Paper - A Human Ovum at the Previllous Stage
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The specimen which is described in this communication consists of what is believedtobeanormalovum thathasbeennotlongimbeddedintheuterus, and it represents the youngest stage of human development that has so far beenrecordedinthiscountry. Itwasdiscoveredbyoneofus(J.H.D.)during the course of a post-mortem examination of a woman, aged 28, who had died from internal hydrocephalus due to fibrous adhesions at the base of the brain which were probably the result of trauma. The post-mortem examination was made not more than ten hours after death, and there is no reason to suppose that the specimen is not normal.
A large corpus luteum was seen in one ovary and this directed particular attention to the uterus; on opening this along the anterior wall the mucous membrane was found to be thick and velvety, and on the posterior wall, towardsthefundus,therewas seenasmallvesicle(Fig.1)projectingabove the surface which was thought to be an early ovum. A small wisp of fibrinous materialwasadherenttothesummitofthevesicle. Nomenstrualhistorywas available.
The opened uterus was fixed in formalin and, after being photographed, a blockoftissuecontainingthevesiclewas removed, cut at 4p,and stainedwith iron-haematoxylin and eosin; blocks of tissue from other parts of the uterus were also removed for study of the structure of the endometrium at a distance from the vesicle; this endometrium presents the characters typical of the premenstrual phase, with large, tortuous and active glands, and a rich blood supply;thesectionsshow,too,thatthefixationandpreservationaregood. In thesectionsoftheblockoftissuecontainingthevesiclethemucous membrane is5mm. thickandisdivisibleintoastratumcompactum,03 mm. thick,and a stratum spongiosum (Fig. 2).
The implantation site can be recognized in the sections with the unaided eye by the pink stain which has been taken up by some dilated glands lying atthebaseofthearea. Contrarytowhathasbeenfoundinseveralyoung specimens, and to what might have been expected from the appearance of the intact vesicle, the implantation site is not much raised above the surface in the sections. Implantation has occurred between the mouths of two glands which are bent round the ovum, and the site of implantation occupies the stratum compactum only. The ovum isnot covered with a decidua capsularis, and the point of entry of the ovum into the endometrium is seen (Figs. 5, 7) as a crater-shaped area, from which the uterine epithelium is deficient, over- lying the summit of the ovum. The aperture of entry is 0-23 mm. wide; it is filed,as with a bung, by the 'operculum' (Teacher, 1924) and iscapped by the 'closing coagulum' or 'Gewebspilz' (Peters, 1899). The latter appears as a loose mass of fibrinoid material containing some leucocytes and it was seen as the small wisp, referred to above, when the uterus was opened.
The ovum (Fig. 3) consists of a slightly flattened chorionic vesicle, the blastocyst,whichhasaninternalmeasurementof047mm. intheequatorial plane, i.e. from side to side, and of 0'28 mm. in the polar plane, i.e. from the surface inward. The inner surface of the blastocyst is smooth and has the embryonic rudiment attached at its base; the outer surface is irregular owing to cellular and syncytial processes growing out from it into the implantation cavity. These processes are stained deeply with haematoxylin and they stand outinsharpcontrastwiththeclearcavityinwhichtheylie(Fig.4).Thesmooth inner surface of the blastocyst is lined with primary mesoderm, and inside this there is the exocoelomic vesicle (Heuser, 1938) enclosed by the exocoelomic membrane (Heuser's membrane). The embryonic rudiment is composed of a thick ectodermal plate which forms the ventral wall of the amniotic cavity, and of a rather thinner entodermal plate which is continuous at its margins with the exocoelomic membrane. There is no yolk sac.
There are no chorionic viliand thus the specimen belongs to the group of ova at the previllous stage, which includes the Miller (1913, and Streeter, 1926), the Kleinhans (Grosser, 1922), the Muller (1930), and the two new Hertig ova of which a preliminary account only has so far appeared (Hertig & Rock, 1939). Further, it corresponds with Streeter & Wislocki's (1938) stage II for the macaque, which they term the 'stage of trophoblastic lacunae' andwhichtheyestimatetobelongtotheperiodfromthe11thtothe14thday. The implantation cavity appears (Figs. 4-6) as an almost empty, clear and circumscribed area and thus stands out in sharp contrast with the adjacent endometriumontheonehandandthedarklystainedtrophoblastontheother; it is this character of the implantation cavity which gave to the specimen a cystic appearance when first seen in the uterus with the unaided eye.
