The Ultrastructure of Primordial Germinal Cells of the ... · desmosomes were absent. Direct...

The Ultrastructure of Primordial Germinal Cells of the FetalTestes and of Embryonal Carcinoma Cells of Mice*

G. B. PIERCE, jR.,f AND T. F. BEALS(Department of Pathology, The University of Michigan, Ann Arbor, Michigan)

SUMMARY

This study compares the ultrastructure of murine embryonal carcinoma cells, themultipotential stem cells of teratocarcinomas, with the constituents of the primordialtesticular tubules in which they arise.

The primordial tubules were composed of Sertoli cells and primordial germinal cells ;the former were well differentiated with Golgi membranes and well developed cisternalendoplasmic reticulum. The ultrastructure of primordial germinal cells bore a strikingresemblance to embryonal carcinoma cells. Few profiles of endoplasmic reticulum andnumerous dispersed ribosomes imparted a uniform stippled appearance to the cytoplasm. Mitochondria appeared prominently because of the lack of other organelles;desmosomes were absent. Direct cytoplasmic communications through openings inthe cellular membranes were observed in primordial germinal cells but never in thecancer cells.

It is concluded that the primordial germinal cells of the lo-day-old fetal testis ofthe mouse satisfy the requirements of multipotentiality and morphological similarityto be the cell of origin of embryonal carcinoma and teratocarcinoma.

It is only in the past decade that a working classificationof testicular tumors has been evolved that clearly delineates the relationships of the tumor types so that rationalapproaches to histogenesis, pathogenesis, prognosis, andendocrinology can be made (4). The fundamental hypothesis of this classification was that embryonal carcinomacells, which were presumed to originate from the germinalcells of the host, were multipotential and differentiatedinto the somatic tissues of teratocarcinomas and themalignant trophoblast of choriocarcinoma.

Some of the problems have yielded to experimentation;for instance, embryonal carcinoma cells of murine teratocarcinoma have been shown to be multipotential stem cells(10, 13, 14, 16, 19-21). Stevens (21) studied spontaneously developing testicular teratocarcinomas in strain 129fetal mice and found that they developed within thetesticular tubules of embryos of 15 days of gestation. Thisstrongly supports the theory of germinal origin of thesetumors.

In an effort to define further the cell of the testiculartubules which originates teratocarcinomas, we havestudied and compared the ultrastructure of fetal testes ofthe mouse and the multipotential embryonal carcinomacells of murine teratocarcinomas. The rationale for thisstudy was based upon the often made observation that

* Supported in part by grants from the American Cancer Society, Inc. (E-105), and the National Institutes of Health (Ca-6113).

t Markle Scholar in Medical Sciences.Received for publication March 2, 1964.

many of the ultrastructural features characteristic ofnormal cells may be retained by their neoplastic counterparts (3, 17, 18, 30).

MATERIALS AND METHODSThe neoplasm employed in this study was the trans-

plantable line of murine teratocarcinoma LS 402VI A (22,23) acquired from Dr. L. C. Stevens in 1957. The tumors,maintained by subcutaneous transplantation at about 30-day intervals in strain 129 mice, were composed of a wideassortment of well differentiated somatic tissues, haphazardly arranged. Aggregates of embryonal carcinomacells, proved in vivo (13, 14, 16) and in vitro (19) to bemultipotential stem cells originating the somatic elements,were scattered throughout (Fig. 1).

For the ultrastructural studies, embryonal carcinomacells were selected from either undifferentiated teratocarcinomas composed almost exclusively of embryonalcarcinoma that had lost its capacity to differentiate, orfrom embryoid bodies known to be multipotential andcapable of differentiation (14, 20). Embryoid bodies wereobtained from the ascitic fluid of mice grafted intraperi-toneally with the testicular teratocarcinoma. Two varieties of embryoid bodies were studied: primitive ones,composed of a core of embryonal carcinoma cells investedby a layer of visceral yolk sac, closely resembling mouseembryo of about 5 days of gestation (Fig. 2) (20), andmore mature ones, with a layer of mesenchyme intervening between the core of embryonal carcinoma and theinvesting layer of visceral yolk sac (14).

