Paper - The histogenesis of the adrenal in the pig

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Whitehead EH. The histogenesis of the adrenal in the pig. (1903) Amer. J Anat. 2: 349 - 361.

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This historic 1903 paper by Whitehead described development of the early pig adrenal gland..



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The Histogenesis of the Adrenal in the Pig

By

R. H. Whitehead, M. D.

From the Hull Laboratory of Anatomy, University of Chicago.

With 6 Text Figures. (1903)

Introduction

This paper gives the results of a study undertaken with the hope of working out the histogenesis of the adrenal in a mammalian embryo, the pig, without any particular reference to comparative embryology.


The great diversity of views concerning the histogenesis of the adrenal held by investigators of recognized ability is a striking feature of the literature of that organ. From the epoch-making publications of Balfour down to the present time scarcely any two authors seem to be in complete accord. A brief reference to the teachings of some of the leading authorities will serve to show the extent of the confusion:

Balfour[1] as the result of his study of fish embryos, advanced the opinion that the adrenal in amniota is developed from two anlages, a mesoblastic and a nervous— the latter being furnished by the sympathetic o-anglia situated along the course of the abdominal aorta. According to this view, the cortex of the mature gland is derived from the mesoderm, while the medulla is contributed by the sympathetic ganglia. This hypothesis received considerable support from investigations by some of Balfour's pupils, notably Mitsukuri, and is, perhaps, the most generally accepted of all the views.

Gottschau[2] noted, as others (M. Braun, Mitsukuri) had done, the nearness of the first trace of the anlage, in the shape of a small cluster of crowded mesenchymal cells, to the inferior vena cava, and believed that it was derived from the mesenchyme. He held that the cortex and the medulla are derived from the same source.

Janosik[3] having observed that the mesothelium in the region of the inferior vena cava and the transverse septum contributes cells to the mesenchyme at the point where the adrenals are formed in mammals, concluded that the anlage of the cortex is derived from the peritoneum. Like Gottschau, he holds that the cortex and medulla are derived from the same source.


0. Hertwig[4] teaches that the cortex is derived from tubules of the Wolffian hody, processes from which grow dorsalward and surround portions of the sympathetic ganglia, which in their turn produce the medulla.

Minot[5] holds that in man the anlage is laid down as a whole by the mesenchyme, the cells composing it afterwards undergoing differentiation into cortex and medulla.

0. Schultze[6] while rather avoiding a general discussion of the subject, affirms emphatically that in Vespertilio murinus the anlage of the adrenal is laid down in toto as a portion of the sympathetic ganglia, to be differentiated subsequently into cortex and medulla.

The citations above have been introduced merely to illustrate the prevalent diversity of opinion. Anything like an adequate review of the literature would he foreigTi to the purpose of this paper, and a complete bibliography may be found in the publication of Aichel presently to be mentioned ; but some of the work which marks the recent revival of interest in the adrenal requires more extended reference.

Minot[7] accepts the mesenchyme as the source of the adrenal, and points out that the colls from the mesothelium collect near the inferior vena cava and the transferse septum to form the mesencliymal anlage. He believes, however, that this is not a special process, as Jano^ik thought, l)ut that " the genetic relation of the whole mesenchyma to mesothelium renders it unnecessary' to assume a special relation for a single mesenchymal organ." He applies the same criticism to observations indicating the mesothelium of the nephrotomes as the source of the adrenal anlage.


As to the medulla Minot says : "That both the cortex and the medulla of the adult organ are formed in man from the mesenchymal cells, as Gottschau showed was the case in several mammals, is, I think, beyond question." If the sympathetic unites with the mesenchynuil anlage, it disappears in the course of development. For : " By a considerable series of observations on the suprarenal capsules of human embryos, I have ascertained that there are groups of cells which gradually disappear and take no part in the production of the adult organ. The cells arc in clusters in the central portion of the organ and stain very readily, so that they stand out conspicuously in the sections. In ajijiearance they resemhle the cells assigned to a sympathetic origin in the rahbit, and I should feel no doubt that they are. the same were it not that I fail to find them in embryos of the second month, so that if they are really of sympathetic origin then the union of the two anlages must take place at a considerably later stage in man than in other mammals. These groups of cells are readily seen in the three-months' embryo, hut in the four-months' embryo they are disappearing and many of the clusters are hollow, their cavities being filled with what is apparently a coagulum ; by the seventh month the clusters have, so far as I havG hitherto observed, entirely disappeared."


