greater detail.

The diagram on PI. XXIX. will enable the reader to follow the ensuing descriptions. The general explanation of the diagram is given in the next section.

The placenta is shaped somewhat like a mushroom : it has a very thick stalk, with a somewhat broader top. The top is bilobate, there being a deep fissure between the two lobes ; this fissure persists at thirteen days (Fig. 8,/) ; its fundus is the subplacenta (Ercolani's cotyledonary organ). The sides of the fissure are, of course, part of the surface of the placenta, morphologically speaking, and bear glands. The three zones of the placenta are well marked. In the outer zone the blood-vessels are very wide, with thickened degenerated epithelium ; the perivascular cells occupy the entire space between the vessels in all that part of the zone towards the muscularis and most of the space in the part towards the glands. Next to the sub-glandular zone, therefore, we see the vessels surrounded, each by its separate thick perivascular coat, while the intervening tissue still consists of anastomosing cells, like those which in earlier stages occupied more of the space and which formed the only packing between the vessels at six days. The blood-vessels convert the layer, by their enlargement, into a spongy tissue, which has been described not only in the rabbit, but in other rodents ; the vessels themselves have been generally described as glands, but the study of their development renders doubt as to their true character impossible. The vessels are partially empty in my preparations, but they contain very numerous leucocytes, nearly all of which have several nuclei apiece, which are conspicuous from their dark staining : there are a few red globules and here and there a little coagulum. As the corpuscles of the embryo are large nucleated bodies, there is no difficulty in distinguishing the foetal from the maternal blood, even in the upper part of the placenta, where the two circulations are juxtaposed. The middle or sub-glandular zone has undergone greater changes still. In it, as likewise in the glandular zone, the perivascular cells have' almost entirely disappeared,[5] but they are, as it were, replaced by multinudeate cells (compare Fig. 14, PI. XXVIII., of these cells from an older placenta) ; their origin appears to be due to the development of clusters of connective tissue cells, which lie scattered about between the blood-vessels ; each cluster consists of from three to six cells lying together and connected on the one hand by short processes with one another, and on the other by longer processes with the cells of adjacent clusters. The larger clusters are separated by membranes from one another, and thus every cluster becomes enclosed in a membrane and appears as a multinucleate cell. The development of these cells would doubtless repay more accurate investigation. The multinucleate cells do not yet form a continuous bed under the placenta, but are divided into parts by masses of very loose connective tissue. At the base of the fissure between the two lobes of the placenta the glands have almost entirely disappeared, but we still find a few unresorbed fragments of their degenerated epithelium ; these fragments are conspicuous by their very deep staining, both of the hyaline substance and of the nuclei : the neighboring tissues are less colored. The fissure itself is like an inverted X ; that is, it is transversely expanded at the base ; the floor of the expansion is thrown up into folds and covered by a cylinder epithelium, which I feel some hesitation in designating as the regenerated uterine epithelium, although it resembles the epithelium on the peri-placenta, where the glands are resorbed and the epithelium reconstituted from its degenerated self. On the other hand, as shown in the next section, there is some proof that the foetal ectoderm penetrates, by villous growths, far into the placenta. It seems possible that the fissure is filled by villous excrescence of foetal origin and that the epithelium of the sub-placenta belongs to the villus. This view does not commend itself to me. Neither upon the upper wall of the expansion nor on the sides of the fissure have I recognized any epithelium. The upper part of the fissure is closed by an ingrowth of connective tissue. Hence the lower part is changed into a shut cavity in the centre of the placenta, and into this cavity the folds covered with epithelium project. So far as I am informed, this curious structure has not been described hitherto, but what appears to be clearly its homologue has been observed by Ercolani, 89, pp. 290, 291, Tav. IV., Fig. I., O, and specially studied by Creighton, 77b. Both of these authors examined late stages when the fissure is completelyfilled by connective tissue, so that there is no space — a condition found in the rabbit at thirteen days. It will be convenient to designate the structure as the sub-placenta. Its occurrence is confined to rodents so far as at present known. Finally, we have to note that at the edge of the placenta, toward the peri-placenta, the sub-glandular layer, which we are now considering, is characterized by the presence of deeply stained fragments of glandular epithelium irregularly scattered through the other tissues and similar in appearance to the remnants of the glands about the sub-placenta. These fragments appear to have been seen by Ercolani, Creighton, Masquelin, Swaen, and others, and variously interpreted, their true nature not being recognized. The disappearance of the glands at the centre and at the periphery of the placenta virtually increases the domain of the sub-glandular layer. The greatest changes have occurred in the glandular layer. Scarcely a trace of the perivascular cells can be found ; the space they formerly occupied is taken up by a very loose embryonic tissue ; the glands are completely altered ; they have lost their special affinity for eosine and cochineal, neither the hyaline substance of which they are composed nor the nuclei they contain being more stained than other tissues (compare Fig. 8) ; they are irregularly cylindrical in shape, very much contorted, and united with one another at irregular intervals, so as to constitute an actual network: they are very much vacuolated ; their deep portions (fundi) are somewhat wider than the upper parts ; here and there one sees a remnant of the original central lumen. The contorted masses, which I consider glands, are apparently the same as have been seen by Mauthner in the placenta at term, 115, p. 121. He describes these cords as consisting of the fused epithelium of adjacent foetal villi, and the spaces I have designated as vacuoles he describes as maternal blood-channels; he states explicitly that he has injected them from the maternal vessels, and in other cases found them gorged with maternal blood. These statements are irreconcilable with my own views, detailed in the present article. The uterine epithelium has entirely disappeared both from the top and the sides of the placenta. The top surface is covered by a very thin layer of flat epithelium. Fig. 8, msth, which is found, when followed out, to be continuous with the lining of the body cavity of the embryo ; it is therefore mesothelium. Underneath this covering, and above the glands, there is a layer of varying thickness containing some large and a few small blood-vessels with embryonic blood in them, and consisting otherwise only of scattered anastomosing connective tissue cells,[6] which can be followed without the slightest break on the one part until they pass directly into the mesoderm of the superjacent embryo; on the other part, down between the glands. Fig. 8, mes ; compare, also, later stages, Figs. 10 and 1 1. Between the glands, also, are blood-vessels containing embryonic blood. On the top surface of the placenta I can find nothing recognizable as even a trace of the foetal ectoderm, which formed a thick and conspicuous covering in the latest previous stage examined (nine days and seventeen hours). At the edge of the top of the placenta. Fig. 8, the relations change : the mesothelium, msth, bends up and leaves the placenta, and together with a few subjacent mesodermic cells joins a sheet of cylinder epithelium, Ecto, which is shown by its connections to be foetal ectoderm. The ectoderm from the point where the mesothelium, msth, bends on to the top of the placenta continues downward, Ecto, to clothe the side of the placenta which faces the peri-placenta. Between the placenta and peri-placenta, as shown in Fig. 9, there is a fissure ; the ectoderm can be followed to the bottom of this, and from there extends, — not on to the peri-placenta, — but turns abruptly back on to the side of the placenta, up which it stretches a minute distance and thereupon ends abruptly. The disappearance of the ectoderm is discussed in the next section.

