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Symposium on the development and structure of the lymphatic system. III. Further evidence on the origin of the lymphatic endothelium from the endothelium of the blood vascular system

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The Anatomical Record.
111.
Further Evidence on the Origin of the Lymphatic Endothelium from
the Endothelium of the Blood Vascular System.
BY
FLORENCE R. SABIN.
From the Anatomical Laboratory, Jotma HopLins University.
The question of the origin of the lymphatic system has now resolved
itself into the question of the origin of its endothelial lining. I s the
lymphatic endothelium angioblastic or does it come from the less differentiated mesenchyme cells? By the one theory the endothelium of the
blood vascular system has become a specific tissue before the lymphatic
system begins and is capable of giving rise to all the endothelium both
of the blood vascular and of the lymphatic systems. By the other
theory, the lymphatic endothelium is formed out of mesenchyme cells,
just as the lining of the primitive blood islands had been formed a t a
much earlier stage. Thus the question is one of the specificity of tissues,
and means how early does endothelium become specific.
The theory that the lymphatics arise from tissue spaces and that the
lining comes from flattened-out rnescnchyme cells is well expressed by
Gulland. H e studied sections of human and other mammalian embryos
and found spaces in the connective tissue of the limb buds, and thought
that these spaces gradually dilated, flowed together and formed lymphatic ducts.'
Budge studied the lymphatic system in chick embryos. He injected
the caelom in chicks 2% days old and found that the fluid passed by
blunt processes out to the limits of the area vasculosa, where it formed
a peripheral sinus. These spaces of the area vasculosa, he thought,
made a primitive lymphatic system, later supplanted by the definite
lymphatic system of which he made beautiful injections along the
allantoic vessels in chicks 18 days old.'
The most recent exponent of this theory is Sala, who has also studied
the lymphatics in thc chick, and finds a series of sacs along the aorta
lGullnnd. Journal of Pnthology nnd Racteriology. Vol. 11, 18W,p. 466.
aBiitlge. Arch. f. Annt. u. Pliys., -4nnt. Abth., 1880 nnd 1887.
The Anatomical Record.
47
which he considers to be lymph hearts. From these mesenchyme spaces
the thoracic duct is formed.8
The first link in the chain of evidence for the vascular origin of the
lymphatic endothelium was the discovery by Langer in 1868 that the
lymphatics in the skin of the frog grow by means of blind sprouts of
endothelial cells. That is, the lymphatic capillaries grow by the same
method as the vascular capillaries.' This method of growth was rediscovered by Ranvier in studying developing lymphatics in the skin of
the embryo pig. Based upon this discovery, he suggested the hypothesis
that the lymphatics grow from the veins.&
If this hypothesis be true, it should be possible to trace the growth
of the lymphatic capillaries into the different tissues and organs. This
has been done in the case of the skin, where it was shown that in
embryos under 20 mm. there are no lymphatic capillaries in the skin.
At about that time the lymphatics reach the skin in the neck and
gradually spread over the body. Thus it is possible to mark out successive zones containing lymphatics. Along the margin of these zones
the lymphatic capillaries can be seen growing out into non-lymphatic
areas. The lymphatics first cover the skin as a single primary plexus
in the subcutaneous tissue. Then a secondary and more superficial
plexus develops from the first and from this second plexus the final
capillaries enter the papillae.
I n studying vascular injections of pig embryos which are to be
demonstrated at this meeting, we have noted that there are non-blood
vascular areas in the skin as well as non-lymphatic areas. In the injected
specimens of embryos 15 to 20 mm. long i t will be seen that the deep
capillaries over the central nervous system have met in the mid-dorsal
line, while the superficial capillaries in the skin do not pass beyond the
myotomes. Thus there is a non-vascular area of the skin dorsal to the
central nervous system, which is narrow over the spinal cord and wider
over the brain. I n the case of the head the non-blood vascular area
persists late, so that it is still present in embryos 5 to 5.5 cm. long. The
skin of the head is also late in receiving its lymphatics, and at this
%ala. Ricerche 11. lab. di anat. norm. d. I-. Univ. di Roma, Vol. VII, 1900,
pp. 263-269. Reviewed in Archives Italienne de Biologie, Tome 34, 1900,
p. 453.
'Langer. Ueber das Lymphgcfiiss-System des Frosches, LVIII Bd. der
Sitzb. d. K. Aknd. (1. Wissensch., I Abth., 18fB.
5Ranvier. Comptes Rendus, 1896 and 1896; Archiv d'Anatomie, Tome 1,
1,997.
