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The brain is responsible for 25% of the body’s metabolism, even
though it only encompasses 2% of the body’s total mass. As with the
rest of the body, metabolism leads to the generation of waste prod-
ucts that need to be cleared, and it is particularly important when it
comes to the brain that this clearance mechanism is efficient and
effective. Therefore, Chapter 5 concentrates on the lymphatic system
in the context of the central nervous system (CNS). J.W. Yun et al.
discuss the three different brain lymphatic clearance pathways that
are currently described, that is, (i) the perivascular pathway, (ii) the
glymphatic pathway, and (iii) the meningeal pathway. These differ-
ent pathways and the role that they play in diseases and conditions
of the CNS, such as Alzheimer’s disease (AD), multiple sclerosis
(MS), and cerebral ischemia (stroke), are reviewed at length. As dis-
cussed in the previous chapter (Chapter 4), aging is a significant con-
tributing factor to peripheral immune responses; additionally, it
also plays a considerable role in central immune responses, incorpo-
rating both the glymphatic system and brain lymphatic vasculature.
Chapter 5 will deliberate aging in the context of the CNS and the
lymphatic system and how the CNS lymphatics can be exploited
for drug discovery programs to identify new therapeutic targets
for the treatment of neurovascular and neurodegenerative
disorders.
Moving on from the CNS, in the next chapter (Chapter 6), B.B. Lee
and M. Amore weigh up the defective development of peripheral
lymphatic system (termed lymphatic malformation (LM)), which is
one of the various forms of congenital vascular malformations (CVMs)
but only affects the lymphatic circulation. It is known that LMs can
present clinically as a solitary/independent lesion or coexist with
other CVMs, often as a hemolymphatic malformation (HLM). Not only
do the authors discuss LMs in detail, but also they provide clinical
and management options for patients with, for example, Klippel-
Trenaunay syndrome.
In Ch apter 7, the lymphatics of the heart are reviewed by
J.S. Alexander and J.W. Yun. The heart is a dynamic organ in terms
of its mechanical propulsion of the blood flow, and as such. Its lym-
phatic system has long remained enigmatic. J.S. Alexander and
J.W. Yun discuss the origins and development of cardiac lym-
phatics, patterning, and functioning, placing particular emphasis
on the roles that the cardiac lymphatics may play in clinical
31. Introduction/overview
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conditions ranging from surgically induced lymphatic distress, to
myocardial infarction, to heart transplantation.
In the final chapter of our book ( Chapter 8), A. Mohr et al. focus on
the concept of the surgical approach of lymphatic reconstruction,
which is commonly used for patients with destructed or obstructed
lymphatic vessels who are suffering from secondary lymphedema.
A main advantage of this surgical approach is that it allows for
additional treatment options for the condition of secondary lymph-
edema especially if patients are resistant to conservative therapy.
However, as with every intervention, there are pros and cons, which
A. Mohr et al. discuss in detail in this chapter, along with the history
of surgical approaches for lymphatic reconstruction.
We hope this volume serves as a starting point for readers both
scientifically and medically minded alike at the level of students
to more advanced readers. Here, we have begun to consider how
this often nearly invisible, parallel sister to the circulatory system
supports the blood vasculature, accomplishing so many diverse
functions that are only recognized when lymphatic dysfunction
occurs. The recognition that lymphatics may contribute to many
clinical conditions opens vast new vistas for the development of
therapies that exploit new findings, mechanisms, and reagents act-
ing on the lymphatic vasculature.
Finally, we would like to thank Kristi and Melanie at Elsevier for
their patience, encouragement, and support. In addition, we thank
all the authors and reviewers without whom this book would not
have been possible.
4 1. Introduction/overview
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CHAPTER
2
Ontogeny and phylogeny of
lymphatics: Embryological
aspect
B.B. Lee
a
, H Suami
b
a
Vascular Surgery, George Washington University Hospital, Washington,
DC, United States
b
Australian Lymphoedema Education, Research and Treatment, Macquarie
University, Sydney, Australia
Historical background
The lymphatic system was first described by Hippocrates in
460–377 BC as “white blood” based on observation of “chyle,” a type
of lymph formed in the digestive system that is transported through
specialized lymph vessels known as lacteals [1,2]. He identified the
lymphatic system correctly as one of the two major circulatory sys-
tems together with the blood vascular system. This newly
discovered lymphatic system was further confirmed by Herophilus
(335–280 BC) and Erasistratus (304–250 BC) through systematic
dissections of human cadavers [3,4]. However, such historical
discovery was largely ignored until Gasparo Aselli rediscovered
the system in 1627, describing mesentery lymphatic vessels in
canines as the “venae albae et lacteae (milky veins)” [5].