J. M. Flint,[8] in the course of a very careful and exhaustive study of the blood vessels of the adrenal, devotes a chapter to the histogenesis of the organ, his observations being made, for the most part, upon pig embryos. He does not undertake to determine the ultimate source of either the cortex or the medulla, but ne states tnat tne cor- no. l. Diagram of relations of sympathetic ganglia developed from cells which wander in from outside the cortex. He was able to trace these medullary cells in the form of small collections passing more and more deeply through the cortex as the age of the embryo increased, until finally thev reached their destination around the central vein. He could follow, not only the masses of cells in their migration, but also the arteries of the medulla, one arteriole for each collection of cells developing jjari passu therewith. He ex])resses decided scepticism as to the derivation of these medullary cells from the sympathetic ganglia.


tpv i;; l-iirl rlnwn fivcf <in/l with the adrenal in pig of 35 mm. f'ajj. ad., capsule of

lex l^ laui CtOWn niSt, ana adrenal; Cap. s. (1., capsule of sympathetic ganglia:

clinu-c flTit tli.i morliillo i- S. ff.. Sympathetic ganglia; Jfa?i., mantle layer of cells ;

sno\\> in.ll inc meciUlia Ib p., prolongations from mantle into cortex.


0. Aichel[9] introduces a new phylogenetic view. From a study of selachians he conchides that the so-called suprarenal bodies, which, since Balfour's work, have generally been considered as derivatives of the s}Tnpathetic ganglia, are really derived from retrograding canals of the Wolffian body; and that the interrenal body, the supposed mesoblastic anlage of the adrenal, is laid down by the peritoneal invaginations (Trichter) of the same body. The interrenal body, alone, he says, is the homologue of the adrenal of higher animals. Along with these considerations of phylogenesis he gives a careful study of the early development of the adrenal in rabbits and moles. In the former animal he finds the first evidence of the adrenal anlage in an embryo 6.5 mm. long. It consists of an invagination of the coelomic epithelium on each side of the attachment of the mesentery corresponding to the region of the anterior third of the Wolffian body. He describes and figures such invaginations as running dorsalward to end in small groups of cells which present numerous mitotic figures. These invaginations have nothing to do with the genital ridge, he thinks, but occur too far forward to be connected with that structure. Moreover, the epithelium at the site of the invaginations shows no differentiation, nor does it present any evidence of cell division. These observations lead him to conclude that the invaginations are the remnants of Wolffian body " Trichter," which body, he says, is already undergoing retrogressive changes in this region (anterior third). Accordingly, the anlage of the adrenal cortex in the rabbit is derived from atrophying Wolffian body invaginations.


In the case of the mole, although he had an excellent series of embryos at his disposal, Aichel was unable to find any such coelomic invaginations as those described in the rabbit; the earliest evidence of the adrenal was a small mass of cells undergoing active karyokinesis in the mesenchyme. In the vicinity he could find some cross sections of tubules which he considered remnants of the Wolffian body, but they had no connection with the anlage of the adrenal. Accordingly, it would appear that in the mole the adrenal arises free in the mesench^^me. Nevertheless Aichel thinks that the ultimate source of the anlage is the same as in the rabbit, although he could not demonstrate such an origin in a well-nigh perfect series of embryos.


As to the origin of the medulla of the gland, he states, without giving an account of his observations thereon, that the medulla is derived from the same source as the cortex.


Josef Wiesel[10] employed pig embryos 1 cm., 2 cm., 2.5 cm. and 3 cm. long for the study of the cortex. He detected the anlage first in pigs of 2 cm. in the shape of a projection on the medial side of the Wolffian body. Ventral from this projection, he says, the coelomic epithelium is highly developed; it shows, however, no differentiation, being similar to the epithelium of the coelomic cavity in general. This finding, he thinks, warrants the conclusion that the cortex is derived from the coelomic epithelium. Of the medulla Wiesel makes a m.ore thorough study. He traces its origin back to the sympathetic ganglia, and describes the passage of medullary cells in collections through the cortex to the vicinity of the central vein in the way previously described by Flint.


Fig. 2. Pig 13 mm. Leitz obj. 3, oc. 4. mesenterj-; W. b., WolflSan body.