The peri-placenta is now characterized by the enormous increase of the perivascular decidual cells and the accompanying expansion of the blood-vessels ; by the disappearance of its glands and by the reconstitution, in part, of its superficial epithelium. The peri-placenta appears like the continuation of the outer zone of the placenta, for it directly adjoins it, is of about the same thickness, and is histologically similar. The bloodvessels are wide with hypertrophied endothelium; the perivascular cells are disposed as in the sub-glandular zone of the placenta ; that is, in the half towards the uterine muscularis they completely fill the intervascular room, but in the half towards the interior of the uterus they form a discrete envelope around each vessel, the spaces between the perivascular coats being occupied by simple connective tissue cells. The glands which at nine days, Fig. 4, were so bulky and conspicuous, have almost completely disappeared, being now represented only by remnants of multinucleate hyaline matter scattered superficially, and easily recognized by their distinctive and conspicuous coloration : some of these remnants are still united with the surface. The epithelium is in two forms : on the half of the peri-placental surface towards the placenta it is entirely in the phase of degeneration, while over the other half it is already reconstituted as irregular cylinder epithelium, the cells of which are more or less separated from one another, and somewhat variable in height ; this epithelium stops abruptly near the middle of the periplacenta and is replaced towards the placenta by a hyaline nucleated layer occasionally thickened into a lump, where the nuclei are clustered ; the cylinder epithelium is deeply stained by the cochineal ; the hyaline epithelium has a marked color from the eosine, and its nuclei are dark with cochineal. The glands are further resorbed under the cylinder epithelium than nearer the placenta.

The ob-placenta is now characterized by the disappearance of its degenerated epithelium, by the fusion of the epithelium of the deep portions of its glands into a new continuous layer, and by the development of peculiar monster cells in its central area facing the placenta. The resorption of the epithelium by vacuolization has already been described in the account of the nine days' uterus, § 3. The epithelium, Fig. 6, gl, is everywhere re-formed as a continuous layer ; portions. Fig. 6, h.ep, of the degenerated layer remain especially near the peri-placenta, but for the most part the new epithelium is entirely uncovered, and in the central region it has grown, so that the glands are already deepened. But the most remarkable feature is the accumulation, opposite the placenta, where the mucosa is much thickened, of the curious bodies, to which I apply the term monster cells. They are round or oval masses many times the size of any other histological element of the uterus or embryo, and possess huge nuclei. They are shown in Fig. 1 7, which represents them at a later stage, when they are further enlarged. I regard these bodies as detached epithelial cells, undergoing degenerative hypertrophy. In spite of long searching for the phases representing their earlyhistory, I have failed to ascertain positively their origin. In the next section the question is recurred to. The monster cells vary in size: the smallest ones lie near the epithelium; the larger ones, for the most part, deeper down and even among the muscular fibres, but a few large cells lie next the surface. The body of the cell is evenly and coarsely granular and resembles the hyaline degenerated protoplasm of the epithelium ; its external outline is distinct, well-rounded, and without processes ; the nucleus, which often has a slight space around it, as if it had shrunk a little, has a clear regular outline, being apparently provided with a membrane ; it is well colored by cochineal, and contains an indistinct network with imbedded granules of various sizes ; in the smaller cells the nuclei have one or two granules much larger than the rest, and which may be spoken of as nucleoli ; the size of the nucleus increases with that of the cell, and at the same time the granulation becomes coarser.

