Paper - The genetic principles of the development of the systemic lymphatic vessels in the mammalian embryo (1910)

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Huntington GS. The genetic principles of the development of the systemic lymphatic vessels in the mammalian embryo . (1910) Anat. Rec. 4: 399-424.

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This historic 1910 paper by Huntington described development of the systemic lymphatic vessels in the mammalian embryo.

Also by this author: Huntington GS. The genetic interpretation of the development of the mammalian lymphatic system. (1908) Anat. Rec. 2: 19-45.

Huntington GS. The phylogenetic relations of the lymphatic and bloodvascular systems in vertebrates. (1910) Anat. Rec. 4(1): 1-14.

Huntington GS. The genetic principles of the development of the systemic lymphatic vessels in the mammalian embryo . (1910) Anat. Rec. 4: 399-424.

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The Genetic Principles Of The Development Of The Systemic Lymphatic Vessels In The Mammalian Embryo

Preliminary Communication

Geo. S. Huntington

From the Anatomical Laboratory of Columbia University

Thibty-Four Figures (Cost of illustrations met by the author)


In 1906, at the 22nd session of the Association of American Anatomists, McClure and I presented a joint communication on the development of the main lymphatic channels in embryos of the domestic cat, in their relation to the venous system.=^ In this preliminary paper we held that the lymphatic vessels of the entire mammalian body are formed by the confluence of perivenous mesodermal spaces, developed, as separate ajilages, outside the intima of the ear^y venous channels, but not communicating with the same, except eventually at certain definite points of lymphalico- venous junction which are secondarily formed. This view pronounces for the ontogenesis of lymphatic endothelial cells, lining the separate mesodermal spaces, independently of the preexisting haemal vascular endothelium. The mesodermal intercellular spaces, thus forming the fundaments of the future lymphatic vessels, are in no sense derivatives from the embryonic veins, although closely associated with them topographically, and eventually replacing the same.

At the time of the publication of the paper quoted, embodying an outline of these views of mammalian lymphatic ontogenesis,

G. S. Huntington and C. F. W. McClure. The development of the main lymph channels of the cat in their relation to the venous system. Am, Jour. Anal., vol. 6, 1907, Abstr. Axat. Rec, vol. 1, pp. 36-41.

McCIure and I were not aware of the fact that the mammalian jugular lymph sacs afford, in the typical mammalian organization, in so far as the same is definitely determined at present, the sole or chief portals of entry of the entire systemic lymphatic circulation into the veins.

We consequently failed to recognize correctly the true morphological type of the adult mammalian lymphatico-venous connections in our earlier preliminary paper, and hence regarded them, at that time, as the direct secondary junctions of the independently developed systemic lymphatic vessels with the veins.

The real significance of the adult lymphatico-venous connections was only subsequently recognized by us in the course of a detailed joint investigation of the area involved. A preliminary account of our studies on the development of the jugular lymph sacs in the embryo of the cat, was presented at the 23rd session of the Association of American Anatomists held at Chicago in December, 1907, and published in the Proceedings of that meeting.^ The details of this investigation, with full critical analysis of all the main developmental stages, in an extensive series of cat embryos, and illustrations of the reconstructions of all important and representative periods, are published in the April niunber of the American Journal of Anatomy of this year.*

After the completion of our joint work on the development of the mammalian jugular lymph sac, I published, in 1907,'^ a genetic interpretation of the development of the mammalian lymphatic system, as a whole, in which I regarded the same as the final product of the union of two genetically different and very unequal components:

1. The entire extensive system of the lymphatic vessels of the adult, including the thoracic and right lymphatic ducts and their tributaries, is formed by the confluence of numerous perivenous and extra intimal intercellular mesodermal spaces, in the sense previously defined. These primary anlages of the future systemic lymphatic vessels are, from their inception, lined by a lymphatic vascular endothelium, whidh is not derived from IJhe haemal vascular endothelium, but which develops independently of the same.

» Geo. S. Huntington and C. F. W. McClure. The anatomy and development of the jugular lymph sacs in the domestic cat. Anat. Rec., vol. 2, pp. 1-18, May, 1908.

American Journal of Anatomy, vol. 10, pp. 177-311, April, 1910. G. S. Huntington. The genetic interpretation of the development of the mammalian lymphatic system. Anat. Rec, vol. 2, pp. 19-45, May, 1908.

The lymphatic channels, formed by the subsequent confluence of these originally discrete and separate mesodermal spaces, follow in large part the embryonic veins closely, but they are neither derived from them, nor do they communicate with them, except at the definite points at which the rudimentary mammalian type of a lymphatico-venous heart is developed.

2. This structure develops, as the jugular lymph sac of the typical mammal, directly from the perivenous capillary reticulum of the early pre- and post-cardinal veins, adjacent to, and including, their point of confluence to form the duct of Cuvier.

This mammalian jugular lymph sac, the rudimentary homologue of one of the more highly organized veno-lymphatic hearts of the lower vertebrates, arises directly from the veins. Subsequently, after evacuation of its blood contents, it apparently separates for a short period completely from the same, and finally establishes two sets of permanent connections:

(a) With the independently formed systemic lymphatic channels of the entire body in the majority of the mammalian types carefully determined up to the present date.

(6) Secondary connections with the venous system, re-entering the same at one or more typical and constant points, and thus forming the link which eventually unites the mammalian lymphatic and v^ous systems, developed primarily independently of each other.

Thus the investigation of mammalian lymphatic development divides itself naturally, in accordance with the postulates of the genetic theory above defined, into three separate and distinct main parts:

1. The development and adult anatomy of the jugular lymph sacs.

2. The development and adult anatomy of the general systemic lymphatic vessels.

3. The mode of union with each other of the two components ju^ enumerated, and the resulting establishment of a continuous centripetal lymphatic vascular system, with definite and constant terminals in the venous trunks.

