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3 Hereditary and Familial Lymphedema
10. Irrthum A, Devriendt K, Chitayat D, et al. Mutations in the transcription factor gene SOX18
underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J
Hum Genet. 2003;72(6):1470-1478.
11. Alders M, Hogan BM, Gjini E, et al. Mutations in CCBE1 cause generalized lymph vessel
dysplasia in humans. Nat Genet. 2009;41(12):1272-1274.
12. Finegold DN, Schacht V, Kimak MA, et al. HGF and MET mutations in primary and second-
ary lymphedema. Lymphat Res Biol. 2008;6(2):65-68.
13. Ferrell RE, Baty CJ, Kimak MA, et al. GJC2 missense mutations cause human lymphedema.
Am J Hum Genet. 2010;86:943-948.
14. Irrthum A, Karkkainen MJ, Devriendt K, Alitalo K, Vikkula M. Congenital hereditary lym-
phedema caused by a mutation that inactivates VEFGFR3 tyrosine kinase. Am J Hum Genet.
2000;67:295-301.
15. Connell FC, Ostergaard P, Carver C, et al. Analysis of the coding regions of VEGFR3
and VEGFC in Milroy disease and other primary lymphoedemas. Hum Genet. 2009;124(6):
625-631.
16. Lohela M, Saaristo A, Veikkola T, Alitalo K. Lymphangiogenic growth factors, receptors, and
therapies. Thromb Haemost. 2003;90(2):167-184.
17. Fang J, Dagenais SL, Erickson RP. Mutations in FOXC2 (MFH-1), a forkhead family tran-
scription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J
Hum Genet. 2000;67:1382-1388.
18. Erickson RP, Dagenais SL, Caulder MS, et al. Clinical heterogeneity in lymphoedema-
distichiasis with FOXC2 truncating mutations. J Med Genet. 2001;38(11):761-766.
19. Witte MH, Erickson RP, Khalil M, et al. Lymphedema-distichiasis syndrome without FOXC2
mutation: evidence for chromosome 16 duplication upstream of FOXC2. Lymphology.
2009;42:152-160.
20. Connell F, Kalidas K, Ostergaard P, et al. Linkage and sequence analysis indicate that CCBE1
is mutated in recessively inherited generalised lymphatic dysplasia. Hum Genet. 2010;127:
231-241.
21. Ferrell RE, Levinson KD, Esman JH, et al. Hereditary lymphedema: evidence for linkage and
genetic heterogeneity. Hum Mol Genet. 1998;7(13):2073-2078.
22. Evans AL, Bell R, Brice G, et al. Identification of eight novel VEFFR-3 mutations in families
with primary lymphoedema. J Med Genet. 2003;40(9):697-703.
23. Spiegel R, Ghalamkarpour A, Daniel-Spiegel E, Vikkula M, Shalev SA. Wide clinical spec-
trum in a family with hereditary lymphedema type I due to a novel missense mutation in
VEGFR3. J Hum Genet. 2006;51(10):846-850.
24. Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothelial growth factor C is required
for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004;5(1):
74-80.
25. Meige H. Dystrophie oedemateuse hereditaire. Presse Méd. 1898;6:341-343.
26. Hoque SR, Mansour S, Mortimer PS. Yellow nail syndrome: not a genetic disorder? Eleven
new cases and review of the literature. Br J Dermatol. 2007;156:1230-1234.
27. Witte MH, Way DL, Witte CL, Bernas M. Lymphangiogenesis: mechanisms, significance and
clinical implications. In: Goldberg ID, Rosen EM, eds. Regulation of Angiogenesis. Basel:
Birkhäuser Verlag; 1997:65-112.
28. Witte MH, Bernas M. Lymphatic pathophysiology. In: Cronenwett JL, Johnston KW, eds.
Rutherford’s Vascular Surgery. Philadelphia: W.B. Saunders Company; 2010:177-201.
39
Part II
Embryology, Anatomy,
and Histology
Chapter 4
Embryology of the Lymphatic System
and Lymphangiogenesis
Stanley G. Rockson
The lymphatic vasculature was first described by Aselli more than three centuries
ago, and the hypothesized embryonic origin of the lymphatic structures was initially
investigated in 19021; nevertheless, it only has been recently, during the era of
molecular biology, that the mechanisms of mammalian lymphatic development
have become well understood.
Long a subject of controversy, the developmental origin of the mammalian lymphatic system has been extensively explored over the last decade. Recent molecular
and structural insights have helped to shed light on this complex and important
topic, which also has distinct implications, not only for molecular therapeutics in
lymphatic vascular disease, but also for the broad field of tumor biology.