Thetrophoblast. Growingfromtheoutersurfaceoftheblastocystarethe trophoblastic processes. In the account which follows, the terminology employed by Ramsey (1938) in her description of the Yale embryo will be used. Thus we are able to recognize central cytotrophoblast, peripheral cytotrophoblast, and plasmoditrophoblast or syncytium.
The central cytotrophoblast (Figs. 7, 8) forms the true wall of the blasto- cyst; it is composed of a single layer of lining cells which, for the most part, appear rather condensed and flattened and have darkly stained, round or oval nuclei, but poorly defined cel walls; in some sections the nuclei are packedcloselytogethergivingadarkbordertotheblastocyst,whileinothers, particularly in the region of the operculum, they are few and far between.
The peripheral cytotrophoblast (Figs. 4-8) appears as sheets, or columns, ofcellsgrowingfromtheblastocystwallintotheimplantationcavity;inother words, it is an extension outward of the central cytotrophoblast. The cels are larger and have more clearly defined walls than have those of the central cytotrophoblast, their nuclei generally are not so darkly stained, nor do they filthecelltothesame extent,sothatthereisoftenaclearspaceleftbetween the nucleus and the cel wall. Beyond the peripheral cytotrophoblast, and alsoextendinginamongst itscelcolumns, aregrey,filmymasses and strands whichmay benucleatedornon-nucleated;thistissueistheplasmoditropho- blast,orsyncytium(Figs.5-8). Itisdevoidofanycelboundaries,andin some places nuclei occur in clumps, like the 'heaped-up epithelial nuclei' describedbyStreeter& Wislocki(1938).
In the plasmoditrophoblast brown granules are seen in many places; similar granules have been described by Johnstone (1914) and Greenhill (1927). Johnstone suggested (p. 270) that they are composed of molecules of blood pigment adherent to a minute droplet of fat, the fat itself having disappeared inthecourseoftheprocessoffixationandstaining.We areofopinionthat this pigment is a formalin-haemoglobin precipitate, and the fact that it is found mostly at the implantation site and in the cells of distended glands which form lacunae of blood rather supports this view, since these are sites of haemorrhage, and it is well known that in slightly autolysed tissues such precipitates are common in histological material. The ovum, and the autolytic ferments present in the trophoblast, may well be responsible for some degree oflocalautolysis. Greenhillimplies(p.340)asimilaroriginofthegranulesin hisspecimen. Ithasnotbeenpossibletomakeanymicrochemicalanalysis of these granules as it would have involved an interruption in the series of slides,butitmay bementionedthattheyareanisotropic,asaretheformalin precipitates. The frequent occurrence of these granules in association with leucocytes provides further support for their origin from blood.
Several authors have referred to the foam-like condition of the syncytium of early stages due to the presence of innumerable vacuoles of various sizes, and the general opinion seems to be that this vacuolated syncytium has been derivedfromamoresolidplasmodiumwhichhasgrownoutfromtheblastocyst wall. Thus Bryce (1908) suggests (p. 43) that the spun-out condition of the plasmodiumorsyncytiumisduetotheformationinthevacuolesofadigestive fluid which, after rupture of the vacuoles, is replaced by maternal blood; the large amount of blood in the implantation cavity is a striking feature of the ovum T.B. 1. Streeter (1926), in his account of the Miller ovum, describes the lacunae as being small near the wall of the ovum and larger as the periphery is approached, and he refers to them (p. 37) as representing the 'histological picture of a process by which a solid mass of trophoblast becomes converted into a sponge-like syncytium'. The Miller ovum shows a lesdefiniteimplantationcavitythanthepresentspecimen.