The description of the placenta at ten and eleven days given by Masquelin and Swaen I have not been able to follow in all respects. Owing to their conclusion that the epithelium of the uterus gives rise to blood, they apply the term cavites hcematoblastiques to apparently all the cavities of the placenta except those of the maternal blood-vessels. I have compared their description very carefully with my own preparations : so far as this enables me to judge, their "cavites haematoblastiques " include the foetal blood-vessels, the vacuoles in the degenerated glands, the spaces included within the epithelial U's described in the next section, and which are supposed to be the tips of foetal villi, the multinucleate cells and perhaps also the sub-placenta. Why the multinucleate cells are included among the bloodforming organs the authors do not render clear. Their failure to recognize the variety of constituents in the glandular layer of the placenta must be ascribed to the want of the perfected methods at present at our disposal. With the means now at command there is no difficulty in obtaining preparations which show indisputably that the glands though degenerated persist intact, and do not give rise to blood cavities nor blood corpuscles as Masquelin and Swaen have erroneously believed.

==Embryo at eleven to thirteen days==As known already, the embryo is completely separated from the yolk sack, and the allantois has grown forth and attached itself to the placenta. The relations of the extra-embryonic structures have been represented by Bischoff in the diagrams of PI. XVI. of his classical memoir on the development of the rabbit. These diagrams have since been reproduced again and again, sometimes with modifications as notably by Kolliker in his manual, and by Van Beneden and Julin. Guided by these and by my own preparations I venture to construct a new diagram, PL XXIX., which I hope will approximate more nearly to the actual relations of the parts, with which we are now concerned.

In the first place it is to be noted that most of the section is occupied by uterine tissue : — compare Fig. 9, PI. XXVIII. The largest space is occupied by the placenta, on the surface of which is situated the embryo, lying upon its side. Opposite (above in the figure) the embryo is the ob-placenta, ob-ply with its central area, containing the monster cells, mo cl ; the inferior wall of the yolk sack is fitted upon, but not attached to, the obplacental surface. The peri-placenta, PP, appears as the continuation of the outer zone, oz, of the placenta ; it has no glands : its blood-vessels are enlarged, and all the space between them is filled with uninucleate decidual cells. This description of the peri-placental structure applies also to the outer zone, oz, of the placenta. A narrow space separates the surface of the peri-placenta from the side of the glandular zone, gl, of the placenta : the letters a and b lie in this space. The placenta consists of three zones : 1°, the upper glandular zone, gl, divided by a fissure, into two lobes. This fissure is partly filled with an ingrowth of embryonic mesoderm, mes ; the transversely expanded bottom of the fissure forms the sub-placenta,; the glandular zone as a whole constitutes a protuberant mass with top and sides clearly distinguishable. Below the sub-placenta is the sub-glandular zone, s.-glz, with dilated blood-vessels and multinucleate decidual cells.

The embryo lies upon the surface of the placenta. From its ventral side spring the allantois, all, and the stalk of the yolk sack ; for the sake of clearness the amnion and pro-amnion are entirely omitted, since they have no direct relation to the uterus.[7] The allantois expands upon the placenta ; the yolk sack expands over the ob-placenta. The cavity of the allantois, all, is of course lined by entoderm ; it is, however, quite small, and in my preparations by no means the spacious vesicle commonly represented, for instance, by Kolliker in his Grundriss (2te Aufi., Fig. ZZ), or by Balfour {Comparative Embryology, II., Fig. 148). The allantoic mesoderm, m,es, on the other hand, spreads out, over the surface of the placenta, down its sides, down into the fissure, f, between the two lobes, and penetrates between the glands, gl, of the placenta ; wherever it goes, the mesoderm carries foetal blood-vessels. The free, i.e., inner or coelomatic, surface of the mesoderm bears the mesothelium, msth', as the extra-embryonic coelom does not extend beyond the top of the placenta, there is, of course, no mesothelium upon the sides of the glandular zone (between a and b), but at the edge of the top of the placenta the mesothelium is reflected back, and after a short course joins the wall of the yolk sack near the sinus terminalis, v.t.

The yolk sack, as has been long known, consists of two parts:[8] 1st, the area vasculosa bounded approximately by the sinus terminalis, vt ; within this area the entoderm is united with the mesoderm, which passes only a very short distance further out ; 2d, the remaining portion without mesoderm, excepting always the pro-amnion, which is included in the area vasculosa ; over this second region the entoderm, en, rests directly upon the outer germ-layer, ecto.