As a component of the mammalian circulation, the vascular components of the
lymphatic system, like all vascular structures, arise from aggregates of endothelial
cells through the combined forces of vasculogenesis and angiogenesis (Fig. 4.1).
The lymphatic vessels appear substantially later than the blood vascular structures.4
In human embryos, this occurs at 6–7 weeks, nearly 1 month after the appearance
of the first blood vessels.5 The earliest identifiable lymphatic precursor in the embryo
is the jugular lymph sac, a paired structure that can be found adjacent to the jugular
section of the cardinal vein.
The origin of these lymph sacs and their relationship to the adjacent cardinal vein
have, until recently, remained at the core of the theoretical controversy.6 The “centrifugal” model, suggested by Florence Sabin, proposed that the primary lymph sacs
arise from endothelial cells derived from the embryonic veins, with subsequent
endothelial sprouting from the lymph sacs into the surrounding tissues and organs.
The contrasting centripetal model of Huntington relies upon the contribution of
mesenchymal precursor cells, termed lymphangioblasts, to give rise to the lymph
sacs, a process that occurs independently of the veins.
2,3
S.G. Rockson
Division of Cardiovascular Medicine, Stanford University School of Medicine,
Falk Cardiovascular Research Center, Stanford, CA, USA
B.-B. Lee et al. (eds.), Lymphedema,
DOI 10.1007/978-0-85729-567-5_4, © Springer-Verlag London Limited 2011
43
44 S.G. Rockson
Mesoderm cells
Hemangioblasts
Tube formation
BM
EC
Pruning and remodeling
V
a
s
c
u
l
o
g
e
n
e
s
i
s
A
n
g
i
o
g
e
n
e
s
i
s
Fig. 4.1 The embryonic
development of the
vasculatures originates from
mesodermally-derived
endothelial cell precursors,
termed vasculogenesis.
Subsequently, the developing
vessels grow and remodel
into a mature vascular
network by endothelial
sprouting and splitting, the
process called angiogenesis.
(Adapted from Oliver
15
)
Although there are lines of evidence to support elements of both of these theories, it
seems that the centrifugal model most closely predicts the process in higher mammals.
Support for Sabin’s centrifugal model was provided by studies in Prox1-deficient mice.
7,8
Prox1 is a homolog of the Drosophila homeobox transcription factor prospero 7, serving
as a master regulator of lymphatic development. The venous origin of the mammalian
lymphatic vasculature recently has been demonstrated by lineage-tracing experiments
and supported by studies in zebrafish.10 However, in Xenopus frogs and avian species,
9
4 Embryology of the Lymphatic System and Lymphangiogenesis
VEGFR-3
+
LY VE-1
+
Prox1
+
VEGFR-3
+
LY VE-1
+
?
Prox1
+
Podoplanin
+
VEGFR-3
+
LY VE-1
+
CCL21
+
Prox1
+
Podoplanin
+
VEGFR-3
+
LY VE-1
+
CCL21
+
Nrp2
+
Lymphatic competence
E9.0-9.5
Lymphatic commitment
E9.0-10.5
Circulating
progenitor
cell
Lymphatic specification
budding and migration
E10.5-12.5
Lymphatic sprouting
blood-lymphatic
vascular separation
E12.5-14.5
Remodeling & maturation
of lymphatic network
E14.5-postnatal
Foxc2
ephrinB2
Nrp2
Ang2
Syk/SLP-76
Spreds
Angptl4
Podoplanin?
AM
HGF
GH
VEGF-D
FGF-2
IGF-1/2
Ang1
PDGF-BB
VEGF-C
Lymph
sac
Lymphangioblasts
Lymphangioblasts
VEGF-A
VEGF-C
45
Fig. 4.2 Lymphatic vasculature development and growth. AM adrenomedullin; Ang angiopoietin;
Angptl angiopoietin-like protein; E mouse embryonic day; FGF fibroblast growth factor;
GH growth hormone; HGF hepatocyte growth factor; IGF insulin-like growth factor; Nrp2 neuro-
pilin-2; PDGF platelet-derived growth factor; VEGF vascular endothelial growth factor.
(Reproduced with permission from Cueni and Detmar)
6
parts of the lymphatic system seem to originate from local lymphangioblasts.
11-13
The
potential contribution of lymphangioblasts to mammalian embryonic lymphangiogenesis
remains conjectured, but unproven. Nevertheless, mesenchymal cells expressing CD31
and CD45, along with lymphatic endothelial markers (Prox1 and LYVE-1), have been
observed in mouse embryos, suggesting that these cells might serve as lymph endothelial precursors.