Ad., adrenal; G. r., genital ridge, lies.,


It will be convenient to consider the genesis of the cortex and medulla separately, as they are separated by a considerable interval of time.

The Histogenesis of the Cortex

Although the anlage appears at a much earlier stage, it will be convenient to begin the observations in an embryo of 13 mm. and trace it towards its beginning. In such an embryo (Fig. 2) the anlage consists of an ovoid collection of cells situated ventro-lateral from the aorta and dorsal from the angle formed by the junction of the ventral surface of the Wolffian lx)dy witli the mesenteric attachment. In the early stages it lies entirely ventral to the glomerular or mesonephric branches of the aorta, but as it increases in size these vessels transfix it. Jt is clearly differentiated from the neighboring structures, not by any distinct capsule, but by young connective tissue more or less condensed and concentrically arranged. It extends as a column of cells in an antero-posterior direction a distance which roughly corresponds with the anterior one-third of the Wolffian body, falling short, however, of the anterior extremity of that body. In the posterior direction it is limited by the posterior cardinal veins : these veins run forward, one on each side, along the medial aspect of the Wolffian body, and are connected by several cross anastomoses, the last of which about corresponds to the junction of the anterior with the middle one-third of the Wolffian body. At this point the left vein virtually bifurcates, sending one division into the Wolffian body of the same side, while the other crosses the median line to open into the right cardinal; the latter soon bifurcates in its turn, one division entering the Wolffian body of its side, the other joining the primitive inferior vena cava. F. T. Lewis,[11] in the course of an interesting account of the development of the inferior vena cava, has suggested that the teriu " subcardinal " should he applied to the portions of these veins which lie posterior to the anastomoses. Immediately anterior to the most anterior of the anastomoses the caudal extremity of the anlage is encountered. The cells composing it have a moderate amount of finely granular cytoplasm, which possesses considerable affinity for acid dyes; their nuclei are vesicular, and contain a fair amount of nuclear sap and some chromatin granules. At this stage capillaries are beginning to make their appearance in the anlage. Ventral to the anlage and running lateralward on the ventral surface of the Wolffian body is a thickening composed, in the main, of mesenchymal cells and blood vessels; it is continuous with the connective tissue framework of the Wolffian body, and is lined superficially by tall coelomic epithelial cells. In these cells mitotic figures are not infrequent, and in some of them, at least, the plane of cleavage is [)arallel with the surface. This epithelium, in many situations, is wrinkled or furrowed, and cells are invaginated here and there into the subjacent tissue either singly or in small collections; none of these invaginations, however, directly reach the anlage of the adrenal. The thickening is coextensive in the anterior direction with the adrenal ; in the posterior direction it is immediately continuous with the anlage of the genital gland — indeed, there seems to be no reason why it should be regarded as anything distinct from that anlage. Prol)ably it is all incorporated into the genital gland in the process of development. Thus, in the pig of lo mm. the genital anlage can be traced quite distinctly through at least 35 sections (10 mik. each) anterior to the caudal extremity of the adrenal anlage.

There is no evidence of atrophy in the Wolffian body, signs of which do not appear until a much later stage. This observation is in accord with the statement of MacCallum, that evidences of degeneration in the pig's Wolffian body do not occur until the embryo is about 100 mm. long.[12]

In embryos 12 and 11 mm. long the ap})earances are quite similar to those just described except as to size.

In the pig of 10 mm. the adrenal anlage is still distinctly visible, and the thickening on the ventral surface of the Wolffian body (at this stage the surface might better be called ventro-medial is well developed. Ventral to the anlage, in the angle between the Wolffian body and the mesenteric attachment there is a deep furrow lined by the coelomic epithelium, which in some situations produces an appearance suggestive of Aichel's finding in the rabbit of an invagination of the epithelium leading to the anlage. In most sections, however, the two structures are separated clearly by veinlets which emerge from the Wolffian Iwdy and run central to the adrenal.