48
The Anatomical Record.
stage the lymphatic vessels which are growing up between the eye and
the ear are at least 3 mm. behind the invading blood capillaries. T h h
makes one of the best places in the body to study growing blood vessels
and growing lymphatics in their relations to new territories.
The second place where the test of the invasion of lymphatics into
new territories has been made is in the intestine. Dr. Heuer, whose work
is to be presented at this meeting, has followed the gradual growth of
the lymphatics through the mesentery to the wall of the intestine. He
has followed the growth of the lymphatics by means of injections of
successive stages and has shown that after entering the intestinal wall
they first grow into the submucosa, making there a primary plexus.
Then a secondary plexus forms beneath the mucosa and lastly the terminal lacteals grow into the villi.
I n Dr. Flint’s recent paper on the development of the lung he has
shown that the lymphatics follow the same general law,-appearing first
in the hilus of the lung and gradually invading the lung itself.s Thus,
as far as developing lymphatics have been studied in relation to their
growth in organs, they first approach each organ from without and then
gradually invade its structures. Therefore, the hypothesis of the growth
of the lymphatics from center t o periphery, from the veins rather than
to the veins, is sustained by the study of the growth of the lymphatics
into the organs.
The second series of experiments in regard to the origin of the
lymphatics has been the tracing of the finished lymphatics back to the
earlier stages and concerns the study of the lymphatic sacs. Everyonc
who has worked on the lymphatic system in early stages is aware of the
extreme difficulty in identifying lymphatics. There are so many structures with which they may be confused in sections that it seems as if
almost the only clue with which to meet the difficulty is to start with
the finished lymphatic system and trace it back to the younger stages.
The finished lymphatics in the skin of the embryo are identified with
great ease by means of injections; their characteristics are so well known
that they cannot be mistaken. In younger stages the character of the
lymphatic capillaries more closely resembles the blood vascular capillaries, so that it becomes even more necessary to have injections that
will show whether the vessels in question are connected with the blood
vascular system or with the lymphatics. By a great number of lymphatic injections it has been shown that the lymphatics in the skin of
Flint. Amer. Jour. of Anat., Vol. M,1906.
The Anatomical Record.
49
the pig run either to the neck or to the groin. In the neck these vessels
run either to a sac or into the group of lymph nodes into which this sac
differentiates.
In studying the cervical heart, the first anlage of the lymphatic
system, I was able to trace it back, first by lymphatic injections, and,
where they failed, by vascular injections, to a stage where it consisted
of a small sac against the jugular vein. The opening of this sac wad
difficult to find in sections even in later stages, where one could watch
the injecting fluid pass from the lymphatic duct into the vein. In these
injected specimens, however, i t was possible to find the valve in sections,
and they showed that the lymphatics entered the vein at a very oblique
angle. Having found how the valves looked in later stages, it was
possible to find them in earlier stages. I followed the origin of the
lymph heart back to a stage in which it is a simple sac connected wit!i
the vein, and interpreted this as a budding out from the vein. This sac
is to be found in embryo pigs about 15 mm. long. Dr. Lewis, of Harvard, approaching the subject after a careful study of the veins, was
able to trace the origin of the cervical sac still further.' He showed
that there is first a plexus, of veins in the region of the sac; these veins
are in free connection with the jugular vein. Then the plexus of veins
is cut off from the jugular and appears full of blood, but without venous
connections. Later the plexus forms a sac and rejoins the main vein.
After it has joined the vein it becomes empty of its blood. This discovery of Dr. Lewis I can entirely confirm. The methods of injecting
embryos have been much perfected in our laboratory, so that we have
many series of sections of complete vascular injections, including embryos from 10-30 mm. in length. In one specimen of an embryo 15 mm.
long, I have the symmetrical sacs in the neck filled with blood in both
sides. On one side a very small amount of the ink injected into the
vein has run over into the sac, showing that it has a small opening on
the one side and none on the other. Thus the origin and relations of
the cervical lymph heart have been traced.
Dr. Lewis discovered a similar sac in the root of the mesentery of s
pig embryo 20 mm. long and identified it as a part of the lymphatic
system. We were working on this mesenteric sac at the time, but had
not been able to interpret it. Mr. Baetjer has traced the origin of
Dr. Lewis' mesenteric sac and its relation t o the thoracic duct. He
Z e w i s , F. T. Amer. Jour. of Anat., Vol.
V, 1905.
50
The Anatomical Record.
will report his work at this meeting and will show that the mesenterk
sac arises from the veins of the renal anastomosis, independently of the
thoracic duct; the receptaculum chyli arises as still another sac, adjacent
to the azygos veins, and in an embryo 3 cm. long the mesenteric sac
and the receptaculum chyli have joined and can be injected. The details
of the origin of the receptaculum chyli Mr. Baetjer is not yet ready
to report.