If we follow the ectoderm around, we find that it leaves the yolk sack, just before the simis terminalis, vt, is reached, and being joined by the mesodermic lining of the coelom passes down b on to the lateral surface between the peri-placenta, P, and the glandular placenta, gl, where, as already described, it bends inwards, and turning back runs a minute distance upwards ; according to my hypothesis it continued earlier over the surface of the placenta, as indicated by the broad dotted line, d. The layer of embryonic epithelium upon the side wall of the rodent placenta has been seen by other observers, among whom may be mentioned Ercolani and Creighton ; the latter, 77b, 560, directs especial attention to it, in the Guinea pig, but refers it to the entoderm. I consider it probable that it is really ectodermal in the Guinea pig, as in the rabbit. Underneath the ectoderm, b, to be seen at eleven to thirteen days at the sides on the placenta, is a layer of mesoderm without any coelom. Now, if my suppositions are correct, then the ectoderm forms at first an independent fold, ba, beyond the terminal vein, vt ; the mesoderm, but not the mesothelium, extends into this fold, which covers the sides of the placenta. The disappearance of the foetal ectoderm from the surface of the placenta, and the penetration of the foetal blood-vessels between the glands, are changes which take place during the eleventh day. How those changes occur, observations on the development at that age must decide. Meanwhile let us make shift with two hypotheses. The first is : The whole of the ectoderm attached to the placenta degenerates and is resorbed. Since the uterine epithelium, as observation indicates, has likewise disappeared from the placenta, the mesoderm, mes, of the allantois, all, is brought into direct and free contact with the connective tissue and degenerated glands of the placenta, and is thus enabled to carry by its own ingrowth the foetal blood-vessels into the very substance of the placenta. The second hypothesis is that the ectoderm and mesoderm have produced villi, which have grown into the placenta. In favor of this latter hypothesis there is certain evidence which I have not yet alluded to. In the deep portions of the glandular layer of the placentas of both eleven and thirteen one finds narrow loops of epithelium like a tuning-fork in shape ; the open ends of the U-loops are towards the top of the placenta ; the epithelium composing them is a cylinder epithelium, which gradually thins out towards the upper end of the legs of the U ; it differs altogether in appearance from the degenerate gland epithelium, the interiors of the U's contain vessels with foetal blood ; so far, then, these structures might be longitudinal sections of the ends of foetal villi. Towards the surface of the placenta the epithelium of the loops thins out, and I have not been able to follow them. If we have to do with villi, we must assume that the ectoderm has become exceedingly thin over their basal portions, but is preserved as a thicker layer over their tips, and my failure to trace the villi would be attributable to the imperfection of my preparations and observations. Balancing the pros and cons leads me to favor the second hypothesis. Let me add that the mesoderm of the embryo is continuous without a break with the interglandular connective tissue ; this statement is correct beyond any doubt, for I have several sections, in each of which the direct passage is observable under the microscope without even displacing the slide. By hypothesis this mesoderm is, however, really separated by a very thin covering of foetal ectoderm from the uterine tissue, and the whole constitutes a system of villi which have grown down like roots into the placental soil.

That there is no communication between the foetal and maternal circulations must be deduced from the fact that the two bloods are never mingled in one vessel, although found side by side in adjacent vessels. The separation of the foetal and maternal blood has already been insisted upon. The full elucidation of the double placental circulation must be left for injections to bring.

In brief : The rabbit embryo is attached to the placenta by the ectoderm, which disappears from the surface of the placenta during the eleventh day; the vascular connective tissue of the allantois grows probably by forming true villi into the placenta, and so comes close to the maternal circulation.

In other rodents the placenta contains foetal vessels ; its surface is covered after a certain stage by a thin epithelium like the mesothelial layer of the rabbit, and by a layer of vascular connective tissue. Hence it seems probable that the structure in the rabbit is typical of the class — compare § 12.

Uterus at thirteen days and three hours

The placenta and embryo are considerably bigger than at eleven days, but the structure of the parts is comparatively little changed.

A complete section is drawn in Fig. 9. The longitudinal muscles, Lin., and the circular muscles cm., form the external covering. They differ in microscopical appearance from the muscles of the resting uterus, but I have not investigated the change in them.

The placenta is very bulky. Its two lobes have begun to form separate protuberances, so that the top of the placenta is no longer a nearly plane surface. The placental surface is covered by the mesothelium, which is a little thicker than in the previous stage, the cells having a greater vertical diameter. Between the mesothelium and the glandular layer, gl, is the vascular mesoderm, several of the large vessels of which are shown in Fig. 9. The central fissure,/, of the placenta is very deep ; it is completely filled with the ingrowth of mesoderm and its accompanying large vessels. At the bottom of the fissure next the outer placental zone, o.z, is situated the sub-placenta, sb.-pl. The section drawn in Fig. 9 does not show the connection between the fissure and sub-placenta, which appears in sections 208-214 of the same series. The thickness of the mesodermic covering of the placenta has increased very considerably, and the larger vessels are now provided with well-marked muscular as well as endothelial walls. Many of the foetal vessels run in spaces which stretch down nearly vertically from the placental surface ; in some cases the vascular columns can be followed until they enter a cap of epithelium which forms a sort of U. These relations suggest the presence of a series of foetal villi covered in part by a very thin epithelium, and covered at their tips by a relatively thick epithelium. This interpretation has been discussed in the previous section. Beside the normallooking epithelium, we find the degenerated glands not much changed from eleven days. The sub-glandular zone, sgl.z, shows further enlargement of the blood-vessels, so that they are now larger than those of the outer zone, o.z, thus reversing the earlier relative proportions ; the multinucleate cells have increased in number and size, and contain more nuclei than at eleven days ; they occupy all, or nearly all, the room between the vessels. Towards the outer zone the vessels are surrounded by the uninucleate perivascular cells, but the intervening tissue consists of multinucleate cells, so that there is a boundary region which cannot be assigned strictly either to the subglaindular or to the outer zone. The outer zone, o.z, is solidly packed with perivascular cells.