The first of these problems, involving the ontogenetic history of the mammalian jugular lymph sacs, having been established in detail by the joint investigations of McClure and myself above quoted, I intend to follow in similar detail the second and third postulates of the theory of mammalian lymphatic development just outlined, and to prove that, in the composite organization of the final adult lymphatic system, the jugular lymph-sacs, of direct venous origin, constitute the links eventually uniting the haemal vascular system of the mammal with the systemic lymphatic vessels, which latter develop independently of the veins, by the confluence of numerous intercellular perivenous mesenchymal spaces. The embryonic veins, along and around which the earliest anlages of the systemic lymphatic channels develop, appear as evanescent and temporary components of the embryonic haemal vascular system. They are not carried into the definite and typical adult venous organization, but they afford, in reference to the correlated lymphatic system, by their separation from the permanent venous channels, and their consequent collapse and atrophy, a series of lines of less resistance in the embryonic body, which paths of easiest progress are utilized by the growing lymphatic vessels. In this way the histological picture of a gradual replacement of an early embryonic vein by a succeeding secondary perivenous or extra-intimal" lymphatic vascular channel is obtained, through the confluence of numerous mesenchymal spaces, surrounding, and eventually replacing, the decadent embryonic veins, but in no sense genetically derived from the latter.

In other words, and in order again to reiterate emphatically the conception of mammalian systemic lymphatic development which I have consistently upheld since my first expression of opinion on the subject, I desire to repeat my conviction that all systemic lymphatic vessels of the mammalian embryo, including the thoracic and right lymphatic ducts and their tributaries, are neither in their genesis continuous centrifugal buds" or sprouts" from sacs of venous origin, wherever situated, nor "multiple outgrowths" or "veno-lymphatic anlages," derived from embryonic veins, such "outgrowths" separating subsequently from the veins, and then fusing into continuous and connected lymphatic channels. The systemic lymphatic vessels of the mammalian embryo, as distinguished from the jugular, or reno-caval lymph-sacs, or from any other adult lytnphatico-venous junctions of equivalent value, are, on the contrary, in my estimation, from their first ontogenetic inception, structurally and genetically independent of the haemal vascvlar system. Their endothelial lining is not derived from the pre-existing embryonic blood vascular endothelium. The multiple independent perivenous spaces forming the anlages of the future systemic Ijrmphatic channels join to form progressively increasing links of longer channel segments, destined in the normal course of development, to become united into a continuous lymphatic vascular system. This lymphatic system finally attains, in the average and tjrpical mammalian forms, one or more permanent connections with the definite venous system through the portals furnished by the rudimentary lymphatico- venous hearts or lymph sacs. The most prevalent mammaUan type of this secondarily acquired lymphatico-venous connection is furnished by the jugular lymph sacs, as outlined in the publications already quoted. While this form of lymphatico-venous junction in the adult is by far the most prevalent tjrpe encountered in the mammalian series,* there is no reason why, in certain mammalian groups, other points of veno-lymphatic communication, inherited, in these specialized types phylogenetically by selection from the available line of multiple pre-mammalian lymphatico-venous hearts, should not be carried into the adult organization as permanent portals of entry of the lymphatic into the venous system.^ The post-caval and reno-caval lymphatico-venous connections recently demonstrated by C. F. Silvester* of Princeton University as uniformly found in the entire group of South American primates, and the intermediate correlated conditions found by myself in Macropus rufus, are readily and correctly interpreted on this basis.

• C. F. W. McClure and C. F. Silvester. A comparative study of the lymphaticovenous communications in adult mammals. Anat. Rec, vol. 3, pp. 634-551, 1909.

^ G. S. Huntington. The phylogenetic relations of the lymphatic and bloodvascular systems in vertebrates. Anat. Rec, vol. 4, no. 1, January, 1910.

The present communication is intended as an outline of the development of the mammalian systemic lymphatic vessels, in order to demonstrate what I believe to be the uniform, constant and consistent ontogenetic principle underljring their formation.

I have been impressed by the fact that the histological pictxires furnished by ungulate, rodent and marsupial embryos are, in reference to the development of the systemic lymphatic channels, relatively obscure and indefinite, when compared with the clearcut and well-defined conditions encoimtered uniformly in the aeliu'oid carnivore. In describing, therefore, in this preliminary account the genetic principle which I believe governs the development of all mammalian systemic lymphatic channels, as distinguished from the lymph hearts of venous origin, I have confined my illustrations to the embiybs of the cat, and have selected certain portions of the thoracic ducts of this animal in the critical stages, as concrete examples of the developmental processes occurring in all other regions of the embryo, as will be fully demonstrated in the complete publications to follow. With the ontogenesis of the systemic lymphatic channels definitely established in this form, it is not diflScuIt to determine, by comparison, the presence of corresponding typical developmental conditions in embryos of the pig, rat and oppossum. But in none of these latter forms are the typical genetic stages as clearly marked, and the tissues as definitely differentiated as in the cat.

The right and left thoracic ducts develop in cat embryos of between 11 mm. and 16 mm. crown-rump measure. Prior to the II mm. stage no anlages of any portions of the future ducts are observable. In the average 16 mm. embryo the separate anlages have usually united into continuous lymphatic channels, which are connected through the jugular lymph sacs with the sy^temic veins.

• Twenty-fifth Session of the Association of American Anatomists, Boston, December 28, 29 and 30, 1909.

I believe that the adult thoracic ducts of the cat are developed by fusion of three distinct and separate regional segments. Each of these segments is in turn formed by confluence of a nimiber of originally discrete anlages, which develop independently of the venous system as extra-intimal or perivenous mesenchymal spaces in the sense previously defined (2, 5). These spaces are applied to, or surroimd, the walls of the embi^onic veins of the lower cervical and mediastinal region. The three main divisions, thus formed independently of the venous system, unite with each other to form the channels of the left and right thoracic ducts, and these channels gain their point of entrance into the systemic veins by uniting with a process of the jugular lymph sacs (thoracic dv^t approach) derived from their dorsal aspect, just cephalad to the common jugular approach.