Additionally, critical structural components such as the collecting
lymphatic vessels and the thoracic duct were also identified for the
first time as additional anatomical structures in the lymphatic sys-
tem. However, this system has been largely neglected for three
5Lymphatic Structure and Function in Health and Disease
https://doi.org/10.1016/B978-0-12-815645-2.00002-2
Copyright © 2020 Elsevier Inc. All rights reserved.
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centuries, due primarily to limited knowledge about its true value
and the technical difficulties involved in identifying its component
parts. Thus, the lymphatic system has been considered less impor-
tant and the often-invisible auxiliary to the blood vascular system.
Until recent years, the lymphatic system has been largely ignored,
while the blood vascular system has been extensively studied,
despite both systems sharing so many functional, structural, and
anatomical similarities. For example, the embryonic origin of the
lymphatic system was initially investigated more than a century
ago [6], but it only attracted proper scientific attention during the
era of molecular biology in the last decade, with the result that
the mechanisms of mammalian lymphatic development have finally
become better understood [7–9]. Indeed, advanced experimental
models to study various aspects of lymphatic biology, both
in vitro and in vivo, facilitated tremendous progress in the research
into the development and function of the lymphatic system;
together with various newly discovered molecular markers to dis-
tinguish between blood and lymphatic vessels, this research chan-
ged the misconception of the lymphatic system as secondary to
the more essential blood vascular system for the first time in two
decades.
Recent advances in our understanding of the embryonic develop-
ment of the lymphatic vasculature include the molecular mecha-
nisms mediating lymphangiogenesis and the role of
lymphangiogenesis in chronic inflammation and lymphogenous
cancer metastasis [10]. Indeed, the growing evidence about how
the lymphatic system contributes to various inflammatory disorders
and lymphedema as well as cancer metastasis has boosted basic
lymphatic research on this second vascular system in higher verte-
brates beyond its basic function in the absorption of dietary fat in the
intestine, immune surveillance, and the regulation of tissue
pressure.
Ontogenic point of view
Like all vascular structures, the lymphatic conduits arise from
endothelial cell aggregates to become an integral element of the
mammalian circulation through the coordinated process of
6 2. Ontogeny and phylogeny of lymphatics: Embryological aspect
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lymphvasculogenesis and lymphangiogenesis (Fig. 1). Different the-
ories have been proposed about the origin of the lymphatic system,
and it has remained a controversial issue since the early 20th cen-
tury. There are two competing theories, the “centrifugal” and the
“centripetal” models, and some areas of contention remain unre-
solved [11–18].
The “centrifugal” model is based on the hypothesis that the lym-
phatic system is derived from the blood vascular system during its
early development, while the “centripetal” model claims that
FIG. 1 Step-by-stepdevelopmentof the mammalianembryoniclymphaticvasculature.
Development of the lymphatics is composed of two steps: lymphangiogenesis and lymph-
vasculogenesis. Some of the cardinal vein endothelial cells commit to the lymphatic lin-
eage (second left). The primitive lymph sac is formed by budding off the vein (bottom left).
Lymphatic endothelial cells sprout and migrate from the lymph sac to form the lymphatic
vascular network (right).
7Ontogenic point of view
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mesenchymal cell-derived lymphangioblasts form the primitive
lymphatic plexuses first before establishing the connections to the
embryonic vein. The “centrifugal” model explains that the primary
lymph sacs arise from the endothelial cell population of the embry-
onic veins early in fetal development and that isolated primitive
lymph sacs then continue to progress through “endothelial
sprouting” to spread as peripheral lymphatic vessels into the sur-
rounding tissues and organs where local lymphatic capillaries form.
In the human embryo, the lymphatic vessels appear at 6–7 weeks,
substantially later than the blood vascular structures [11] and nearly
1month after the appearance of the first blood vessels [12]. The
paired structures of jugular lymph sacs adjacent to the jugular sec-
tion of the cardinal vein are the earliest identifiable precursors of
embryonic lymphatics. However, the origin of these lymph sacs
and their relationship to the adjacent cardinal vein have remained
controversial until recently [10,13]. Although Sabin FR demon-
strated with experiments on ink injection into the veins of pig
embryos that the lymphatic system is derived from the early embry-
onic vein [14,15], the presence of lymphangioblasts as lymphatic
progenitor cells and the critical role they play have also been vali-
dated in embryonic development of the nonmammalian lymphatic
system [16–18].
In contrast, the “centripetal” model explains the process indepen-
dently of the veins, postulating that the lymph sacs are developed
from lymphangioblasts, the mesenchymal precursor cells [19,20].