In our ovum the vacuolated network (Figs. 7, 8) seems to be made up largelyofcoagulatedproteinwithbranchingcellsscatteredthroughit;thesecells appeartobepartlytrophoblasticandpartlystromal,andsomearedegenerate. This appearance isno doubt produced, so far as the protein is concerned, by fixation, and it seems probable that in life the contents were mainly fluid or gelatinous with strands of fibrin, amongst which the cells of the trophoblast were growing out from the blastocyst as in a tissueculture. We believethat our ovum, the Miller ovum, and the ovum T.B. 1, show progressive stages in the dissolution of the originally more solid plasmodium, the present specimen being at a stage intermediate between the Miller ovum, and the ovum T.B. 1, wherethevacuoleshavebecomefiledwithblood.TheMullerovum we believe tobeatastagesimilartoours.TheembryoKleinhans,judgedbythecondition of the implantation cavity, seems to be at a stage intermediate between the present specimen and the ovum T.B. 1, for it shows a cavity which is fairly clearcutbutwhichcontainsrathermorebloodthanispresentinourspecimen. By the same criteria, the two new Hertig ova are both at stages earlier than either the present specimen or the Miller ovum; Hertig's no. 7700 in particular shows an almost solid plasmodium surrounding the trophoblast wall.
Teacher (1924) refers to the two generations of syncytium, the destructive and temporary syncytium-the 'Implantations-syncytium' of Grosser-and the permanent syncytium of the chorionic villi-the 'Zotten-syncytium' of Grosser. Itisthisfirstgenerationofsyncytiumthatwehavebeforeus,and we get the impression that itshows evidence of destructive action and also of beinginaprocessofdegeneration,foritisadegeneratetissueandyetitseems able to open into capillaries and, contrary to what Streeter found in the Miller ovum, into glands also. Streeter further stated that he was unable to find any evidence of destruction or ingestion of the stroma cells by the syncytial loops; inthepresentspecimen,asserialsectionsareexaminedfromthenon-implanta- tion area towards the blastocyst, the first change seen is that the stroma becomes oedematous, the spaces between the cels are increased, and their nuclei become enlarged and paler. By the appearance of their nuclei these maternal stroma cels can be distinguished from the cels of the trophoblast, and in sections through the periphery of the implantation cavity they can be recognized without any doubt, though they are not numerous and their period of survival would appear to be short; here and there they can be seen lying in a mass of the filmy grey tissue that has been recognized as syncytium.
It may be suggested here that much of the lacy, network-like, appearance ofthetrophoblastseemstobeduetodestructionofitscels,by autolysisor by extracellular digestion, or by a combination of both processes; the general picture suggests the presence of some rather active ferment, or of conditions causing autolysis. We believe that many of the spaces between the tropho- blastic branches may contain autolysed blood, the more so because the red celsinmany ofthecapillariesinthevicinityareautolysed,thoughnot inthose fartheraway. Thisinterpretationisinconformitywiththesuggestionwe made aboveconcerningtheoriginofthepigmentedgranules.Thus, there does seem to be evidence of the digestion of the stroma cels by the syncytium in this specimen, and we believe that such destruction must have been extensive, for there islitleevidence ofthe stroma having been simply pressed outward, as Streeter found to be the case in the Miller ovum, though in some places it is arranged more or less in concentric lamellae as if it had been pushed aside to someextent. Itdoesseemthatthemainmethodofenlargementofthecavity, withthenecessaryremovalofthestromacels,isbyaprocessofoedemaofthe stroma,degenerationofitscelsandtheirautolysisordigestion. Itisnote- worthy that there is a strip-the 'border-zone'-of degenerated and necrotic stroma alround the implantation cavity, except where itisin contact with a gland (Figs. 4, 5).