The ontogenetic history of the ducts may therefore be considered under four headings, viz.:

1. The '^Thoracic duct approach^' of the jugular lymph sac, forming the terminal of the adult duct on each side.

2. The pre-azygos segment.

This includes two distinct and separate channels:

(a) The ventral mediastinal or broncho-mediastinal lymphatic trunk J which drains the ventral mediastinum, viz.,* the pericardial, tracheal, bronchial, lateral oesophageal and thymic areas.

This lymphatic channel, associated with the pulmonary arteries, develops through confluence of a large number of separate and independent extra-intimal lymphatic spaces following and surroimding the embryonic venous plexuses of the ventral mediastinum. The chain formed by these spaces eventually unites, directly or indirectly, with the similar chain forming the anlage of the pre-azygoS segment of the thoracic duct.

(b) The pre-azygos segment of the thoracic duct includes the portion of the main channel from the point of its entrance into the jugular lymph sac, through the thoracic duct approach of the latter, caudad to its intersection with the dorsal surface of the aortic arch.

In the adult aoimai this segment f onns the relatively long portion which ascends cephalo-sinistrad from the point where the duct par « company with the right azygos vein, under cover of the aortic arch, and the vertical portion of the left subclavian artery, dorsal to the vertebral vein and to the left innominate conjfluence, to its junction with the jugular Ijrmph sac. In this part of its course the thoracic duct receives the Ijonphatic return from the ventral mediastiniun through channels which join it to the ventral mediastinal trunk as just defined. The pre-azygos segment of the main duct is again formed in the embryo by confluence of independent mesenchymal spaces around and along the prevertebral and dorsal mediastinal venous plexuses of the embryo.

3. The azygos segment comprises the portions of the thoracic ducts caudal to the level of the aortic arch. It develops, again independently, as the result of fusion of a niunber of extra-intimal* mesenchymal spaces closely applied to the ventral surface of the azygos veins, and of their ventro-medial tributaries, or surrounding the latter.

4. The post-azygos segment, through which the thoracic ducts establish their connection with the Receptaculiun and the system of the abdominal lymphatics.

The piupose of the present paper is to employ the facts ascertained in regard to the development of the two thoracic ducts as a concrete illustration of the genetic principles underlying the formation of all systemic lymphatic organization.

For this piupose the right and left ducts will be regarded as bilateral equivalents, as they actually are in certain stages. As a matter of fact the right channel in the main azygos region is the first portion to differentiate clearly and offers the best illustration of lymphatic histogenesis in the earlier and critical stages.

Inasmuch as the development of the post-azygos segment of both ducts is intimately connected with that of *the principal abdominal lymphatic channels, and hence requires for its elucidation a detailed consideration of these structures, I will confine my illustrations in the present paper to the development of the two main anterior segments, viz., the pre-azygos and the azygos portions of the entire duct, with the distinct understanding that identical ontogenetic processes are responsible for thedevelopment not only of the post-azygos segments of the ducts and the mesenteric lymph sacs, but for all other syBtemic lymphatic channels of the entire body.

I. PRE-AZYGOS SEGMENT OF THE THORACIC DUCT A. Ventral or hroncho-medidstinal trunk

The area in which this lymphatic channel develops, is shown topographically in fig. 1, a transverse section of the upper thoracic region in a 12 mm. embryo (series 78, shde 5, section 9.) The lymphatic anlages arise in the mesenchyme between the pulmonary arteries (10) ventrally, the coelom laterally, the precardinal veins (3, 6), vagi (22), trachea (9) and aorta (7) dorsally. This area is indicated by the x in fig. 1.

In the earlier stages (embryos between 11mm. and 14 mm.) an extensive ventro-medial capillary network obtains along and between the main venous lines of the right and left sides, involving the caudal part of the internal jugular, the common jugular and innominate veins.

Now, if the ventral portion of this venous plexus i^ followed caudad into the upper thoracic region, the following observations can be made in stages of the proper length, and adecjuately fixed and stained:

(1) In embryos between 1 1 and 12 mm. only venous capillaries are found, in the majority of cases.

(2) In 13 mm. embryos certain of the venous radicles entering into this plexus are partly surrounded and enveloped by independently developed extra-intimal lymphatic spaces, the first anlages of the future ventral mediastinal lymphatic channel.

Fig. 2 shows a section of this region in a 13 mm. embryo (series 107, slide 9, section 40).

Between left pulmonary artery (10) and aorta (7) are branches of the ventral mediastinal plexus. One of these (4) is partially surrounded by a lymphatic anlage (5), but the process of replacement is in its earliest phases.

(3) In the 13.5 mm. embryo the full and convincing proof of the extra-intimal derivation of this channel is given.

Fig. 3 shows a transverse section of the upper thoracic region of a 13.5 mm. embryo (series 189, slide 8, section 36) . Just ventromesad of the left vagus nerve and its encircling vein is a venous radicle (4) almost completely surrounded by an extra-intimal lymphatic space (5) in the process of replacing the atrophying vein with which it is so closely associated. The corresponding structures are seen on the right side (4, 5).

Fig. 3A shows the extra-intimal lymphatic space and the contained vein on the left side of this section in a higher magnification (X 300). It will be seen that the lymphatic space nearly envelops the venule. The latter, if followed cephalad and caudad, is found separated from the functional venous channels. It appears collapsed and shrunken, and contains only a few degenerating erythrocytes. We are deahng here with a further advance in the conditions found in the immediately preceding 13 mm. stage. (Fig. 2, series 107, slide 9, section 40). The venous core of the earlier lymphatic anlage is in process of further recession and degeneration, as the perivenous lymphatic space enlarges and more and more completely replaces the antecedent venous channel upon and around which it develops. On the right side of fig. 3 (series 189, slide 8, section 36), the section has cut the corresponding vein and the enveloping extra-intimal space at right angles, so that the central kernel of the shrinking vein (4), still containing a few red blood cells, is nearly surrounded by the replacing extra-intimal lymphatic (5) . The vein, or rather its remnant, bears a relation to the perivenous replacing lymphatic which is exactly the same as that of a collapsed inner tube to the enveloping shoe of a pneumatic tire. The inner skin of the shoe and the rim of the wheel represent the lymphatic intimal endothelium. The space between them and the collapsed inner tube is the lumen of the future ventral mediastinal lymphatic channel. The inner tube itself is the embryonic vein upon which the secondary lymphatic channel is built. In the course of further development it disintegrates and disappears, leaving a clear lumen to the lymphatic channel which thus secondarily replaces it. "

Usually the replacing lymphatic begins as an extra-intimal channel partially surrounding the embryonic vein which it is destined to replace. This leads in the course of further development to an expansion of the lymphatic space not concentric with the axial line of the shrinking vein. The remnant of the vein retires to a point on the intimal circiunference of the new lymphatic channel and appears to project into the latter.