I n regard to the posterior lymph sacs, I can demonstrate them in
sections, but have not studied them further. Thus far it has been shown
that there are six primitive sacs which form the anlage of the lymphatic
system. Four of these sacs are paired, two in the neck and two in the
groin, while two are unpaired, one at the root of the mesentery and the
other behind the aorta forming the receptaculum chyli. All of these
sacs arise independently, all have a complete lining of endothelium and
the three that have been studied with care, namely, the two cervical sacs
and the mesenteric sac have bcen shown to arise from the veins.
We must now take up the question brought up by Dr. Huntington and
Dr. McClure as to whether these sacs are the first lymphatics. At our
meeting last year, Dr. Huntington and Dr. McClure showed a series of
models representing the development of the lymphatic system. Some
of the later models showed the true cervical lymphatic sac, easily
identified as the sac which I had published as the first anlage of the
lymphatic system, a point which had been confirmed by Dr. Lewis. In
disagreement with both Dr. Lewis and myself, these models carried the
origin of the lymphatics back to much earlier stages, showing them in
cat embryos 8 to 8.5 mm. long. Dr. Huntington and Dr. McClure
describe oval or spindle-shaped spaces arising along the veins as the
result of shrinkage and condensation of primitive redundant precardinal
vein channels. These spaces they describe as situated without the
intima of the reins in the peri-intimal adventitious tissue and are not t o
be confounded with the mesenchymal spaces of Sala, since they develop
in territory formerly occupied by the veins themselves. From this it is
not clear what forms the lining of these spaces; since the veins at this
stage have only a lining of endothelium which rests on a connective
tissue syncytium. these spaces must be lined either by endothelium or by
the connective tissue, unless one imagines them as formed by a sagging
of the endothelium away from the surrounding tissue so that the spaces
are bounded by endothelium on the one side and the connective tissue
on the other.
The Anatomical Record.
51
I have cut many new sets of serial sections of various stages of pig
embryos, from 10 to 16 mm. long, and am-convinced that these early
lymphatics cannot be demonstrated. Spaces exist, but they are not part
of the lymphatic system. In the first place, there are a very interesting
series of spaces, which encircle many of the nerves and may be called
peri-neural spaces. These peri-neural spaces, which were excluded from
the lymphatic system in my earlier work, since they are easily injecteli
but nerer connect with the lymphatic system, are large and prominent
in early embryos. Inasmuch as the nerves are often close to the veins,
the peri-neural spaces often touch the veins. I have many specimens
showing that these peri-neural spaces are like the arachnoid from which
they can be injected, and I will later shorn their development. They
are especially large around the growing tips of the nerves and they will
be demonstrated at this meeting. These peri-neural spaces are to be
distinguished from lymphatics by the absence of endothelium, by the
fact that they arise from the destruction of connective tissue and by
their following the nerves. They have undoubtedly great physiological
significance, and may supply the place of a lymphatic system to the
nervous system, since it never receives true lymphatics.
Besides these peri-neural spaces, there are true rounded spacs in the
mesenchyme which undoubtedly contain lymph but which are not a
part of the lymphatic system. There are also veins, or blood capillaries,
which are exceedingly difficult to trace in relation to other blood capillaries in uninjected specimens. Just as in adult tissues one cannot trace
a capillary plexus completely without injecting it. so one meets the same
difficulty in the embryonic stages. From a careful study of new sets of
sections of early stages we feel that the true lymphatics cannot be
demonstrated before the appearance of the lymph sacs, and therefore
think that the importance of the lymph sacs as the first-lymphatics is
fully emphasized. It seems to me that it is now possible to define the
lvmphatic system as a series of vessels lined by endothelium which arise
from transformed veins and eventually open into the veins. All tissue
spaces bordered only by connective tissue and all the serous sacs are to
he excluded from the lymphatic svstem morphologically. Previous t o
the formation of the lymph sacs, the anlagre of the lymphatic system,
there are no spaces which have been proved to become a part of the
t m e lymphatic system.8
'Inasmuch as the discussion whir11 followed the rending of the papers of
the Lymphatic SFmposium of 1908 mill not be pnhlished, I should like t o
52
The Anatomical Record.