The implantation cavity
The implantation cavity measures 1-0 mm. in its equatorialdiameterand0575mm. initspolar.Ashasbeenmentionedabove, it appears as an almost empty, clear and circumscribed area, and though this character of emptiness is an appearance only, yet in this character and in the sharpoutlineofthecavitythespecimenshowsaconditiondifferentfromwhat is found in other early ova, with the exception of that described by Muller, in that these have an implantation cavity more or less filedwith blood, and with an irregular and indefinite outline. The cavity rests on two glands which havebeensogreatlydistendedwithbloodthattheirepitheliumhasbeenquite flattened and resembles the endothelial lining of a blood vessel, for which it was at first mistaken (Figs. 3, 5 and 8). The distension affects mainly the deeperpartsoftheglands.Brewer (1937)statesthatinalhuman pregnancies reported there is an accumulation of blood in the uterine glands, and, in the Edwards-Jones-Brewerovum whichhedescribes,theglandsarecertainlyvery distended with blood, but the only specimen besides the present one that shows a comparable distension is that described by Herzog (1909). As to the cause of the distension in the present specimen, it is clear that in the case of one gland at least it is due to the fact that it does not open on the surface, its lumen being occluded with syncytium and its mouth incorporated in the implantationcavity. Itisthereforedistendedinpartwithblood,andinpart withitsownsecretionwhichhasnoexit. Inanothercase,theglandhasburst on to the surface (Fig. 6) and its contents have been expelled into the uterine cavity where they form a wisp of fibrinous material impregnated with leucocytes.
The closing coagulum and the operculum
A wispoffibrinousmaterialhas been alluded to already as the closing coagulum which caps the aperture of entryoftheovum intotheuterinemucousmembrane(Figs.1,3,5,7and8). The structure of this coagulum and of the contents of the implantation cavity isessentiallysimilar,anditmay beregardedasapartofthecontentsofthe cavity which has become free on the surface owing to the absence of any deciduacapsularis,andtothedisappearanceoftheuterineepitheliumoverthe point of entry of the ovum. The closing coagulum is also continuous in part with the contents of the gland which has burst on one side of the ovum. The very thin covering of the ovum was recognizable in the intact specimen, for theovum hadtheappearanceofatinycyst,likeablisterinthethickmucous membrane,withitspoleglisteningthroughthethincovering. Itisinteresting to note, in connexion with the origin of the closing coagulum, that Brewer (1937) showed a much larger and more organized 'blood clot' overlying the surfaceepitheliumattheimplantationsite,andhesuggestedthatitscharacter indicated previous bleeding into the uterine lumen; the implantation cavity in Brewer's ovum contains a good deal of blood, and this may explain the difference in the appearance of the closing coagulum in his specimen and in ours.
Theimplantationcavitydoesnotsurroundtheovum completely,forinits superficial part it is interrupted by the presence of the operculum (Figs. 2, 5). As so well described by Schlagenhaufer & Verocay (1916), quoted by Teacher (1924, p. 179), the operculum, 'as the stopper of a bottle, as the keystone of a vault.closes the entrance to the implantation cavity with its precious contents'. Itisclearlyanoutgrowthofthecentralcytotrophoblastatthe superficial pole of the ovum, and it fils the space between this part of the ovum andtheuterinecavity. Instructureitisliketheperipheralcytotropho- blast of the rest of the ovum, except that it is rather less cellular and more vacuolated; in it are some small masses of syncytium and a few degenerated maternal stroma cels.The whole mass has a degenerated appearance and gives the impression of being a tissue, derived from proliferation and outgrowth of the cytotrophoblast, which has nearly outlived its usefulness. In some sections(Fig.8)theoperculumandtheclosingcoagulumarecontinuous. Over the aperture of entry the uterine epithelium is deficient (Figs. 5, 7). Farther laterally it forms the sides of the crater-like area occupied by the operculum, butbothhereandintheadjacentglandsitisflattenedandhastheappearance ofhavingbeenstretched.Thisisquiteunliketheappearanceoftheepithelium lining the uterus and the glands generally, which is columnar.