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1554 Cancer Research Vol. 24, October 1964

The fetal testes were obtained from strain 129 fetuses of15 or 18 days of gestation (timed from detection of vaginalplugs) (Fig. 3). The tissues were fixed in either Bouin's

fixative for embedding in paraffin for light microscopy orveronal-buffered 1 per cent osmium tetroxide, pH 7.2with sucrose (2), for embedding in either Vestopal W (11)or Araldite (8) for electron microscopy. Tissues forultrastructural examination were cut on a Porter-Blum orLKB microtome, with diamond knives, and were examinedon an RCA-EMU 3-F electron microscope. For purposesof cellular identification, sections l p thick were cut andstained with Azar B bromide for light microscopy, whilethe adjacent thin sections were examined ultrastructurally.

RESULTS

Ultrastructure of fetal testicular tubules lo and 18 daysafter fertilization.â€”The primordial tubules of the 15-day -old embryo were composed of solid cords of cells enclosedwithin a basement membrane (Fig. 4). Two types ofcells were identified in correlated light and electron microscopic studies. The larger, which were the primordialgerminal cells, formed the central nidus of the primordialtubule. The smaller, which lined the basement membrane and invested the germinal epithelium, were Sertolicells (Figs. 3, 4).

No major ultrastructural differences were noted betweenthe cells of the 15- and 18-day-old specimens.

The ultrastructure of the cytoplasm of primordialgerminal cells bore a striking resemblance to that of embryonal carcinoma cells. This cytoplasm, which wascomposed mainly of clusters of free ribosomes, had aground glass appearance at low magnification. Profilesof endoplasmic reticulum were sparsely distributed andappeared to be lamellar or tubular rather than cisternal(Figs. 5-7). Several clusters of fine vesicles and pairedmembranes, considered to be the developing Golgi apparatus, were occasionally observed in paranuclear position.Since the mitochondrial matrix was more dense than therest of the cytoplasm, these bodies stood out in sharp reliefin a regular pattern around the nucleus. They were ofthe usual configuration and contained a few small osmi-ophilic bodies (Figs. 4, 6). Multivesicular bodies werefrequently seen (Fig. 6). The cellular membranes of theprimordial germinal cells were undulating but not villousand were free of desmosomes. It was not uncommon toobserve direct communication of cytoplasm through largeopenings in the cellular membranes of adjacent primordialgerminal cells (Fig. 7). These communications mightcontain an organelle, but spindle fibers that could providean explanation for the connection have never been observed. Some of the connections were long and tunnel-like, imparting a bar-bell appearance to the connectedcells.

The nuclei, which were round, contained a nucleolus ofusual configuration and were invested by a double nuclearmembrane. This membrane was typical, since it contained numerous pores, and its outer layer, on rare occasions, appeared to bud off small vesicles into the cytoplasm.

The Sertoli cells were less than one-half of the size of theprimordial germinal cells and could be easily distinguishedfrom them by the degree of organization of the cytoplasm.

In contrast to the poorly developed endoplasmic reticulumof the germinal cells, the cytoplasm of the Sertoli cellscontained a fairly well developed cisternal form of roughand smooth surfaced endoplasmic reticulum. Golgi complexes, too, were well developed so that the Sertoli cells,even in fetal life, imparted the appearance of a differentiated type of cell (Figs. 4-6). These cells were always inintimate contact with the primordial germinal cells, butcytoplasmic communications, as described by others in therat (29), were not observed between germinal cells andSertoli cells. Long streamer-like bands of this well differentiated cytoplasm were insinuated between primordialgerminal cells (Figs. 3, 6, 7). The Sertoli cells of themouse fetus, like those of the adult human (5), had welldefined cellular membranes. The nuclei were usuallyoval and contained a single nucleolus.

The tubular basement membrane, which was alwayslined by Sertoli cells, was less well formed at 15 than at 18days of development. It followed the contours of theSertoli cells and blended with reticulin fibrils on its external surface (Figs. 4, 5).

Ultrastructure of embryonal carcinoma cells.â€”Embryonalcarcinoma cells had the same ultrastructural appearancewhether they were multipotential (in embryoid bodies) orwhether they had lost their multipotentiality through theprogression attendant upon prolonged transplantation.Furthermore, they bore a striking resemblance to the primordial germinal cells described above and to embryonalcarcinoma cells of the human (Pierce and Beals, unpublished, and [25]).

Embryonal carcinoma cells were characteristically arranged in clumps and were mononuclear, with a highnucleocytoplasmic ratio. As is so often the case withhighly malignant cells, the nuclei were indented and contained at least one large nucleolus. Mitotic figures werenumerous.