We pass now to the third important point in connection with the
origin of the lymphatic system, namely, the series of blind spaces, definitely lined with endothelium, which Dr. Lewis has pictured in a series
of most careful reconstructions of the development of the lymphatics in
the rabbit.B In a rabbit embryo of 11 mm., or 14 days, he pictures the
lymphatic system as consisting simply of the cervical sac. Later, in
embryos nearly 15 and 17 days old, he pictures isolated spaces along the
external mammary and umbilical veins. Dr. Lewis does not picture
any of these spaces in the pig of 20 mm., where the entire system consists of the cervical sac, the mesenteric sacs and the receptaculum chyli,
but if the later stages of the cat and rabbit embryos show them, one
should be able to find them in pig embryos older than the stage of 20 mm.
Thus Dr. Lewis agrees in regarding the sacs as primitive anlagen of
the lymphatic system, but disagrees in .finding multiple endothelial
.anlagen associated with the growing system of ducts. Since these spaces
are lined with a definite endothelium, they form a much more serious
obstacle to the theory of growth of the lymphatics from the endothelium
of the veins than the more indefinite spaces t o be found in earlier
embryos, and I cannot but think that if these multiple endothelial-lined
isolated spaces do exist along the veins in the later stages, they would
form serious evidence against the theory of the origin of the lymphatics
add one or two footnotes to my paper to bring out the points in which we
now all agree and those in which there a r e still differences of opinion. I n
this paper, if I seem to lay too much emphasis on the method of t h e origin
of the lymph sacs, i t is because that was the chief point of controversy at the
meeting of 1907. Since we have all come to agree that t h e lymph sacs arise
from the veins, that they are preceded by a plexus of veins which separate
from the main veins, then unite to form lymphatic sacs and subsequently
join the vein again, i t is clear that t h e most fundamental and important
evidence for the venous origin of the lymphatic system still stands. We
may then regard a s established by the recent American work on the lymphatic
system that the primary lymph sacs are derived from the veins. that their
endothelial lining is derived from the venous endothellum, and that the
permanent openings of the lymphatics into the veins are secondary rather
than primary. In regnrd to the primary lymphatic sacs or hearts, In
mammals, only the jugular lymph sacs and t h e mesenteric lymph sac have
been thoroughly investigated. The posterior lymph sacs, the receptaculum
chyli and probably symmetrical lymph sacs along the subclavian veins for
the lymphatics following the deep vessels of the arm and the external
mammary veins need further study.
'Lewis. Zbid.
The Anatomical Record.
53
from the veins. Or at least if the lymphatics, in their growth, do pick
up isolated endothelial-lined spaces, we shall again be left without a clue
as to the origin of the lymphatic system. These multiple anlagen would
then need to be traced back to their origin before any gendralization in
regard to the lymphatic system could be made.
I have not had the same material as Dr. Lewis with which to test his
numerous anlagen, but if they be general, one should be able to find
them, whenever lymphatics are invading a new territory following the
veins. I have, therefore, tested the point in the zone of the skin previously described where both invading blood vessels and invading lymphatics can be studied. The test was made in this way: The lymphatic
plexus between the eye and the ear in pigs 50 to 55 mm. long was
injected. Some of the injections were made complete, which can be
done in this way: after withdrawing the needle the finger is laid on the
plexus and gentle pressure applied until the terminal sprouts just rupture. Other injections were left purposely incomplete, and some specimens were not injected at all. Serial sections of all the specimens were
made, cutting parallel to the surface of the skin, and then the specimens
were studied with reference to whether there are isolated vessels in front
of the growing lymphatics. The first important point is to be gained
from watching the injections. It will be often seen in making an injection that large, long sprouts run out in front of the plexus; often from
such a long sprout a slender side channel will suddenly shoot out and
open into a large space which might easily appear isolated in sections.
When this second large vessel is full a second slende; channel will open
up from it and carry the injection mass back to meet the main plexus.
Thus it might have been injected at first from the main plexus, but the
mass runs easiest into the wide channels and the very slender, collapsed
vessels open up only under pressure. From these experiments one may
readily expect difficulties in tracing the connections of such spaces in
uninjected specimens.
The serial sections bring out three points: First, that in complete
injections there are no vessels which have not received the injecting
mass. Secondly, in partial injections and uninjected specimens there are
endothelial-lined vessels which can bc traced only with difficulty or not
at all to the primary plexus. Thirdly, since some of the injecting fluid
often flows out of the vessels when the needle is withdrawn, one can find
reesels containing ink and which must have been injected from the
plexug, and pet one cannot trace their slender connections. From this
54
The Bnatomical Record.