The blood vesels
Fig.9 is a photograph of asectionthroughthemiddleof theovum,andonithavebeenmarkedwithinkalthebloodvessels. Itshows thattheendometriumiswellsuppliedwithblood. Small,thick-walled,spiral arteries and larger and thinner veins are seen in the stratum spongiosum, but capillaries only are present in the stratum compactum. There is no definitive blood sinus at the base of the ovum, such as is described by von Mollendorff (1921a) in the embryo 'Sch.', and by Ramsey (1937, 1938) in the Yale and Lockyer embryos; instead, there are numerous small vessels round the implantation site which ultimately join into two main veins, one rather larger than the other. The capillaries of the stratum compactum are opened by the syncytium and become incorporated in the implantation cavity, giving rise, at least in part, to the clear spaces of the cavity.
The embryonic rudiment
Theembryoisfoundontheinnersurfaceofthe basalwalloftheblastocyst. Itconsistsofathickectodermalembryonicplate which forms the ventral wall of an otherwise thin-walled amniotic cavity, and of a rather thinner entodermal plate which has not yet differentiated into any partofadefinitiveyolksac. Spreadingoutfromthesidesoftheamniotic cavity are the cels of the primary mesoderm which, when traced in a lateral direction, form a continuous lining for the inside of the blastocyst (Figs. 7, 8, 10 and 11). Within this primary mesoderm there is an even thinner layer (Figs. 5, 7 and 8), the exocoelomic membrane (Heuser, 1938); this encloses a large, more or less spherical, cavity which we thought at firstwas the yolk sac, admittedly a good deal larger than we had expected to find in an ovum at this stage. This membrane will be referred to in more detail after the other parts oftheembryohavebeendescribed. Itisunfortunatethatanumberofsections containing the embryo have been lost and it is thus not possible to make a completereconstruction,butthefollowingarethemeasurementsoftheembryo taken in the middle of the ten sections in which it occurs:
- Embryonic disc 0.1 x 002mm.
- Endodermal plate 0.14 x 0.016mm.
- Amniotic cavity 0.04 x 0.09 mm.
The celsofthe ectodermal and entodermal plates do not differmuch; in each (Figs. 10, 11) the cels are closely packed, here and there piled up two deep, butstandinginacolumnararrangementintheectodermandlyingendtoend intheentoderm.The celboundariesarenotwelldefined,butthenucleiare largeandgranular,exceedingthoseofthecentralcytotrophoblastbutequalled by some of those of the peripheral cytotrophoblast.
Inadiscussionoftheformationofthehuman yolksacStieve(1931)shows a section through the embryo, Werner which resembles our embryo in having what he thought to be a large yolk sac. This was our interpretation also at first, but we have since had the opportunity and advantage of seeing Dr Streeter's beautiful photographs of the two new Hertig ova, of having his personal opinion about them, and of having read Heuser's (1938) paper on the 'Early development of the primitive mesoblast in embryos of the rhesus monkey'. The stages illustrated in Heuser's publication are of particular interest,forStreeter(1933)hasshownthatthedifferenceindetailofformand in rate of differentiation and growth between man and monkey does not become appreciabletilthe end ofthe second month, and that known ages of macaques may be transferred to human embryos at least for the first month orsixweeks. Itisthereforeprofitabletocompareourovumwiththestages of the macaque described by Heuser, since, as we have suggested above, our specimen fals into the stage of development which Streeter & Wislocki attribute in the macaque to the period from the 11th to the 14th day, and Heuser gives photographs of embryos of the 11th, 12th and 13th day.
Themoststrikingdifferencebetweeneachofthesespecimensandourovum isseenintheconditionoftheentoderm.We havedescribedtheentoderm plate as being nearly equal in thickness to the ectoderm plate and have stated thatthereisnodefinitiveyolksac. Heuser's11thdayembryoshowsnoyolk sac,butinthespecimenofthe12thdayitisjustbeginning,andinthespecimen ofthe13thdayitisseenclearly. Inrespectofthedevelopmentoftheyolk sac, then, our embryo corresponds with one of the 11th day in the macaque, the chief difference being in the thickness of the gut entoderm which, in the macaque, consists of a flattened layer of only one cell in thickness spread out on theinnersurfaceoftheinnercelmass.