Free ribosomes, which were exceedingly abundant, except in the cortical areas of the cytoplasm, were arrangedin rosette-like configurations and dominated the cytoplasm. Outpouchings of the outer nuclear membraneswere observed rarely and appeared to terminate in small,ribosome-encrusted profiles of endoplasmic reticulum.The cytoplasm was extremely undifferentiated and almostdevoid of endoplasmic reticulum; that which was presentwas lamellar or tubular (Figs. 8, 9). No viral particleswere observed in embryonal carcinoma cells, although theywere invariably present in the endoplasmic reticulum ofparietal yolk sac carcinoma cells (18), which, as we haveshown previously (15, 19), differentiated directly fromembryonal carcinoma cells.

The mitochondria were not remarkable in shape, distribution, or in internal arrangement. Multivesicularbodies were not as numerous as in primordial germinalcells. Cellular membranes lacked desmosomes and wereregular in contour with little tendency to villous formation.No communications were observed between adjacent cells.

Since embryonal carcinoma cells are multipotential (10),it was not surprising that entoderm and mesenchyma,which have been shown to be early and frequent productsof somatic differentiation from embryonal carcinoma,should be observed. Small areas often contained typical



PIERCE ANDBEALS-â€”Ultrastructureof Germinal Cells 1555

undifferentiated embryonal carcinoma cells (Fig. 8),embryonal carcinoma cells beginning differentiation (Figs.9,10), and differentiated somatic elements (Fig. 1). Cellsbeginning differentiation had more endoplasmic reticulum(Fig. 10), microvilli, and desmosomes than typical embryonal carcinoma.

Interspersed with the embryonal carcinoma cells of theteratocarcinomas were aggregates of parietal yolk sac carcinoma cells, which were embedded in neoplastic hyalin.These parietal yolk sac carcinoma cells were identical tothose described previously and contained arrays of ribo-some-encrusted cisternae of endoplasmic reticulum, theorganelle shown to be the site of synthesis of neoplastichyalin (18). Moreover, the endoplasmic reticulum oftencontained particles that appeared to be viral in nature.

DISCUSSION

The theories of histogenesis of testicular tumors agreethat the normal counterpart of the embryonal carcinomacell must be a multipotential type of cell (4, 26). Thetheory most widely accepted in this country is that embryonal carcinoma arises from primitive germinal cells ofthe host (4, 7). Proponents of this theory have foundstrong support in Stevens' demonstration that teratocar

cinomas of mice arise within the primordial testiculartubules of strain 129 mice of 15 days' gestation (21). The

primordial testicular tubules of this strain and age, whenexamined ultrastructurally, were composed of Sertoli cellsand primordial germinal cells. The latter, with a cytoplasm characterized by a paucity of endoplasmic reticulumand large numbers of free ribosomes, were easily distinguished from the smaller, well differentiated Sertoli cells.Moreover, these primordial germinal cells bore a close resemblance to embryonal carcinoma cells. We agree thatit is often impossible to prove the identity of cellular types ;nevertheless, a normal constituent of the primordial tubulehas been found that meets the requirements of multipo-tentiality and morphological appearance necessary for theestablishment of the histogenesis of a multipotential tumorknown to arise within the primordial testicular tubules.

In the case of extragonadal teratocarcinomas, it wouldseem reasonable to believe that they could originate fromprimordial germinal cells misplaced in early fetal life, ashas been so often postulated. Witschi (27) has demonstrated the route of migration of primordial germinal cellsfrom the yolk sac through the mesenteries to the gonad.These cells are already determined and normally have along period of latency. It is assumed that, if they weremisplaced, they would express their inherent multipoten-tiality when appropriately stimulated.

The embryonal carcinoma cells and primordial germinalcells of the testis closely resemble the developing ova of therat as described by Odor (12) and Yamada el al. (28) andthe fertilized ova described by Sotello and Porter (24).Since teratocarcinomas, and on rare occasions embryonalcarcinomas, are found in the ovary, it is concluded thatthey arise from the germinal elements of that organ.

Cytoplasmic connections were often observed betweenadjacent primordial germinal cells of the testis in thisstudy. Similar observations have been made in sperma-tids of the cat (1), human (9), and other species (6). Like

those of later development, the connections of the primordial germinal cells were not artefactual and often contained organelles but never fibers. Although their significance is not known, it would appear that incompletecytokinesis is a developmental trait of germinal and othercells.

ACKNOWLEDGMENTS

The authors wich to acknowledge the technical assistance ofMiss F. Pruchnicki, Miss J. Goodwin, and Mr. Matthew Harden.The help and criticism of Drs. B. Naylor and A. J. French weregreatly appreciated.