Huntington and McClure et al. [20] claimed that the primitive lym-
phatic vessels arise independently from the lymphangioblasts in the
mesenchyme with no connection to the veins until they fuse with the
lymph sacs through centripetal growth to establish venous connec-
tions as a secondary process. This theory was further supported by
the findings of experimental work in the quail-chick chimera system
on lymphangioblasts in the avian wing bud before the emergence
of the jugulo-axillary lymph sacs [21,22]. The distal wing buds of
3.5-day-old chick embryos were grafted into the same place in
3–3.5-day-old quail embryos to determine the origin of the lym-
phatic endothelium. The vascular endothelial growth factor
receptor-3 (VEGFR-3) and QH1 double staining of the 10-old-day
chimeric wings revealed that lymphatics were formed from both
chick and quail endothelial cells [22]. This work shows that the early
8 2. Ontogeny and phylogeny of lymphatics: Embryological aspect
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lymph sacs appear to arise as sprouts from adjacent veins, while at
the same time, mesenchymal lymphangioblasts also grow toward
those lymph sacs.
There is much evidence to support both centrifugal and centrip-
etal theories, but the centrifugal model appears to more closely mir-
ror the process in higher mammals. The studies in Prox1-deficient
mice gave crucial support to Sabin’s centrifugal model [23,24] and
have subsequently been confirmed by others [25, 26]. However, mes-
enchymal cells expressing CD31 and CD45 along with lymphatic
endothelial markers (Prox1 and LYVE-1) observed in mouse
embryos suggest that these cells might serve as lymph endothelial
precursors [27]. This gives ongoing support to the centripetal
hypothesis [17,28], particularly in the tissue-specific brain, cardiac,
intestinal, visceral, and dermal lymphatics [9], despite the fact
that Sabin’s claims that lymphatic endothelial cells are exclusively
derived from the endothelium of the venous system has been
the most widely accepted historically, with further support by
Wigle et al. [14,15,24].
Phylogenetic point of view
The cardiovascular circulatory system of blood vessels and the
heart develops much earlier than the linear conduit system of the
lymphatic vessels. However, there is some evidence that this first
vascular system included some lymphatic functions to provide all
living organisms with crucial defense mechanisms irrespective of
their size [29]. For example, macrophages appear first in the circu-
lation of the lympho-hematic system in insects before erythrocytes
develop, demonstrating that lymphatic function is primary.
Indeed, the early blood vessels in vertebrates have some structural
characteristics of lymphatics in that they express the lymph endothe-
lial receptor flt-4, which represents VEGFR-3. This unique characteris-
tic remains until the definitive lymphaticsdeveloplater, at which time
flt-4 is restricted to those structures alone, which are formed either
from mesodermal lymphangioblasts or from the primary vessels [29].
In addition, the heart is not the only organ to pump cells for cir-
culation. “Lymph hearts” are present in lower vertebrates and also
develop in some birds transiently. Even in human beings, there is a
9Phylogenetic point of view
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vestigial form of the contractile system for the lymphatic circulation,
defined as the “lymphangion,” which circulates immune cells.
Hence, the blood vascular system in mammals can develop from
the primitive lymphatic system of lymph hearts before the definitive
lymphatics develop.
Lymphatic vessels independent of the blood vascular system are
identified firstly in cartilaginous fish. In bony fish, arteries and veins
are connected by blood capillaries and form a closed blood vascular
system and are completely separate from the lymphatics [30].
Recently, a primitive lymphatic system was discovered in zebra fish
[26,31] that demonstrates evolutionarily preserved structural and
cellular features and has become extremely valuable in various
genetic studies.
The lymphatic vessels are well developed in tailed amphibians
such as salamanders and newts. In amphibians without tails such
as frogs and toads, the superficial lymphatics fuse during metamor-
phosis to form large subcutaneous lymph sacs in the adult animals
[30,32]. Amphibians, reptiles, and flightless birds have developed a
specialized lymph heart for lymph drainage and transport through
the lymphatic system (Fig. 2). However, the lymphatic system of
FIG. 2 Schematic diagram illustrating the lymphatics and lymph hearts (arrows) in
salamander, frog, and avian embryos.Salamanders have pairs of lymph hearts located
segmentally on each side of the lateral lymph duct. Frogs have a pair of anterior and pos-
terior lymph hearts. Avian embryos temporarily develop posterior lymph hearts. Based on
Kotani M. The lymphatics and lymphoreticular tissues in relation to the action of sex hormones.
Arch Histol Cytol 1990;53:1–76.