The resulting histological pictures are hence in many cases quite analogous to the appearance of a mesonephric glomerulus in its relation to the lumen of a WolflSan tubule. Of course, as in the case of this illustration, a section, for example, in the axis of the line A-B will divide the shrinking vein and the enveloping Ijmiphatic in such a way as to produce the following picture:

This, however, is exceptional.

This is not a haphazard process, observed only occasionally, in a limited number of embryos, and then only in single sections, or, at most, in a few successive sections. In any average embryo of the proper length the same structures appear in the same situation and in identical relationship to the embryonic environment. It is often possible to follow the forming lymphatic with its atrophied vein kernel for long distances, and in different embryos of the same crown rump measure the constant repetition of identical histological pictures is remarkable.

There are, of course, individual cases of variation, in which systemic lymphatic development is either more advanced or more retarded than is normal for the average run of embryos in a given stage. But if a very large number of embryos of each typical period are exammed and compared the average stage of extraintimal lymphatic development attained by the majority of individuals in each period is remarkably constant and uniform. I shall have occasion, in the complete publication, to refer again in detail to the question of chronological embryonic variation.

The existence of the perivenous lymphatic spaces in this and other regions of the embryo has been so often denied by recent contributors to the subject, or, if admitted, explained in every possible way except on the basis of the correct interpretation, that I publish in this paper a series of micro-photographs of five successive sections through the pretracheal mediastinal regionof a 13.5 cat embryo (series 189, slide 8, sections 36 to 40) (figs. 3 to 7).

Fig. 3, above described, shows the general topographical area involved. Figs. 4 to 7 are cut down to economize space.

In all five figures the atrophying vein kernel (4) and the replacing lymphatic anlage surrounding the same (5) have been cut obliquely on the left side of the embryo, and hence give longer stretches of the structiu^s (4 and 5) involved. On the right side the plane of section is more at right angles to both the venous core and the enveloping lymphatic space in the first four figures. In fig. 7 the lymphatic space of the right side terminates in characteristic fashion blindly and the atrophied vein merges imperceptibly into the surrounding mesenchyme. The remnants of j>artially degenerated eiythrocytes in the Imnen of the atrophied venous core are especially clearly seen in all the sections on the left side.

Of course the photographs, and especially the reduced reproductions, offer far less striking histological pictures than the stained and differentiated slide, although they sufficiently well demonstrate the actual conditions.

In the illustrations only a few of the more marked areas of lymphatic replacement of decadent venules are indicated by the leaders 5 and 4 respectively. Numerous other smaller areas of identical significance are seen on close examination in adjacent parts of the field.

In the succeeding 14 mm. stage the ontogenetic process just outlined is, in the average embryo of this measure, fully developed.

Fig. 8 shows a section of a 14 mm. embryo in this region (series 214, slide 13, section 13). Comparison with fig. 3 will show the existence of the identical relations between the same decadent vein and the replacing extra-intimal lymphatic on both right and left sides. The embryos are cut approximately in the same plane and hence the resulting pictures are almost identical.

Figs. 9, 10, 11, and 12 show corresponding sections of the same embryo further caudad.

In fig. 9 three areas are indicated by leaders in which the atrophied vein (4) is in relation with the enveloping and replacing extra-intimal lymphatic anlage (5) . In the succeeding section (fig. 10) the two dorsal areas have practically become confluent, and the tortuous and collapsed endothelial bag representing the remnant of the decadent venule (4) can be followed for some distance. The ventral area in fig. 9 offers only an indistinct central venous core (4), surrounded by the lymphatic anlage (5). In the succeeding section (fig. 10), however, the unmistakable relationship and significance of the two spaces is clearly revealed.

The two successive sections of the same slide of this embryo, shown in figs. 11 and 12, give remarkably distinct histological pictures of lymphatic ontogenesis, and also show the gradual increase in the area of the lymphatic perivenous compartment as compared with the contained venous remnant. In both sections a few red blood cells are still to be noticed within the lumen of the latter.

Finally, in another 14 mm. embryo (figs. 13 and 14, series 212, slide 10, sections 5 and 6) conditions identical with the preceding are well shown on both sides of two successive sections. The same decadent venules (4) and the associated enveloping perivenous lymphatic anlages (5) are fotmd in the typical situation between trachea, aorta and vagi dorsad and the pulmonary arteries ventrad.

Fig. 14 likewise oflfers the explanation of the fact that the average 14 or 14.5 nun. embryo affords the clearest and most distinct pictures of systemic lymphatic ontogenesis. In these stages the decadent vein (4), detached from the functional venous channels, is still relatively large, while the perivenous lymphatic space (5) has also markedly increased in size as compared with the 13 mm. stage. The two structures, taken together, form therefore striking histological objects in the field. Subsequently, with the further degeneration and final complete elimination of the venous kernel, and the condensation of the perivenous lymphatic space into a definite lymphatic channel, the lumen of the latter appears relatively smaller. Thus in two successive sections of a 15 mm. embryo (series 216, slide 10, sections 32 and 33, figs. 15 and 16) the identical lymphatic anlage (5 in figs. 15 and 16) can readily be traced, but appears now as a wide channel with clear lumen. The central venous core, so prominent in the earlier stages (13, 13.5 and 14 mm.) has either disappeared entirely, or is merely indicated by insignificant remnants (4). The same conditions, with further condensation of the mesenchyme, and consequent further reduction of the lymphatic lumen, are encountered in the 15.5 and 16 mm. stages (fig. 17, series 215, slide 14, section 13, 15.5 mm. and fig. 18, series 230, slide 12, section 25, 16 mm.)