evidence we doubt if such isolated yessels really exist in f r o n t of growing
lymphatics. Of the accuracy of Dr. Lewis’ observations o n these anlagen
we have no question; they undoubtedly exist in serial sections, so we
question n o t the observation, b u t the limitations of the method. If in
a d u l t tissues sections without injections are wholly inadequate t o show
all of the blood capillaries, it is obvious t h a t they m u s t f a i l more conspicuously with lymphatic capillaries where the walls are t h i n n e r and
t h e channels are often excessively small a n d collapsed. Thus, where ‘I
have been able t o put t h e test of injection, there are n o isolated anlagen
of endothelial-lined spaces preceding the growing lymphatics.l0
T h u s . the reworking of the subject of the origin of the lymphatic
system seems t o m e t o have emphasized the f u n d a m e n t a l distinction
between tissue spaces in the mesenchyme and t h e endothelial-lined lymphatics. The first lymphatic endothelium is derived f r o m the venous
“As was stated in the Arst footnote, we are all agreed in regard to the
method of origin of the primary lymph sacs a s f a r as they have been
studied. The differences o€ opinion have wholly to do with the growth of
the lymphatics after the lymph sacs have been formed. There are before
us three possibilities : flrst, one suggested by the isolated eudothelial lined
spaces shown in Dr. Lewis’ reconstructions along the course of veins near
growing lymphatic zones. These might be interpreted as the formation of
multiple lymph hearts from t h e veins. There is no theoretical objection to
this interpretation, but, if I judge correctly, Dr. Lewis wisely refrains from
making it definite for lack of positive evidence. My work offers some
suggestion that a more adequate method than that of serial sections alone
may eventually show that these isolated rings of endothelium a r e iu reality
connected with the lymphatic endothelium. The second possibility is that
to the lymph sacs are added tissue spaces lined by mesenchyme and that these
tissue spaces form tjie lymph trunks. This position seems to me wholly
untenable, it means t h a t the lymphatics first arise from venous eiidotheliuiii
which is growing by the method of sprouting; then the system grows by
additions of a new kind of lining cell, and subsequently returns to its
primitlve method of growth, namely, the sprouting of endothelium. This
seems to me out of harmony with the laws of growth as f a r as we know
them. The third possibility, which seems to me the most likely to be correct.
is that the lymphatics grow from the various primary lymph snrs by the
sprouting of endothelium and grndually spread over the body. Wherever
it has been possible t o test this method it has been found t o hold. I believe
that it is only the difficulty of making lymphatic injections in the early
stages immediately after the formation of the lymph sacs that makes this
point still a n open question. It can undoubtedly be settled by further studies
of growing lymphatics, and these studies must be based on the crucial point,
which is to And the source of all of the endothelium of the lymphatic syotetn.
The Anatomical Record.
55
endothelium, not by a simple process of budding, but by a transforming
of reins into the primitive lymphatic sacs. To recapitulate, (1) all the
lymphatic vessels arise by a process of sprouting from the lymph sacs,
which in turn are formed from the veins; (2) no lymphatics have been
demonstrated in embryos before the lymph sacs are formed; and ( 3 ) the
additional anlagen of Dr. Lewis can be injected from the lymphatic
system and therefore must also arise from it. In uninjected specimens
the connections cannot always be seen.
IV.
The Origin of the Mesenteric Lymph Sac in the Pig.
BY
WALTER A. BAETJER.
From the Anatomical Laboratory, Johns Hopkins University.
I n the study of the origin of the lymphatic system, it has been found
that there are certain primitive sacs arising in different regions which
represent the earliest lymphatics. To find the origin of these sacs is,
therefore, the most fundamental part in the study of the origin of the
system as a whole. The cervical lvinph sac or heart, which is the first
to appear, has already been workcd out and proven to come from the
veins. In this work, which was undertaken for the purpose of tracing
the development of the thoracic duct, it was subsequently found that
the relation of this duct to a sac at the root of the mesentery must first
be rlctermined, inasmuch as the latter appears before there is any anlage
of the receptaculum chyli.
This sac, located in the root of the mesentery between the Wolffiaii
bodies, and just ventrad to the renal anastomosis of the subcardinal veins,
was first noticed by Dr. Lewis, of Harvard, in following the transforniation:: of the vena c a n inferior in rabbits.’
I n this paper, in the plate illustrating the vessels of the region, the
lower portions of the subcardinal reins are detached from the rest, and,
“though colored blue,” like the veins, they are described as spaces in the
mesentery, suggesting the lymph hearts of the chick. It is also stated
that they may be snhcarrljnal dcrivatires. Tn a litter papcr Dr. Lewis
makes it more Pure that thcse resselq are
*I,ewis, F. T. Amer. Jour. Aniit.. Yol. I. lWl-01.
*Lewis, I?. T. Aiiier. .Tour. Aunt.. Val. V. 1MG.
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