REFERENCES

1. BURGOS, M. H., AND FAWCETT, D. W. Studies on the FineStructure of the Mammalian Testis. I. Differentiation of theSpermatids in the Cat (Felis domestica). J. Biophys. Biochem.Cytol., 1:287-300, 1955.

2. CAULFIELD, J. B. Effects of Varying the Vehicle for OsOj inTissue Fixation. J. Biophys. Biochem. Cytol., 3:827-30, 1957.

3. DALTON, A. J.; LAW, L. W.; MALONEY,J. B.; ANDMANAKER,R. A. An Electron Microscopic Study of a Series of MurineLymphoid Neoplasms. J. Nati. Cancer Inst., 27:747-91, 1961.

4. DIXON, F. J., JR., ANDMOORE, R. A. Testicular Tumors: AClinicopathologic Study. Cancer, 6:427-54, 1953.

5. FAWCETT,D. W.; ANDBURGOS,M. H. The Fine Structure ofSertoli Cells in the Human Testis. Anat. Ree., 124:401-2, 1959.

6. FAWCETT, D. W.; ITO, S.; AND SLAUTTERBACK,D. The Occurrence of Intercellular Bridges in Groups of Cells Exhibiting Synchronous Differentiation. J. Biophys. Biochem. Cytol.,5:453-Â«),1959.

7. FRIEDMAN, N. B., ANDMOORE, R. A. Tumors of the Testis:Report on 922 Cases. Mil. Surgeon, 99:573-93, 1946.

8. GLAUERT, A. M., AND GLAUERT, R. H. Araldite as anEmbedding Medium for Electron Microscopy. J. Biophys.Biochem. Cytol., 4:191-94,1958.

9. GUILLON, M. G. Recherches sur la structure des spermatidesdans le testicule humain. Observations de microscopic Ã©lectronique. Bull. Fed. Gynec. Obstet., Franc., 12:531-42, 1960.

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12. ODOR,D. L. Electron Microscopie Studies on Ovarian Oocytesand Unfertilized Tubai Ova in the Rat. J. Biophys. Biochem.Cytol., 7:567-74, 1960.

13. PIERCE, G. B. The Pathogenesis of Testicular Tumors. J.Urol., 88:573-84,1962.

14. PIERCE, G. B., AND DIXON, F. J. Testicular Teratomas. I.Demonstration of Teratogenesis by Metamorphosis of Multi-potential Cells. Cancer, 12:573-83, 1959.

15. . Testicular Teratomas. II. Teratocarcinoma as anAscitic Tumor. Ibid., pp. 584-89.

16. PIERCE, G. B.; DIXON, F. J., ANDVERNEY, E. L. Teratocar-cinogenic and Tissue Forming Potentials of the Cell TypesComprising Neoplastic Embryoid Bodies. Lab. Invest., 9:583-602, 1960.

17. PIERCE, G. B., ANDMIDGLEY, A. R. The Origin and Functionof Human Syncytiotrophoblastic Giant Cells. Am. J. Pathol.,43:153-73, 1963.

18. PIERCE, G. B.; MIDGLEY, A. R.; SRI RAM, J.; ANDFELDMAN,J. D. Parietal Yolk Sac Carcinoma: Clue to the Histogenesis ofReichert's Membrane of the Mouse Embryo. Am. J. Pathol.,41:549-66, 1962.

19. PIERCE, G. B., ANDVERNEY, E. L. An in Vitro and in VivoStudy of Differentiation in Teratocarcinomas. Cancer, 14:1017-29, 1961.

20. STEVENS, L. C. Embryonic Potency of Embryoid Bodies Derived from a Transplantable Testicular Teratoma of theMouse. Develop. Biol., 2:285-97, 1960.

21. . The Biology of Teratomas Including Evidence Indicating Their Origin from Primordial Germ Cells. Ann. Biol.,1:585-610, 1962.



1556 Cancer Research Vol. 24, October 1964

22 STEVENS, L. C., ANDHUMMEL, K. P. A Description of Spontaneous Congenital Testicular Teratomas in Strain 129 Mice.J. Nati. Cancer Inst., 18:719-47,1957.STEVENS, L. C., AND LITTLE, C. C. Spontaneous TesticularTeratomas in an Inbred Strain of Mice. Proc. Nati. Acad. Sci.,40:1080-87, 1954.SOTELO, J. R., AND PORTER, K. R. An Electron MicroscopeStudy of the Rat Ovum. J. Biophys. Biochem. Cytol., 5:327-42, 1959.