No impartial observer can mistake the significance of the conditions here shown. Every stage of the process can be followed in detail. The behavior of the decadent embryonic vein, and its relation to the enveloping extra-intimal lymphatic channel, are absolutely demonstrated. The endothelium of the shrinking vein has no share in furnishing the independent lymphatic endothelium of the replacing mesenchymal space, and nowhere, in the entire process, is there the faintest suggestion of an outbud or of a splitting oflf from the circimiference of an otherwise valid embryonic vein of "lymphatic" or "veno-lymphatic" anlages.

The conditions here described are definite ontogenetic /acte remarkably constant in every embryo of the proper age. They cannot be disregarded in promulgating theories of mammalian lymphatic development. The only conclusion which seems to me to be warranted by actual observation is that certain embryonic veins form, during the process of their atrophy and final elimination from the definite venous organization, the supporting lines along which certain of the perivenous extra-intimal lymphatic anlages first develop. The initial development of lymphatic spaces, is, however, by no means confined to the immediate environment of a degenerating embryonic vein. The same field which demonstrates the histogenetic processes above described in the development of the extra-intimal Ijonphatic spaces surrounding a decadent vein will, at the same time, show niunerous equivalent lymphatic spaces developing independently of antecedent veins as enlarging intercellular mesenchymal clefts.

These early lymphatic anlages, formed independently of antecedent embryonic venous capillaries, are smaller and offer less striking pictures, than those which develop in association with an atrophying vein, and which hence reach a greater size at a relatively early period. They are more difficult to differentiate, but their existence can on close examination be absolutely determined, and their connection with the larger perivenous lymphatic spaces can be established.

The fact that numerous early embryonic venous channels, large and small, atrophy and disappear during the normal course of subsequent development, appears to afford a more favorable field for the greater development of the adjacent mesenchymal intercellular spaces, so that these enlarge more rapidly, as the correlated vein recedes. This relationship appears, however, to be based exclusively on the physical and mechanical advantages which the abandoned and shrinking primary venous line affords to the adjacent mesenchymal spaces for more rapid enlargement in the sense of replacing the disappearing vein and occupying secondarily the space formerly filled by the haemal channel. This is evidently an important factor in determining the size and extent of the final lymphatic channel reciting from the confluence of the originally separate and independent perivenous anlages. Consequently, in the adult, the largest and best defined systemic lymphatic vessels either accompany reduced adult remnants of a relatively larger embrj'onic venous channel, or, in case of the latter's entire default, topographically replace the same. Now, while this relation manifests itself strikingly in many parts of the body, it is quite evident that the development of lymphatic channels occurs in other parts independently of preceding veins, by the confluence of independent intercellular mesenchymal spaces.

In judging regarding the genetic principles underlying mammalian systemic lymphatic development it is absolutely necessary clearly and correctly to value the relations above detailed between degenerating early embryonic venous channels and the systemic lymphatic anlages developed in association with them and destined to eventually replace them more or less completely topographically. I can readily see why certain recent contributions to the subject assume that the well defined lymphatic channels of a later stage are the direct derivatives of the equally well defined venous plexuses of earlier embryos, since they cover each other mutually absolutely in the topographical sense. Such an assumption is, however, in my opinion, faulty, because it is based on insuflBcient or inaccurate observation, and fails in correctly interpreting the genetic factors responsible for the topographical replacement of an earlier vein by a later lymphatic channel.

Again, a careful consideration of the facts above detailed, must inevitably lead to the conviction that the real developmental processes active in systemic lymphatic ontogenesis can never be determined by injection of embryos however successful. A glance at the preceding illustrations will show that a successful injection of the embryonic venous system might very well, before complete detachment has occurred, fill from the permanent haemal channels the still large and patent portions of the venous plexus already for the most part surrounded by the extra-intimal lymphatic anlages. Such a preparation would lead the observer to conclude that the line of the future lymphatic channels was still altogether venous. He would have no means of determining the co-existing true lymphatic anlages, nor could these be demonstrated by a simultaneous lymphatic injection, because, at this period, they are isolated segments of the future lymphatic chain, not yet in communication with each other, or with the veins through the jugular lymph sacs, or with any other channel system, from which they could be filled. Subsequently, when the continuity of the systemic lymphatic vessels has been established, and can be demonstrated by injection, the site of the former venous plexus is occupied by lymphatics, but the conclusion that these are the former veins, directly transformed into lymphatics, is just as aroneous, as the same conclusion based on the examination of serial sections in different stages, in which the topographical replacement of the earlier vein by the later lymphatic is taken as the only criterion, and as affording proof of their genetic identity.

In view of the facts ai)solutely established by direct and repeated uniform observation in embryos of Felis domestica, it seems to me that it is worth while to examine the available evidence here offered in this form carefully and impartially, rather than torture an interpretation into mammalian lymphatic ontogenesis which is not supported by the actual conditions found in embryos of this specific mammalian type.

The cat may differ in its details of lymphatic development and in its adult lymphatic organization from the conditions obtaining in certain other mammalian types, as yet imperfectly determined. And yet these differences, established and maintained within the natural limits of the mammalian class, cannot, if they actually exist, be basic. In any given individual mammalian form, the systemic lymphatic vessels, whatever their adult relation to and connection with the venous system may be, must develop in accordance with a genetic ground plan common to all mammalia.

B. The development of the proximal portion of the thoracic duct proper J between the termination of the thoracic duct approach of the jugular lymph sac, and the beginning of the azygos segment of the thoracic ducts, caudal to the level of the aortic arch.

In the earlier purely venous stages a venous plexus between oesophagus and vertebral column drains caudo-laterad into the mesal surface of the main jugular and innominate trunks. This plexus continues the supra cardinal line cephalad beyond the level of tl^e azygos-Cuvierian junction. The terminals of this plexus are frequently joined by dorsal somatic venous tributaries near their entrance into the main vein.