Heuser states (p. 384) that 'Cells delaminating from the inner surface of the thickened trophoblast seem to be continuous with the primitive entoderm beneaththeinnercelmass'. Hefindsthatbythe11thdaythesecellsbecome continuous with a layer that has split off from the ventral surface of the ento- derm sheet so that a complete envelope, the exocoelomic membrane, isformed, havinganoriginpartlytrophoblasticandpartlyentodermal. Inourovum such a membrane is present, but its origin is not as clear as in the macaque; it appears (Figs. 3, 8, 10 and 11) to be continuous in the embryonic region not with a layer of cels split off from the entoderm but with the edges of the entoderm itself, nor is it certain (though it is probable) that the remainder has arisenbyasplittingofffromtheinnersurfaceofthetrophoblast. Itthus appears that, as far as the development of the exocoelomic membrane is concerned, our ovum is at a stage earlier than that of the macaque at the 11th day.
We havereferredabovetotheprimarymesodermasformingacontinuous liningfortheinsideoftheblastocyst. Heuserfindsthattilthe13thday, 'exceptinasmallzonearoundtheembryo itself,thereislitleifanyaddi- tional mesoblastic tissue', that is, additional to the tissue that has formed the exocoelomic membrane. Our ovum has a trilaminar blastocyst (Fig. 7) composed of an outer trophoblast, a middle primary mesoderm, and an inner exocoelomic membrane; it thus corresponds, as regards the development of the mesoderm, with a macaque of some days later than the 13th. The primary mesoderm looks as ifitmight well have been derived from a splitting off of cels from the inner surface of the trophoblast, and in the embryonicregionitiscontinuouswithcelslyingatthesidesoftheectodermal plate and the amnion (Figs. 8, 10 and 11). These cells extend for some distance outward from the embryo and help to filthe space between the trophoblast and the exocoelomic membrane. This is seen particularly well in a glass-plate reconstruction in which the mesoderm cells are shown to be more numerous here than elsewhere.
With regard to the entodermal plate, we are unable to see more than one formofcel,though,insome sections,on theventralsurfaceoftheplatethere areafewcelswhicharelessdarklystainedthanthemajority,andwe can seeno filmofflattenedcelswhichmightgiverisetothebasalportionofthe exocoelomic membrane; nor can we seeany splittingoffofcellsfrom itsventral surfacetoformtheventralwalloftheyolksac.We believeourspecimentobe at a stage antecedent to the completion of the exocoelomic vesicle.
For some years ithas been believed that the human yolk sac appears early in development and is already present in the youngest known specimens, that the yolk sac develops by a process of cavity formation in the ventral part of theinnercelmass,andthatalitswallsareofentodermalorigin. Ithasbeen believedthattheseconditionsholdgoodforotherprimatesalso. Forexample, J. P. Hill (1932), in his Croonian Lecture, described the condition of the yolk sac in the earliest catarrhine embryo then known, the 'Keim S' of Nasalis larvatus (Selenka); he believed it was at 'the stage when an originally solid endodermal yolk-sac primordium is in course of becoming converted into a hollow vesicle by a process of vacuolization' (p. 108).
More recent work on primate material by Heuser, Stieve, and Streeter has cast some doubt on the truth of these older theories, and Streeter (1937), in discussing the origin of the yolk sac in primates, states that its earliest cels are differentiated 'as a thin membrane between which and the gut endoderm there arises a narrow cleft. This cleft becomes rapidly distended and so forms the conjoint yolk sac cavity and gut cavity. This cavity is therefore dual in origin and is bordered on its dorsal part by cells that are to form the gut endoderm, an induced product or migratory element from the embryonic ectoderm. It is bordered on its ventral part by the yolk sac endoderm which is a derivative of the primitive mesoblast and is essentially tropho- blastic.'