The sub-placenta,, lies still deeper than before, being now close to the outer zone. Its epithelium is undergoing hyaline degeneration, and accordingly is irregularly thickened, and its nuclei are multiplied : the substance of the layer stains deeply with eosine.

The peri-placenta, P, differs from that at eleven days, principally in having the perivascular cells as a solid packing throughout the whole of its extent, except just where it adjoins the glandular layer of the placenta. As at eleven days, its covering epithelium is reconstituted on the part towards the sub-placenta, and is in the phase of degeneration towards the placenta.

The ob-placenta,, shows everywhere a marked growth of its glands ; as illustrated by Fig. 10, the glands are follicular; their cavities wide. The glands are not branched or pouched, as the appearances in the sections suggest ; they are broad tubes closely packed, and are necessarily cut obliquely in most cases. The rather ragged-looking epithelium is composed of long cylinder cells (Fig. 10), with the nuclei at various heights, and the protoplasm a good deal colored by the cochineal. The connective tissue of the mucosa has also grown, and forms both thin inter-glandular dissepiments and a thickened sub-glandular stratum. In the centre of the ob-placenta the mucosa is still further thickened to make room for the monster cells, which lie for the most part below the glands, but are found also between the glands and in the superficial portion of the muscularis. At one point the ob-placenta is interrupted by a protuberant mass, X, resembling the peri-placenta in structure ; it consists of crowded perivascular cells with dilated blood-vessels, and is covered by epithelium. As I have seen nothing analogous to this mass in any other specimen of any age, it must be regarded as a singular sporadic variation from the normal processes of development.

The origin of the monster cells I am inclined to seek in the uterine epithelium, as stated in § 7. The appearance of their cell bodies, and of their nuclei at once suggest this origin on account of the similarity with the appearance of the degenerated epithelium elsewhere. We find, also, the smallest monster cells near the epithelium. In Fig. 1 1 portions of the epithelium of the peri-placenta are represented. The cells are all multinucleate, as seen both in vertical section, A, and surface views, B ; occasionally, but very rarely, there is a cell with the nuclei gathered together in a central mass, with an indistinct line enclosing the bunch. Fig. \\, c. These cells are larger than the rest, and their protoplasm is somewhat degenerated. If such a cell were to detach itself, and hypertrophy and the bunch of nuclei to break down, it would resemble a monster cell. Yet I can find no evidence that such a metamorphosis actually takes place in the ob-placenta. In the ob-placenta itself there appear a few epithelial cells with a single nucleus which are slightly enlarged, and are possibly the initial stages of monster cells, but between them and the youngest monster cells observed I have failed to discover any intermediate stages. The difficulty of finding the first stages of the monster cells indicates that their development must be extremely rapid, almost sudden.

Uterus and embryo at fifteen days and four hours

The swelling of the uterus has considerably increased ; the placenta is larger ; the cavity containing the embryo is very much larger ; the peri-placenta has grown but little. We notice now that of the six folds of the uterus, the two placental have expanded both in width and thickness to a far greater extent than the remaining four folds, except that the lateral expansion of the two ob-placental folds, by attenuation of their walls, has enabled the ob-placenta to occupy an extent of the circumference of the uterus which is about equal to that taken up by the placenta proper ; only about one-sixth of the whole circumference is allotted to the peri-placenta. With the naked eye one can see that the fissure of the placenta has opened so that the surfaces of the two lobes of the placenta now face each other like the sides of a V ; the surface of each lobe, though somewhat irregular, is as a whole arched. The glandular zone is perhaps slightly thicker than at thirteen days, but the diameter of the sub-glandular zone is markedly lessened, owing apparently to the opening of the interlobal fissure and the consequent flattening of the surfaces of the lobes. With a hand-lens one easily recognizes that the blood-vessels of the vascular zone of the placenta are of much greater diameter than at thirteen days, while the dissepiments between the vessels are not only relatively but absolutely thinner than before : this observation does not necessarily involve the conclusion that there has been an actual loss of tissue, for the placenta as a whole has increase in bulk. Let us turn now to the microscopical examination.