Some of the elements of this eariy embryonic prevertebral venous plexus are secondarily replaced by perivenous or extraintimal lymphatic spaces in exactly the same way as in the development of the ventral mediastinal duct. The resulting, originally separate, extra-mtimal lymphatic anlages, having replaced the venule along and around which they developed, imite with each other and form the pre-azygos segment of the thoracic duct, between the thoracic duct approach of the jugular lymph sac and the level of the aortic arch, at which the azygos portion of the thoracic ducts begins.

The general area in which this development proceeds, is indicated in the topographical fig. 1, by the letter F.

The embryonic stages between 13.5 and 15.5 nun. furnish abundant evidence of this genetic process. Figs. 19 and 20 show two sections of a 14 nmi. embryo (series 210, slide 9, sections 23 and 26) in the prevertebral area of the upper thoracic region. The anlage of the pre-azygos segment of the thoracic duct (5) is seen on the left side of the interval between oesophagus and the prevertebral plexus (17) and sympathetic nerve (1). The sections show the identical characters previously noted in the development of the broncho-mediastinal trunk, but both the decadent central venous core of the anlage (4) and the perivenous lymphatic space (5) are larger and better developed.

These pictures are again constant in embryos of the appropriate stages. The lymphatic anlage can be accurately traced from its indefinite beginning among the perivenous mesenchymal intercellular clefts through a number of successive sections to its similar distal termination in the same intercellular plexus. Following the sections from this point caudad through a varying intervening area in which no distinct lymphatic channel appears, the same line will sooner or later reveal the repetition of the same process, and the formation of another link in the still disjointed chain of primitive lymphatic anlages, eventually destined to unite into the continuous-channel of the pre-azygos segment of the thoracic duct.

II. The Azygos Segment of the Thoracic Duct

This main part of the thoracic duct develops by the confluence of the extra-intimal lymphatic anlages, which begin to appear in the 12;5 mm. embryo, are clearly marked in the 13 and 13.5 mm. embryo, increase in the 14 nmi. stage, become confluent to form longer segments in the 16 and 15.5 mm. embryos, and finally unite into the bilateral and continuous channels of the thoracic ducts in the average 16 mm. embryo, although instances are not rare in which the complete continuity of the thoracic ducts is not attained until a later stage. These extra-intimal lymphatic anlages develop in close association with the ventral aspect of the azygos veins and their ventral branches, but are from the beginning genetically distinct and independent of the same.

In the earlier and purely venous stages, the azygos veins receive, in addition to the terminals of the supracardinal plexus, larger dorsal somatic tributaries from the body walls and from the interior of the vertebral canal, and smaller ventromedial branches which drain the periaortic space close to the wall of the main arterial vessel . When these ventral azygos tributaries appear they occupy in general the position described by McClure as characteristic for the cardinal collateral plexus of the Marsupalia.*

The ventro-medial azygos tributary plexus is found in the purely venous condition, before any perivenous lymphatic development associated with it has begun in this region, in embryos of 11 and 12 mm. (Fig. 21, series 213, slide 11, section 29, 11 mm ; fig. 22, series 217, slide 11, section 27, 12 mm.). The plexus occupies the area ventral to the intersegmental aortic branches and the sympathetic nerves, between the aorta and the main azygos trunks.

Later, in 13.5 to 14 mm. embryos, portions of this early plexus appear detached in certain areas of the sub-azygos region from the main venous trunks. In many cases the line of the obliterated connection can still be traced for a time as a strand of differentiated mesoderm, and the separated elements of the azygos plexus still contain frequently red blood cells in the earlier stages. The lymphatic anlages of the thoracic ducts form along and around these degenerating elements of the azygos plexus, as extra-intimal or perivenous spaces, in exactly the same manner as above described for the regions further cephalad.

• C. F. W. McClure. The anatomy and development of the post-cava in Didelphis marsupialis. Am. Jour. Anat., vol. 5, 1906.

The recognition of this reduced ventro-medial tributary system of the azygos veins is of the greatest importance to the correct interpretation of the mammalian thoracic duct development. Not only do the extra-intimal lymphatic anlages of the azygos segments of the duct form along and around these venules, but in the sktne way the anterior part of the mesenteric lymphatic network of the abdomen has its origin in the extra-intimal lymphatic spaces which develop around the caudal continuation of the ventral plexus in front and along the sides of the abdominal aorta, in the root of the dorsal mesogastrimn. These perivenous lymphatic spaces subsequently unite to form the receptaculum and establish, on one hand, connections with the independently developed intestinal lymphatic channels, and, on the other, with the thoracic duct.

McClure, in a paper published in 1908,^^ on the development of the thoracic ducts in the cat, very clearly described and figured this secondary and evanescent line of the venous capillary plexus along the innominate and azygos veins which forms the basis for the subsequent development of the main segments of the thoracic duct. I can completely confirm the accuracy of his obse vations on this Structure, which he for the first time mapped out and demonstrated completely. I am obliged to differ from him, as shown in the preceding pages, in reference to the interpretation of the r61e taken by the temporary venous plexus in the development of the thoracic ducts. I cannot regard the ducts as arising directly from the detached venous elements of the plexus, but beheve, as here shown, that these elements are secondarily replaced by independent extra-intimal lymphatic spaces, which then join to form the continuous channels of the thoracic ducts.

• C. F. W. McClure. The development of the thoracic and right lymphatic ducts in the domestic cat. Anat. Am., Bd. 32, nos. 21 and 22, 1908.

I am quite convinced that, in determining definitely question i as intricate as are the relations between developing haemal and lymphatic channels in the mammalian embryo, a very large number of individual examples of each stage are absolutely necessary. I feel that if McClure had had at his command the amount of material on which this communication is based, his conclusions would have coincided with those here expressed, and he would not have assigned to the thoracic ducts a genetic origin diflferrent from that- which we upheld for all systemic lymphatic development in the mammalian embryo in our first joint publication on the subject in 1906 (2), and which, with the exception of the thoracic ducts, he still regards as the fundamental basis of systemic lymphatic development.