25. TOMOYOSHI,T. Electron Microscopic Observations of the Normal and Neoplastic Testis. Acta Urol. Japan, 8:581-96, 1962.

26. WILLIS, R. A. Pathology of Tumours, 2d ed., p. 330. London:Butterworth and Co., Ltd., 1953.

23

24

27. WITSCHI,E. Migration of Germ Cells of Human Embryos fromthe Yolk Sac to the Primitive Gonadal Folds. Carnegie Institute Pubi. No. 575, Washington. Contrib. Embryol., 32:67-80,1948.

28. YAMADA,E.; MUTA, T.; MOTOMURA,A.; ANDKOOA, H. TheFine Structure of the Oocyte in the Mouse Ovary Studied withthe Electron Microscope. Kurume Med. J., 4:148-60, 1957.

29. ZEBRUN, W., ANDMOLLENHAUER,H. H. Electron MicroscopicObservations on Mitochondria of Rat Testes Fixed in Potassium Permanganate. J. Biophys. Biochem. Cytol., 7:311-14,1960.

30. ZELICKSON,A. S. An Electron Microscopic Study of the BasalCell Epithelioma. J. Invest. Dermatol., 39:183-87,1962.

FIG. 1.â€”Clumps of embryonal carcinoma cells (arrows) are interspersed with primitive glandular structures and mature braintissue. Note the primitive neuroepithelium (top) that has differentiated directly from embryonal carcinoma. X 450.

FIG. 2.â€”These immature embryoid bodies, which were derivedfrom the teratocarcinoma, are composed of a central core of embryonal carcinoma overlain by visceral yolk sac. X 380.

FIG. 3.â€”This illustrates the appearance of the fetal testiculartubules of the mouse at 18 days of gestation. Note the largegerminal cells surrounded by small, darkly stained Sertoli cells.X 450.



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Fio. 4.â€”Thiselectron micrograph is a scan of a primordialseminiferous tubule, illustrating portions of two centrally placedgerminal cells (G) surrounded by Sertoli cells (5). The tubule isenclosed by a basement membrane (RM). Occasional lipoidalinclusions may be seen in the Sertoli cells; mitochondria of thegerminal cells are numerous, perinuclear in position, and have adark matrix. X 8,500.

FIG. 5.â€”Themargin of a tubule at higher power. The basement membrane (KM) follows the contour of the Sertoli cell andblends with fine reticular fibrils externally. The Sertoli cell (S)has well developed Golgi regions (g) and well developed rough-surf acedendoplasmic reticulum. The germinalcell (G)is typicallyuiulilÃ¯erentiated, with a small Golgi zone, scant endoplasmicreticulum, and a profusion of free ribosomes. Nucleus (A7).X 10,000.

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FIG. 6.â€”Portions of germinal cells (G) separated by wedge-like extensions of the cytoplasm of a Sertoli cell (S). The germinal cells contain little endoplasmic reticulum, an occasional multi-vesicular body (MB), mitochondria, and myriads of free ribo-somes. The nuclei (A') and nucleoli are not remarkable. The

Sertoli cells are well differentiated with many Golgi membranes(g), and endoplasmic reticulum; 15-day fetal testis. X 18,600.

Fio. 7.â€”Acytoplasmic bridge (arrow) connects two primordialgerminal cells (G). It contains no spindle elements; 15-day fetaltestis. X 18,600.

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FIG. 8.â€”The nature of the cytoplasm of undifferentiated embryonal carcinoma is illustrated. Xote the lack of desmosomesand of endoplasmic reticulum. There are a profusion of freeribosomes, many mitochondria, and occasional lipoidal inclusions.The nuclei (.V) contain several nucleoli. Teratocarcinoma. X10,500.

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FIG. 9.â€”Portionsofembryonal carcinoma cells that have begundifferentiation are illustrated. Note the increase in short profiles of rough-surfaced endoplasmic reticulum and the Golgi zones(g) in comparison to the embryonal carcinoma cells of Fig. 8.Peculiar dense granular membrane-bound inclusions may be seenin the upper and lower right corners. Teratocarcinoma. X14,500.



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FIG. 10â€”Thesecells are still embryonal carcinoma cells, although they have attained an extreme degree of differentiation.Numerous profiles of dilated rough-surfaced endoplasmic reticu-lum may be seen. Teratocarcinoma. X 22,(KX).

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1964;24:1553-1567. Cancer Res G. B. Pierce, Jr. and T. F. Beals Testes and of Embryonal Carcinoma Cells of MiceThe Ultrastructure of Primordial Germinal Cells of the Fetal

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