The placenta differs but little, except in the respects above mentioned, from the stage last described. The mesodermic covering of the placenta is well marked, Fig. 12, mes, and the foetal mesothelium, msth, is perfectly distinct ; it leaves the placenta at its edge to curl over on to the yolk sack, just as at an earlier stage. Fig. 8, msth. The side of the lobe next the periplacenta is clothed by ectoderm essentially as described at eleven days and partially shown in Fig. 8, ecto ; but the ectoderm is now more irregular than at earlier periods and is thrown into small folds near the point where it is reflected back on the placenta ; similar appearances are clearly indicated in Ercolani's memoir, 89, Tav. IV, Fig. i, i, i, for the Guinea pig. It is quite possible that the folds are more developed in the rabbit later. The placental glands are very much contorted. Fig. i2,gl,gl; very coarsely grandular, with numerous irregular vacuoles and with the nuclei lying for the most part against or near the outer surface of the gland. Fig. 13, gl: the nuclei no longer stain deeply as they do during the first stage of the gland degeneration. Fig. 7. In the upper part of the placenta the glands are much narrower and more widely separated than in the deep part of the layer, as can be seen in Fig. 12, which takes in about half of the glandular layer from the surface down ; towards the surface the glands often form wide loops. Fig. 12, and join one another, making a network with closed meshes. As regards the supposed foetal villi, I find the columns of the foetal mesoderm running down more distinctly than at thirteen days, but as before, the only epithelium which I clearly distinguished, is that in the deepest part of the glandular layer disposed as if covering the tips of the villi. The blood-vessels are very numerous, and some of those above the glands in the foetal mesoderm are very large. Fig. 12, v. It will be remembered that these vessels belong to the foetal system and that the plexus of vessels, which is so conspicuous upon the surface of a freshly excised placenta, pertains therefore to the embryo. At certain points there rise thin membranes from the surface of the placenta, which carry good-sized vessels : whether these are accidental or constant, I am unable to say. Examined with a still higher power, Fig. 1 2, the glandular layer shows the peculiarities of its structure still more clearly ; the mesothelium, msth, upon the surface, though composed of flat cells, has considerable thickness ; the mesodermic cells, mes, are for the most part spindle-shaped and their processes anastomose \ the foetal bloodvessels, V, V, come close against the glands, gl; if, therefore, there is a layer of foetal ectoderm separating the foetal mesoderm from the uterine tissues, it must be very inconspicuous from extreme thinness.

As to the relations of the sub-placenta, my preparations are unsatisfactory.

The sub-glandular layer shows the vascular endothelium advanced in degeneration, the cells projecting far from the surface.

Many parts of the vessels are filled with coagulum, suggesting thrombi formed during life, as has been asserted to occur normally in the human placenta. For the most part, the vessels contain normal blood, save that there is an excess of leucocytes ; in some vessels, however, there are large clear refringent bodies which look like vesicles. What these bodies are I am unable to say — possibly they come from breaking down of the endothelium. The multinucleate cells, Fig. 14, are large and very much crowded ; they contain each a dozen nuclei, more or less, I have nothing of importance to add to the previous descriptions.

In the outer zone we notice at once that the expansion of the blood-vessels is far less active near the muscularis than further in ; indeed, we might subdivide the zone into an outer compact and an inner cavernous layer. The vascular epithelium is far degenerated, Fig. 16; A is a surface view; B and C vertical sections; each cell forms a more or less independent projection ; the cells vary extremely in size ; the nuclei are either single or multiple ; in the former case they may be small and comparatively regular, or large and very irregular in shape ; in the latter case they are of unequal sizes. The perivascular cells are innumerable; their appearance is indicated by Fig. 15 ; but where the blood-vessels are wider, or, in other words, towards the glandular zone, they exhibit signs of breaking down ; the signs in question are indistinctness of outline, granular appearance of the protoplasm, and the difficulty of staining the nuclei. As the changes are slight, they are perhaps accidental. It must be left for future examination of later stages to show whether they do break down or not. I also think that there is a tendency for the multinucleate cells to invade the territory of their uninucleate neighbors.

The peri-placenta agrees with the outer zone of the placenta in its parenchymal structure, except as to two points : 1°, it is now invaded to a slight extent by the multinucleate cells, at the spot nearest the placental glands ; I have no reason to suppose that these cells actually migrate into the peri-placenta, but presume that they arise in situ ; 2°, near the ob-placenta there are in some parts young monster cells lying close under the epithelium ; the evidence is better here than anywhere else I have observed that the monster cells arise from the epithelium.

The ob-placenta now has monster cells throughout almost its entire extent, but the greatest accumulation is where they first are developed, directly opposite the placenta. In this region (Fig. 17) they occupy not only the connective tissue of the mucosa, a, b, but also the territory of the circular muscular coat, where they lie, c, between the bundles, muse, of muscular fibres, which they have forced apart to make room for themselves. The smallest monster cells, a, are found nearest the lining epithelium, ep ; those at the base of the mucosa, b, are bigger, but the biggest of all are those which lie in the outer part of the muscularis, c ; if, therefore, the cells arise from the epithelium and migrate outwards, they must grow while they move. My preparations show in the nuclei of the monster cells certain large, deeply stained fragments which are perhaps chromatine. Fig. 18. Owing to the stretching of the uterine walls, the regenerated glands of the ob-placenta are no longer follicular as at thirteen days (Fig. 10), but are again stretched out, so as to approximate a second time to the form of shallow, open cups, which they had at eleven days (Fig. 6) ; but where the monster cells have accumulated most (Fig. 17), the only distinct trace of the glands is the irregularity of the free surface covered by epithelium, ep.