Through Dr Streeter's kindness we have had the pleasure of examining photographs of the two new Hertig ova and of an ovum of the macaque at about the same stage of development. The Hertig ova are at much the same stage as our own and, like it, show ectodermal and entodermal plates and an exocoelomic membrane which appears to be continuous with the edges of the entodermalplate.Themacaqueovum isataratherlaterstage,andinitthe exocoelomic membrane is separate from the entodermal plate and forms a closed exocoelomic vesicle on the ventral side of the entoderm. A yolk sac is present, and consists of a small vesicle with its dorsal wall formed by the entodermal plate and its ventral wall by cells which look different from those at the base; they are smaller, more flattened, and have more darkly stained nuclei, and they resemble the cels of the primary mesoderm and the dorsal wall of the amniotic cavity. The study of our own specimen and of the photographs of the Hertig ova and the macaque lead us to believe that the older theories must be revised; for we find that the Hertig ova and our own, the youngest human specimens thus far known, have no yolk sac. The macaque ovum strongly suggests that the yolk sac does not arise by a process of cavity formation in the inner cel mass, and shows that the cels of the dorsal wall of the yolk sac are quite differentinappearancefromthoseofitsotherwalls. Streeter's(1937)sug- gestion, quoted above, at firstfiled us with astonishment and confusion, for it seemed that, in his view, there was no such thing as entoderm sui generis if the gut entoderm is a migratory element from the embryonic ectoderm, and if the yolk sac entoderm is derived from the primitive mesoblast and is tro- phoblastic in origin. The dificulty, however, seems to be one of terminology andofthedistancebackintheirdevelopmentalhistorytowhichthedifferent layersaretraced.
After careful study, we agree with what we believe to be Streeter's views and the course of development seems to us to be as follows: The inner cell mass becomes differentiated into a thicker dorsal part, the embryonic ecto- dermal plate or embryonic disc, and a thinner ventral part, the embryonic entoderm. The exocoelomic membrane splits off from the inner surface of the trophoblast and becomes adherent to the edges of the embryonic entoderm, so that there is formed a temporary exocoelomic vesicle bounded dorsally by entoderm,andelsewherebycelssplitofffromthetrophoblast.A layerofcells splits off from the ventral surface of the embryonic entoderm and joins with the cels of the exocoelomic membrane, or else the exocoelomic membrane grows round on the ventral surface of the entoderm and then becomes separ- ated from it. Thus there is formed finally a complete exocoelomic vesicle, detached from the entoderm, occupying the interior of the blastocyst. The primary mesoderm, which has meanwhile been split off from the inner surface of the trophoblast outside the exocoelomic membrane, spreads as a thin layer over the ventral surface of the embryonic entoderm, between it and the exocoelomicvesicle.A cleftthenappearsbetweenthisfilmofprimarymeso- derm and the embryonic entoderm, so that there is formed a cavity bounded dorsallybythecelsoftheembryonicentoderm,andelsewherebycelsderived from the primary mesoderm. This cavity is the yolk sac, but, as Streeter pointed out, its dorsal wall will later be that of the gut, whilst its other walls will be those of the yolk sac proper. The alternative to this suggestion of the formation of the yolk sac is that the primary mesoderm does not spread over the ventral surface of the entoderm, and that the cleft is not between meso- derm and entoderm but within the entoderm itself. In opposition to this, however, it must not be overlooked that, at least in the macaque, the cells of the dorsal wall of the cleft are quite different from those of its other walls.
Aswiththeyolksac,thecelsoftheventralwalloftheamnion aredifferentfromthoseofitsotherwalls(Figs.8,10and11). Itsventralwall isformedbycelsoftheembryonicectoderm; thecelsofitsotherwallsare smaller, more widely spaced and more mesodermal in character. Streeter.& Heuser (1935) called attention to this sudden transition in the structure of thewallsoftheamnioticcavity,andsuggestedthatwhilstthefloorwasformed bytheectodermofthegerm-discpropertheremainingwallsweretrophoblastic in origin.