In the pig of 8 mm. (Fig. 3) the anlage occupies the space between the aorta and the mesenteric attachment medially, the Wolffian body laterally, the me^onephric arteries dorsally, and the coelomic epithelium ventrally. It does not now extend as an unbroken column of cells as in the previous embryos, but is interrupted at about its middle third. This interruption seems to be mechanical, being due to a large glomerulus of the Wolffian body, which reaches so far medialward as to leave no space for the adrenal at this point. The propinquity of the anlage to the coelomic epithelium has increased to such an extent that it is extremely difficult to define any boundary between the two structures (Fig. 4) ; and the difficulty is not lessened by attempts to draw distinctions between the cells composing them. Mitoses are frequent both in the anlage and in the epithelium. The furrow previously mentioned is still present, but the anlage lies against the lateral wall of the furrow rather than at its bottom. As a result of these findings, it was somewhat confidently expected that younger embryos would reveal an invagination of the coelomic epithelium such as Aichel found in the rabl^it; but such was not the case. In embryos of 7 and G mm. no evidence of the anlage could be found, except, possibly, a suggestion of thickening at the usual situation. In the hope of finding something more definite, six embryos varying from 8 to 6 mm. were sectioned, but none of them furnished any additional light.


Fig. 3. Pig 8 mm. Leitz obj. 3, oc. 4. ^d., adrenal ; Mes., mesentery ; W. b.. Wolffian body ; W. d., AVolffian duct.


It is clear that one would not be justified in drawing positive conclusions from these findings ; but such testimony as they bear would seem to be on the side of those who hold that there is a genetic relation between the coelomic epithelium and the adrenal cortex. One may suppose that the anlage is laid down by invaginations occurring suddenly and hence missed in the embryos sectioned, or by epithelial cells wandering into the mesenchyme. In the latter case, however, we should still have to decide whether the cell-wandering is sufficiently direct and great to constitute a distinctly special process in this region.

The Histogenesis of the Medulla

My observations are entirely in accord with the conclusion of Flint,[13] that the medulla of the adrenal is developed from certain small cells found in the pig of 35 mm. at the periphery of the cortex just within the capsule. He seems to have shown beyond a doubt that these cells are the ancestors in direct line of the mature medullary cells. The problem left, therefore, is to trace these cells to their source. The results of the present study point to the sympathetic ganglia as that source.


Tracing the relationship between the adrenal and the sympathetic ganglia in the course of their development, we find that in the pig of 13 mm. the ganglia are quite small. They lie dorso-lateral from the aorta nearly opposite to the dorsal border of the Wolffian body, and are connected with the spinal nerves by the splanchnopleural branches. Smaller collections of ganglion cells with many mitotic figures can be seen running ventralward on each side of the aorta. The latter grow rapidly, so that in the pig of 16 to 18 mm. there are chains of ganglia of considerable size lying between the adrenal and the aorta. Other ganglia lie immediately dorsal to the adrenal. From these ganglia nerve fibres arise, and, accompanied by cells, run lateralward along the dorsal and ventral aspects of the adrenal. Particularly large nerves pass along the medial aspect of the adrenal, some of which lie squarely against it, and in some cases even transfix it near its periphery. These nerves are not numerous, and there seems to be no reason to regard them as anything but the nerves to adjacent anlages which come into close relationship with the adrenal en route to their destination.



Fig. 4. Pig 8 mm. Leitz obj. 7, oc. 4. Ad., adrenal; Mes., mesentery; C. coelomic epithelium; G., glomerulus; W. t., tubules of Wolffian body.


In the following successive stages the increase in size both of the adrenal and the ganglia is very rapid; so that in the pig of 25 mm. the space between the adrenal and the aorta is occupied to a great extent by the sympathetic ganglia, and the latter are separated from the adrenal only by its capsule.


In pigs of from ;>(» to o.") unn. a new ek'nient is added to the anlage. Immediately beneath the capsule there are seen collections of small cells, the nuclei of which stain deeply and are surrounded by very scanty cytoplasm. In thick sections (Fig. 5) these are seen to be arranged around the cortical portion in a mantle-like layer, from which offshoots are proceeding inward between the rows of cortical cells. Towards the lateral aspect of the adrenal this mantle becomes very thin, or is even entirely lacking; but along its dorso-medial surface it is thick, and its prolongations into the cortex are numerous and extensive. In this latter region the capsule of the adrenal adjacent to the ganglia is much broken up, or even wanting over consideralile areas ; so that in these situations there is nothing between the ganglia and the cortical portion of the adrenal except the mantle of cells previously mentioned. Through the gaps in the capsule cellular strands, often of considerable size, connect the mantle on the inside with the ganglia on the outside. The connection is sometimes so intimate that what is seen in one section as a distinct ganglion may appear in another as an integral part of the mantle. The anatomical similarity of the cells composing the mantle, the connecting strands, and the ganglia is so great that it is exceedingly difficult to draw any distinctions between them (Fig. 6). One easily gets the impression that strands of cells from the ganglia enter the adrenal along its dorso-medial aspect, and, growing along the lines of least resistance, si)read out beneath the capsule and send in prolongations between the cortical rows. The continuity between the mantle and the sympathetic ganglia, and the identity in appearance of the cells composing them seem to offer anatomical evidence quite positive in character.