The embryo and its appendages do not show much alteration in the parts concerning us in the present article. We may, however, note especially two changes in the outer germ layer. 1°. On the strip of ectoderm between the vena terminalis of the yolk sack and the points where the ectoderm joins the placenta, there are a number of thickenings, which form small papillae upon the outer surface of the layer. These outgrowths are solid ectoderm, and like the buds of the villi of the human chorion contain no mesoderm. Whether these structures do become actual villi in later stages, I am unable to say. 2°. Over the yolk sack the ectoderm has become a cylinder epithelium, of which the outer surface is irregular, each cell projecting a little more or less than its neighbors. A similar modification occurs in the opossum according to H. F. Osborn, 61 A, 378-379, PI. XVII., Fig. 4, and Selenka {Entwiekelmigsges. d. TJiiere, Taf. XXVIII., Fig. 5). It is probable that the ectoderm assumes this modification in other mammals, where it remains attached to the yolk sack owing to failure to form a complete chorion.


It will be remembered that the observations cover the period of from six to fifteen days only, and do not include the eleventh day, when several important developments occur.

In the resting uterus of the rabbit there are six longitudinal folds. The ovum attaches itself on or between the two folds nearest the mesentery, and the placenta is there developed ; the two adjacent lateral folds form a cushion (the peri-placenta) about the placenta, but the two folds opposite the mesentery are flattened out by the stretching of the walls to form the swelling to contain the embryo ; they constitute the ob-placenta. In the region of the placenta the mucosa undergoes an enormous hypertrophy : there is likewise an enlargement, but much slighter, of the peri-placenta.

The entire epithelium lining the uterine swelling degenerates ; its nuclei proliferate, and its protoplasm hypertrophies, becoming at the same time hyaline and granular. The degeneration affects the glands also. The degenerated epithelium becomes vacuolated and in large part resorbed. The process goes on with distinctive features in each of the three primary divisions of the swellings.

The connective tissue increases by hyperplasia in the peri-placenta and to a still greater degree in the placenta, and is transformed for the most part into uninucleate perivascular decidual cells, but also in part, — namely, immediately below the glandular layer of the placenta, — into large multinucleate cells. In the placenta, and to a less extent in the peri-placenta, there is a new formation of blood-vessels, which subsequently enlarge to great size, although their only walls are an endothelium which undergoes rapid hypertrophic degeneration.

In the placental region the uterine epithelium degenerates and disappears, but the glands are preserved as irregular anastomosing rows of coarse granular matter, with numerous vacuoles and scattered nuclei, but without central lumina. Below the glands is a zone containing wide vessels and large multinucleate cells. The outer layer has wide blood-vessels, with numerous uninucleate decidual cells, which arise from the connective tissue cells and arrange themselves in successive coats around the blood-vessels until they occupy the entire room between the vessels.

The embryo is attached at first to the surface of the placenta only by the ectoderm, to which the mesoderm soon joins itself. As soon as the coelomatic fissure appears, we can speak of a foetal chorion adhering to the placenta. When the allantois grows out, it forms the stalk of connection between the embryo and the placental chorion. After the development of the chorion, the free surface of the placenta is, of course, covered by mesothelium (the epithelium of the coelom). Outgrowths of the chorion penetrate the glandular layer of the placenta ; whether these outgrowths are in the form of villi in the sense that they preserve a covering of foetal ectoderm was not ascertained, although the tips of the outgrowths appear to have such a covering, and there is no mingling of the foetal with the maternal circulation. The coelom of the embryo does not extend to the edge of the placenta next the peri-placenta, but the mesoderm does, and is covered by ectoderm.

In the peri-placenta, the glands degenerate and disappear completely, but the covering epithelium is reconstituted except on the part near the placenta. The blood-vessels and connective tissue change as in the outer zone of the placenta, though later. At the fifteenth day a few young monster cells were found near the surface.

In the ob-placenta the degeneration and resorption affect only the surface epithelium and the upper part of the glands ; the deep portions remain as a series of shallow cups, having been stretched transversely by the expansion of the ob-placenta ; the epithelium of the cups unites into a new continuous layer ; the glands grow up into follicles and are again stretched out by the expansion of the walls. Meanwhile there appear monster cells, which probably arise by the hypertrophy and migration of single cells of the epithelium ; they are characterized by the granular hyaline appearance of their bodies, by the coarse granulation and large scattered fragments of chromatine of their nuclei, and by their hugeness. The monster cells continue to enlarge and subsequently invade the whole thickness of the annular muscularis. They appear first and are always most numerous directly opposite the placenta, but they are ultimately present throughout the ob-placenta.

The relations of the embryo having been outlined in § 8, with the aid of Plate XXIX., it is not necessary to recapitulate them again.