It has been thought that the human amniotic cavity develops, like that of the bat, by a process of cavity formation in the more dorsal part of the inner celmass, thatthedorsalwallofthecavityiscloselyadherenttotheinner surfaceoftheblastocyst,and thatthecellsofalitswallsareofectodermal origin. Our ovum, the Hertig ova, and the macaque ovum referred to above, al show the same characters of the amnion (Fig. 11). The cavity is rather flattened in a ventro-dorsal plane, more so in the other specimens than in ours. The ventral wall is thick and formed by the embryonic ectoderm, the other walls are very much thinner and formed by cells that resemble those of the primary mesoderm. The dorsal wall is not continuous with the inner surface of the trophoblast, but is attached to it only indirectly through the inter- vention of a few scattered mesoderm-like cels. That the cavity has arisen by cleft formation seems clear, but it is not so certain whether the cleft has been formedwithinthedorsalpartoftheinnercelmass orbetweentheinnercell massandthetrophoblast. Ifthecleftarosewithintheinnercelmassone would hardly expect to see such a difference between the cells of the ventral wall and the other walls of the cavity, and the amnion would be more closely attachedtothetrophoblast. Ifthecleftoccurredbetweentheinnercelmass andthetrophoblastitwouldmean theseparationoftheinnercelmassfrom theinnersurfaceofthetrophoblastand thefilingofthegap between thetwo with primary mesoderm, resulting in the formation of a cavity bounded everywhere, except ventrally, by cels of the primary mesoderm. The latter seems to be the more probable course and would explain the characters of the amnion described above, though it is more accurate to speak of a gradual separationofthedorsalpartoftheinnercelmass from theinnersurfaceof the trophoblast accompanied by a filinginofthe space with mesoderm rather than of any actual cleft formation.
It thus appears that the yolk sac and the amniotic cavity have a rather similar method of development and that, as Heuser (1938) pointed out, the original inner cell mass is responsible for the formation of a small part only of the actual embryo, that is, the germ disc or embryonic ectoderm and a thin film of entoderm on its ventral surface.
A descriptionisgivenofahumanovum attheprevillousstageofdevelop- ment which was obtained at an autopsy.
The implantation cavity is unusually well defined and free from blood. It liesbetween and above greatly dilated glands which are almost filedwith partly haemolysed blood, and of which one has burst into the uterine cavity. The closing coagulum appears to be derived partly from the contents of this ruptured gland, and partly from the contents of the implantation cavity. The operculumfilstheapertureofentryintotheuterinemucous membrane; itis an outgrowth from the wall of the blastocyst, and gives the impression of havingalmostoutliveditsusefulness.
The blastocyst shows, growing from its outer surface, cytotrophoblast and syncytium; the syncytium is at the stage intermediate between the formation of the 'Implantations-syncytium' and the 'Zotten-syncytium' of Grosser. The blastocyst is a trilaminar vesicle, its outer wall being the trophoblast, its middle the primary mesoderm, and its inner the exocoelomic membrane. Theembryoisattachedtothebasalportionoftheblastocyst,andiscomposed of an ectodermal embryonic plate, an entodermal plate, and an amniotic cavity. There is no yolk sac. The origin of the exocoelomic membrane, the yolk sac, and the amnion isdiscussed. Itissuggestedthattheexocoelomicmembraneisderived,like the primary mesoderm, by splitting off from the inner surface of the tropho- blast, that, in agreement with Streeter's suggestions, the yolk sac has its dorsal wall derived from embryonic entoderm and its ventral wall from primarymesoderm,thattheamnionhasitsventralwallderivedfromembryonic ectoderm and itsdorsal wall from primary mesoderm, and that the inner cel mass is responsible for only the embryonic ectoderm, or germ-disc, and a thin layer of entoderm on its ventral surface.
The authors are indebted to Mr W. Kiffin, of the Pathology Department, the University of Liverpool, for the preparation of the sections; to Mr C. Wilmott, of the British Postgraduate Medical School, University of London, and to Mr A. Welch, of the Anatomy Department, University College, Cardiff, for the photographs; and to Mr Douglas Kidd, of Liverpool, for the coloured drawing.TheyarealsoindebtedtotheJointAcademicCommitteeofUniversity College, Cardiff, for a grant towards the expenses of the publication of this paper, and to Dr George L. Streeter for his personal interest in the specimen and for photographs of the Hertig ova and of a macaque ovum.
The following papers have been consulted, but not alare referred to inthetext:
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