FiG. 5. Pig 35 mm. Leitz obj. o, oc. 4. S. g., anlages of sympathetic ganglia; Man., mantle layer of cells; X, columns of cells connecting sympathetic anlages with mantle; ^or., cortical portion of adrenal ; C"'., isolated portion of cortex ; Cap., capsule of adrenal. Section 25 mm. mikrons thick.


Fig. 6. Pig 35 mm. Section 5 milvrons thicli. Leitz obj. 7, oc. 4. S. g., portions of sympathetic ganglia; Mem., mantle layer of cells; Cc, portions of cortical columns; Med., collections of medullary cells.


Two objections to this view present themselves : May not the mantle cells be derived from the periphery of the cortex? My preparations afford no foundation for this hypothesis. There is no evidence that karyokinesis is more abundant at the periphery than elsewhere in the cortex, and there is entire absence of transition forms between the cortical cells and those of the mantle. Again, granting that the mantle cells are derived from the sympathetic ganglia, may they not subsequently perish in great part, as has been shown to be the case with many neuroblasts in the substantia gelatinosa of the spinal cord, and as Minot thinks probably occurs in the human adrenal? I think the work of Flint, many of whose preparations he has kindly allowed me to examine, furnishes the answer to this question. It seems to me that he has fully demonstrated that the cells which compose what has been termed in this paper the mantle are the direct progenitors of the medulla.


Conclusion

  1. In the pig's adrenal the anlage of the cortex is laid down much earlier than that of the medulla, being first seen at the stage of 8 mm. It is probably derived from the coelomic epithelium.
  2. The anlage of the medulla appears first in pigs of 30 to 35 mm., at which time it lies spread out like a mantle along the periphery of the cortex. The findings indicate that it is derived from the anlages of the sympathetic ganglia.


Since the above was written there has appeared an article by Alfred Kohn,[14] alluding to the existence in various parts of the body of small nodular collections of cells characterized especially by the fact that they assume a brown color when fixed in chromic solutions. Kohn traces the origin of these bodies to the anlages of the sympathetic ganglia, and proposes therefore to call them paraganglia. He believes that their extracts possess the property of greatly elevating the blood pressure. If these interesting views are correct, they furnish further testimony in favor of the derivation of the adrenal medulla from the sympathetic; for Henle's reaction is a property of the medulla, and it is well known that extracts of the adrenal elevate the blood pressure.


I desire to express my indebtedness to Miss M. E. Poindexter for the accompanying illustrations.

References

  1. The Development of Elasmobranch Fishes, London, 1878.
  2. Arch. f. mikr. Anat. u. Entwick., Leipz., 1883, S. 412-4.58.
  3. Arch. f. mikr. Anat., Bonn, Bd. XXII, 1883, S. 738-745.
  4. Lehrbuch der Eutwicklungsgeschichte des Menschen und der Wirbelthiere, Jena, 1897.
  5. Human Embryology, New York, 1897.
  6. Grundriss der Entwicklungsgescliichte des Menschen und der Saugethiere, Leipz., 1897.
  7. Minot Op. cit., pp. 485-489.
  8. Contributions to the Science of Medicine, by the Pupils of W. H. Welch, Baltimore, 1900, pp. 153-231.
  9. Arch. f. mikr. Anat., Bonn, Bd. LVI, 1900, S. 1-80.
  10. Ueber die Entwickelung der Nebenniere des Schwaines besonders der Marksubstanz. Anat. Hefte, Wiesb., 1901, Bd. XVI, S. 115-150.
  11. Am. Jour. Anat., Bait., Vol. I, pp. 229-24.
  12. J. B. MacCallum: Notes on the Wolffian body of Higher Mammals. Am. J. Anat., Bait., Vol. I, pp. 245-260.
  13. Flint "Op. Cit.
  14. Chromophile Cells and Chromophile Organs, reviewed in Journal of the American Medical Association, Chicago, 1903, Vol. XXXIX, p. 706.

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