It is necessary to exercise great care in the critical stages in order correctly to distinguish between the degenerating vessels of the plexus and the extra-intimal lymphatic anlages replacing them, and to compare results obtained from a number of embryos of the same stage. If this is done there can remain no doubt that the azygos segments of the two thoracic ducts in the embryos of the cat develop by confluence of extra-intimal perivenous lymphatic spaces. These anlages appear at first as isolated spaces, either surrounding the retreating veins or closely applied to part of their circumference and subsequently to the ventral wall of the main azygos trunks^ usually laterad to the points where the ventral plexus connects with the main azygos channel. Thus, compare the micro-photographs of series 34 and 214, figs 23 to 32. In the succeeding stages these numerous separate lymphatic anlages coalesce into longer continuous channel-segments. It is again noteworthy that in stages between 13.5 mm. and 14 mm., the still separate and distinct lymphatic anlages are relatively larger and more clearly evident than in the subsequent (15 mm. to 15.5 mm.) stages in which they have more extensively joined to form longer links of the system. Finally, in the 16 mm. embryo, where usually all the sieparate segments are assembled into the continuous channel of the thoracic duct, additional new mesenchymal spaces are added and thus a second and permanent increase in size and caliber of the latter appears to begin, which can be traced in the subsequent stages as. occurring in correlation with the reduction of the adjacent azygos trunks. The mammalian systemic lymphatic vessels seem to thus share with the embryonic veins this tendency towards apparently excessive diffuse plexiform development in their respective early genetic stages. Subsequently the definite channel, lymphatic or haemal, seems to concentrate along static lines, as a vessel of relatively smaller caliber, out of the antecedent more generalized plexus, and from this stage on further growth centres on the definite vessel replacing the earlier diffuse plexus.

In a 14 mm. embryo (series 34, Princeton Embryological Collection, slide 31) the main azygos trunks have increased in size, have approached the dorso-lateral circmnference of the aorta more closely, and the interazygos anastomosis has developed.

The ventro-medial plexus is, however, still present in the typical position — (figs. 23 and 24, 4: series 34, slide 31, sections 18 and 19.)

Further cephalad (slide 28 of the same embryo), the beginning extra-intimal replacement of this plexus by the lymphatic anlages of the thoracic duct is encountered (figs. 25 and 26, series 34, slide 28, sections 19 and 20). The venule (figs. 25 and 26, 4), still containing a few red blood cells, is almost completely detached from the definite azygos venous channel, although its original continuity with the same can ^ill be traced by a strand of differentiated mesenchyme representing the obliterated channel of communication. This central detached venous kernel (4) is surrounded by the extra-intimal lymphatic space (5) .

Figs. 27 to 30 show successive sections from two slides of another 14 mm. embryo (series 214), in which the process of Ijrmphatic replacement of the azygos plexus is further advanced. All trace of the original connection of the central venous core (4) with the azygos systeia is lost in these sections. The detached and abandoned venule is entirely empty and forms a partially collapsed endothelial tube surrounded, as before, by the perivenous lymphatic anlage of the thoracic duct (5). The four figures show this development both at the level qf the inter-segmental arteries (figs. 27 and 28) and in the intervals between these aortic branches (figs. 29 and 30). The figures published here are not isolated sections to which the conditions described are confined, but the same structures extend cephalad and caudadfora considerable distance. The same embryo again shows, further caudad, admirably the first inception of the Ijrmphatic anlage in relation to the ventromedial azygos plexus. (Figs. 31 and 32). The vein undergoing Ijrmphatic replacement (4) is detached from the remainder of the plexus, but the original connection is still indicated. The lymphatic space (5) has developed, as yet, only on the lateral aspect of the abandoned vein, and has not yet completely enveloped the same. Comparison with the sections further cephalad, esfpeciaUy with figs. 27 and 28, at the intersegmental arterial level, clearly indicates that in course of further development additional portions of the ventro-medial venous plexus will be involved and included in the enveloping extra-intimal lymphatic, and that, in attaining this condition, the thoracic duct anlage will extend relatively further dorsad and thus come into closer apposition with the mainazygos trunks.

I am bound to draw, from the observations here recorded, the following conclusions:

1. The pre-azygos and azygos segments of the thoracic ducts of the cat are formed by confluence of separate and independent lymphatic anlages, which develop from intercellular clefts in the prevertebral mesenchyme. A large proportion of these early lymphatic anlages develop as extra-intimal para- or peri-venous mesenchymal spaces along the early mediastinal and azygos plexuses and their tributaries.

2. These spaces, whether developed directly in the mesenchyme, or in association with regressive embryonic veins, are from their first inception independent mesenchymal intercellular clefts. Their origin is independent of the veins which they are subsequently to replace topographically. They are neither buds" derived from the veins, nor are they portions of the primitive veins separated or ' ' split off " the main channels. Their Ijrmphatic intimal endothelial lining develops with their first appearance from the indifferent mesenchymal cells lining the spaces, and is the result of the adaptation of these cells to the new mechanical and physical conditions imposed on them by the space formation.

The lymphatic endothelium does not arise by sprouting/' or otherwise, from the pre-existing haemal vascular endothelium of the early embryonic veins.

As a matter of fact, in place of being derived from the endothelium of the blood channels, the intima of the degenerating vein can in hundreds of observations be followed through its stages of disintegration, partial reversion to indiflferent mesenchymal cells, and final complete elimination, within the lumen of the extraintimal lymphatic channel partly or completely enveloping the venous rudiment. Nowhere is there the slightest indicatio of budding or "sprouting," or of any other active process on the part of the degenerating haemal endothelium.

3. The above named individual segments of the thoracic and right lymphatic ducts, thus formed through confluence of a large nrnnber of separate and independently developed mesenchjrmal and perivenous anlages, finally unite with each other to form a continuous bilateral channel, which secondarily effects a junction with the thoracic duct approach of the jugular lymph sac, through which the general lymphatic system gains its entrance into the venous system.