10 2. Ontogeny and phylogeny of lymphatics: Embryological aspect
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flying birds and mammals lost the lymph heart through the further
evolution of the lymphatic system and acquired lymph nodes for
immune functions instead. Avian and reptilian lymphatics only
differ from mammals in that the jugular lymph sac in mammals is
more highly developed as an anterior/cervical veno-lymphatic
heart [26,27]. Therefore, the lymphatic system is believed to have
appeared first in vertebrates [33] as an essential component of the
immune system and to maintain fluid homeostasis within the body.
Vasculogenetic point of view
Through the late 1990s, the identification of lymphatic endothelial
cell (LEC)-specific VEGFR-3 [34] gave momentum to the study of
lymphvasculogenesis study using lymphatic-specific molecular
and cellular markers. Although VEGFR-3 expression is detectable
in a majority of vascular endothelial cells during early development,
VEGFR-3 is the first lymphatic-specific marker restricted to lym-
phatic plexuses at later stages of development and post develop-
ment [34]. VEGF-C (a ligand for VEGFR-3)-deficient mice are
unable to form rudimentary lymphatic vessels even though the
endothelial cells remain committed to the lymphatic lineage. This
mutant phenotype can be rescued by VEGF-C and VEGF-D, another
VEGFR-3 ligand showing VEGFR-3 specificity [35].
The tremendous increase in knowledge of lymphatic develop-
ment at the molecular level over the last two decades allowed
lymphvasculogenesis to be redefined according to newly discov-
ered tissue markers. Lymphvasculogenesis is now further verified
through four distinctively different stages: lymphatic competence,
commitment, specification, and vascular coalescence and
maturation [13].
Lymphatic/LEC competence to respond to the initial induction sig-
nals for lymphatic vascular differentiation [36] is represented by the
cellular expression of flt-4 gene that encodes for VEGFR-3 [10]
together with lymphatic vessel endothelial hyaluronan receptor-1
(LYVE1) [19,37]. They represent crucial molecular signaling path-
ways to prime LECs to initiate lymphatic development [38,39].
For example, mouse embryos that lack VEGFR-3 expression die
without lymphatic development. VEGF-C/VEGFR-3 signaling also
11Vasculogenetic point of view
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plays a key role across multiple stages of lymphatic vascular devel-
opment because VEGF-C binding to VEGFR-3 transduces signals
that promote lymphatic endothelial cell survival, proliferation,
and migration [40,41] so that mouse embryos that lack VEGF-C
do not develop lymph sacs [42].
Lymphatic commitment is represented by the expression of Prox1,
which has a central role in explaining the centrifugal mechanism that
is a homolog of the Drosophila homeobox transcription factor pros-
pero 7 and serves as a master regulator of lymphatic development.
Prox1 expression is the exclusive nuclear transcription to cells of com-
mitted lymphatic lineage [19]. This expression represents a clear-cut
shift in commitment of the venous endothelial cells to a lymphatic lin-
eage [20]. The expression of Prox1 within the embryonic endothelial
cell is sufficient for lymphatic commitment. Prox1-positive lymphatic
endothelial cells subsequently bud and migrate away from the veins
[9] to form an initial lymphatic plexus and further develop the lymph
sacs [43–45]. However, the initiation of Prox1 expression in venous
endothelial cells is dependent on the transcription factors Sox18
[46] and Nr2f2/Coup-TFII [47] in mammals [9]. Prox1 is a homolog
of the Drosophila homeobox transcription factor prospero 7 and
serves as a master regulator of lymphatic development.
Lymphatic endothelial cell specification involves the mandatory
expression of the molecular markers of LEC identity that lead to
the unique lymphatic endothelial phenotype. These include podo-
planin and VEGFR-3 and neuropilin 2 [43–46]. When the newly
developing LECs leave the veins, the lymphatic cell population
establishes complete autonomy in the venous microenvironment
through these unique developmental steps. Peripheral migration
occurs, and budding and migration precede the formation of pri-
mary lymph sacs. The cells form capillaries in a centrifugal fashion,
establishing the lymphatic vasculature [10].
Vascular coalescence and maturation. The embryonic peripheral
lymphatic vasculature goes through the process of substantial mat-
uration and remodeling, including the development of valve appa-
ratus. FOXC2, which is highly expressed in adult lymphatic valves,
specifies a collecting lymphatic vessel phenotype [48,49]. Valve
development is also dependent on GATA2 [50]. Selective knockout
of GATA2 in the murine lymphatic endothelium leads to major
defects in valve structure and causes distended collecting lymphatic
12 2. Ontogeny and phylogeny of lymphatics: Embryological aspect
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