Comparison with other rodents

The history of the rabbit's placenta elucidates also that of the Guinea pig, of which we possess descriptions by Bischoff, Ercolani, 89, Creighton, 77a, 77b, Tafani, 134, and others. These authors being unaware of the nature of the metamorphoses of the uterine glands, and not knowing the disappearance of the foetal ectoderm over the placenta, but, on the contrary, seeking for foetal placental villi, lacked the necessary basis for a correct interpretation. Ercolani was further misled by his erroneous belief that the placental tissues of the mother arise as new formations, not as metamorphosed constituents of the uterine mucosa, but coming after the assumed but non-occurrent complete destruction of the mucosa. Tafani' s work betrays gross inaccuracy, for he based his figures and descriptions upon schematic notions, based in their turn upon very superficial, and often entirely false, observations. To justify a judgment so severely unfavorable, it is necessary only to direct examination to some of Tafani's plates. His drawings of the human placenta, for instance. I.e. Tav. VII., leave a great deal to be desired ; in Fig. i the sections of the villi are altogether too large and too few ; the separate triangle of tissue at the edge of the placenta does not exist ; the decidua is represented without any compact layer, and its gland cavities are made into blood-vessels. The section of the rabbit's placenta (Fig. 2, Tav. IV.) is even more open to criticism, since it is impossible to determine the foundation of observation. Ercolani, on the other hand, was an observer of considerable ability, and his numerous memoirs on the placenta are valuable, although his hypothesis of neoformazione led him to adopt an unfortunate terminology which makes it difficult to follow him. Creighton observed with more impartial objectivity. That Bischoff was a first-class observer every one knows ; he never leaves any confusion between what he saw and what he inferred ; for us he has the disadvantage of having written before the developments of recent histology. On the whole, we probably do best to turn to Ercolani, who figures 89, Tav. IV., Fig. I., a section of a placenta of a Guinea pig near full term. Let us compare it with the rabbit's placenta.

It is discoidal, pedunculate, and bilobed. The upper surface is covered by a thin epithelium beneath which is a layer of vascular connective tissue, Z, extending over the sides of the placenta, g, f, f, and down between the lobes, q : the epithelium therefore corresponds entirely with the placental mesothelium of the rabbit. The upper portion of the placenta, /, corresponds to the meshwork of degenerated glands in the rabbit's placenta. The layer of epithelium, i, i, m, covering the side of the placenta, corresponds to the foetal ectoderm in a similar position in the rabbit ; at an earlier stage it resembles very closely in appearance what I find in the rabbit (Creighton, 77a, p. 560, PI. XIX., Fjg. b, c, c, c,). Deep down under the space between the lobes of the placenta comes the sub-placenta, Ercolani's cotyledonary organ, O, which was compared above with the sub-placenta of the rabbit ; the thick pedicle of the placenta, e, n, n^ corresponds to the sub-glandular layers of multinucleate decidual cells, which has encroached upon and apparently replaced the outer zone of uninucleate decidual cells, which is present earlier, as it is in the rabbit. At the side of the placenta is the peri-placental thickening, g.d, and springing from it the so-called refiexa, c, which is probably only the peri-placenta hypertrophied. The refiexa is entirely absent in the rabbit. In regard to what I suppose to be the glands, P, neither the descriptions nor the figures of Ercolani suffice to indicate their character.

The interpretation offered differs in nearly every respect from Ercolani's own ; and yet though I have no preparations of the Guinea pig's placenta, and am acquainted with the organ only through the publications of others, I think the homologies drawn may be accepted with considerable security ; but let me add that I am well aware that their actual justification can come only from the specimens.

Sections of the rat's placenta near full term show that the structure in that species is strictly comparable to what exists in the rabbit. The surface is covered by a thin epithelium overlaying a vascular connective tissue layer ; the vacuolated tubular glands, very much degenerated, occupy the greater part of the placenta, leaving only a thin vascular zone from which the outer zone is lost, and which is therefore occupied solely by the much altered sub-glandular zone of multinucleate cells. There are many differences in details of structure from the rabbit, but the fundamental likeness is self-evident.

As the similarity of the placentae of various rodents has been noted by previous authors, it is probable that the type of placental organization is the same throughout the class.

  1. Although this use of the term mesentery is etymologically indefensible, it seems permissible, and not likely to lead to misunderstanding any more than the etymologically indefensible terms cell, endothelium, terminology, etc., etc.
  2. The specimen described by Ercolani I consider to have been probably really only about thirteen days,
  3. Compare Bischoff, Entwickelungsgesch. d. Kaninchens, p. 13S, and von Baer, Entuiickelungsgesch. II., 232.
  4. Wood's Reference Handbook of the Medical Sciences, II., 143; article, Chorion.
  5. This statement is perhaps not correct. There are certain spaces surrounded by epithelial or epithelioid cells to be seen in the upper part of the sub-glandular and in the lower part of the glandular zone; these spaces I have interpreted as parts of the glandular system, but they are perhaps maternal vessels with perivascular cells. The uncertainty as to their character could be probably removed by the examination of the ten days' placenta, which presumably offers the intermediate stages.
  6. A layer closely similar to this, and presumably homologous with it, exists in the Guinea pig (Creighton, 77a, p. 558), in the rat (Ercolani), and other rodents.
  7. For diagrams of the pro-amnion, etc., see Van Beneden et Julin. Copies of their figures are given in Buck's Reference Handbook of the Medical Science, VI., 32.
  8. Leaving the pro-amnion out of consideration.

Minot, C.S. Uterus And Embryo (1889) - I. Rabbit II. Man - Plates

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