4. The thoracic ducts, especially in their pre-azygos and azygos segments, and in the area of the tributary ventral mediastinal trunk, offer the most striking and convincing evidence of the truth of the extra-intimal theory of systemic lymphatic development in this mammaUan embryo, in the relation exhibited by the first perivenous lymphatic anlages to early embryonic venous channels which they siuround and subsequently replace.

For this reason I have selected the thoracic ducts as representative systemic lymphatic channels, whose developmental history will serve as a concrete illustration of the genetic principles expressed in this communication. Many of the details of the thoracic duct development are here designedly not considered, although they are of great importance and significance.

These questions can be much more clearly and comprehensively studied in their relation to the adult anatomy of the ducts and their mode of union with the system of the abdominal lymphatics. They will be considered in detail in a more extensive memoir on mammalian lymphatic development to be presently published.

As above stated, the development of paits of the thoracic ducts is introduced in this paper solely for the purpose of affording a concrete illustration of the general principles underlying the development of all the systemic lymphatic channels in the particular mammahan embryo (Felis domestica) here considered. The same principles obtain in systemic lymphatic genesis in all mammalian types which I have had the opportunity of examining, but the embryos of the cat offer by far the most conclusive, consistent and striking evidence.

5. The early independent genetic history of the spaces, which I have above described as the first anlages of the thoracic duct channels in the embryos of the cat, and the fact that in subsequent stages they appear consistently and in every possible combination as extra-intimal or perivenous mesenchymal spaces, following and surrounding the branches of the prevertebral, ventral mediastinal and ventro-medial azygos venous plexuses, excludes to my mind, the possibiUty of considering them as direct derivatives from the venous plexuses, or as so-called '* venous outgrowths " of the innominate and main azygos veins, subsequently detached from the parent trunks. The actual conditions observed and here described are too obvious and constant to admit of any doubt. They can be verified by any observer on sufficient material of the proper stages. I think it is time for investigators engaged in solving the problem of mammalian lymphatic development to abandon superficial lines of comparison and generahzation, based often on isolated and insuflBcient observations, or, as in the injection experiments, on methods which, from the nature of the problem, are utterly inadequate and almost barbarous. Results obtained from observations of this kind are, at their best, misleading, when dealing with a genetic question as delicately balanced as is the relation between developing haemal and lymphatic channels in the mammalian embryo.


The series here figured and described are in the embryological collection of Columbia University, with the exception of series 34, which belongs to the embryological collection of Princeton University. I am greatly indebted to Prof. C. F. W. McClure for the opportunity of stud3dng this series and of publishing the four sections shown in figs. 23 to 26.


Sympathetic nerve.



Intersegmental arteries.



Precardinal, resp. azygos vein of


right side.



Degenerating vein.



Extraintimal or perivenous lym


phatic space surrounding degen


erating embryonic vein.



Precardinal, resp. aaygos vein of


left side.












Pulmonary arteries.



Dorsal somatic tributaries.

Prevertebral venous plexus.



Carotid artery.

Thyrocervical artery.

Internal jugular vein.

Common jugular vein.

Primitive ulnar veno-lymphatic.

Ventral mediastinal venous plexus.

Subclavian artery.

Innominate vein.

Right auricle.


Fig. I Transverse section of anterior thoracic region of 12 mm. cat embryo (series 78, slide 5, section 9, X 50).


Fig. 2 Transverse section of anterior thoracic region of 13 mm. cat embryo (series 107, slide 9, section 40, X 225).

Fig. 3a Extra-intimal lymphatic aniage and contained atrophied vein of same section as fig. 3, magnified 300 diameters.


Fig. 3 Transverse section of anterior thoracic region of 13.5 mm. cat embryo (series 189, slide 8, section 36, X225).

Fig. 4 Same, section 37.

Fig. 5 Same, section 38.


Fig. 6 Same, section 39.

Fig. 7 Same, section 40.


Fig. 8 Transverse section of anterior thoracic region of a 14 mm. cat embryo (series 214, slide 13, section 13, X 225).


Fig. 9 Same, section 15.

Fig. 10 Same, section 16.


Fig 11. Same, section 21.

Fig. 12 Same, section 22.

Fig. 13 Transverse section of anterior thoracic region of a 14 mm. cat embryo, (series 212, slide 10, section 5, X225).

Fig 14 Same, section 6.

Fig. 15 Transverse section of anterior thoracic region of a 15 mm. cat embryo, (series 216, slide 10, section 32, X 225).

Fig. 16 Same, section 33.



Fig. 17 Transverse section of anterior thoracic region of a 15.5 mm. cat embryo (series 215, slide 14, section 13, X 225).

Fig. 18 Transverse section of anterior thoracic region of t^itocbhWiV^fc^Oy IL


Fig. 19 Transverse section of anterior thoracic prevertebral area of a 14 mm. cat embryo, (series 214, slide 9, section 23, X 225).

Fig. 20 Same, section 26.


Fig. 21 Transverse section of middle thoracic region of a 11 mm. cat embryo, (series 213, slide 11, section 29, X225}.

Fig. 22 Transverse section of middle thoracic region of a 12 mm. cat emi (series 217, slide 11, section 27, X 225).


Fig. 23 Transverse section of middle thoracic region of a 14 mm. cat embrvo, (series 34, Princeton University Embryological Collection, slide 31; section 18, X 225).

Fig. 24 Same, section 19.


Fig. 25 Same, slide 28, section 19.

Fig. 26 Same, section 20.


Fig. 27 Transverse section of middle thoracic region of a 14 mm. cat embryo (series 214,f slide 15, section 10, X225).

Fig. 28 Same, section 11.


Fig. 29 Same, slide 14, section 16.

Fig. 30 Same, section 17.


Fig. 31 Same, slide 15, section 27.

Fig. 32 Same, section 28.

Cite this page: Hill, M.A. (2021, April 17) Embryology Paper - The genetic principles of the development of the systemic lymphatic vessels in the mammalian embryo (1910). Retrieved from

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