According to the current prevailing model, lymphatic vasculogenesis would occur
in four identifiably distinct stages: lymphatic competence, commitment, specification,
and vascular coalescence and maturation (Fig. 4.2).
Lymphatic competence is the capacity of cells to respond to the initial induction
signal for lymphatic vascular differentiation.15 The priming of lymphatic endothelial cells (LECs) to initiate lymphatic development is likely dependent on a form of
molecular signaling that is distinct from that found in blood vascular development.
LEC competence is recognized through cellular expression of lymphatic vessel
endothelial hyaluronan receptor-1 (LYVE1)
tor receptor-3 (VEGFR3; also known as Flt-4).
die before lymphatics develop. Mouse embryos that lack VEGF-C do not develop
lymph sacs.
14
18
7,16
and vascular endothelial growth fac-
17
Mouse embryos that lack VEGFR-3
46 S.G. Rockson
Lymphatic commitment is characterized developmentally and functionally by the
expression of prospero-related homeobox 1 (Prox1). This is a nuclear transcription
factor whose expression is exclusive to cells of committed lymphatic lineage.7 Prox1
expression shifts commitment of venous endothelial cells from the default blood
vascular fate to a lymphatic lineage.8 The mechanism of this differential and ordered
expression is still incompletely understood, although, most recently, both SOX18
and COUP-TFII have been identified as potential activators of Prox1 expression.
19-22
As the contributory expression pathways continue to be identified, it is clear that
Prox1 is necessary and sufficient for lymphatic commitment. The molecular milieu
in which Prox1 operates is still not well understood; neither the downstream initiating and regulatory factors nor the other upstream supplemental events have been
entirely identified.
Lymphatic endothelial cell specification involves the expression of the distinguishing molecular markers that impose the unique lymphatic endothelial phenotype. As the cells attain a higher level of differentiation, additional lymphatic-specific
markers are expressed, with concomitant suppression of blood vascular expression
profiles.8 Through these developmental steps, the committed lymphatic cell population establishes complete autonomy from the local venous microenvironment.
Peripheral migration occurs. Budding and migration precede the formation of primary lymph sacs throughout the embryo. Secondary budding and migration mark
the final stages of lymphatic development. The cells thus form capillaries in a centrifugal fashion, establishing the lymphatic vasculature throughout the bodily tissues and organs.
17
An important event in lymphatic development is the necessary separation
between the flow of blood and lymph. A tyrosine kinase, Syk, and an adapter protein, Slp-76, are critical for lymphatico-venous separation. Deficiency of either Syk
or Slp76 has been shown to create abnormal connections between blood vessels and
lymphatics, with resultant blood-filled lymphatics and chylous hemorrhage.23 Most
recently, the mechanism of this process has been further elucidated: in the embryo,
platelets aggregate at sites of lymphatico-venous connections, triggered by binding
of LEC-specific podoplanin to C-type lectin receptor 2 (CLEC-2), which is specifically expressed in platelets; this leads to activation of Syk and Slp-76.
24,25
After the appearance of the embryonic peripheral lymphatic vasculature, these
vessels must experience substantial maturation and remodeling. One of the important maturational events is the development of the valve apparatus. A forkhead transcription factor, FOXC2, is highly expressed in adult lymphatic valves. It seems that
FOXC2 specifies a collecting lymphatic vessel phenotype.
26,27
The ephrins and the angiopoietins may also play a role in lymphatic vascular
maturation. In mutant mice, faulty expression of ephrinB2 leads to hyperplasia of the
collecting lymphatics, absent valve formation, and failure of lymphatic capillary
remodeling28 Angiopoietin 1 and 2 (Ang1 and Ang2) also participate in the maturation of the lymphatic vasculature.
agonist, in contradistinction to its role in the blood vasculature.
29-31
In the lymphatics, Ang2 is a Tie2 receptor
29
Lymphatic valve
development apparently also requires normal expression of integrin-alpha9 and
deposition of its ligand, fibronectin-EIIIA, in the extracellular matrix.
32
4 Embryology of the Lymphatic System and Lymphangiogenesis
47
All of these developmental events are interrelated and complex. New molecular
participants in the process continue to be identified. Although lymphangiogenesis is
a critical pathway in embryonic development, it has a counterpart in wound healing
and inflammation.
33,34
These molecular pathways may also have direct implications
for future molecular therapeutics in lymphedema and other lymphatic vascular dis-
3,35
orders.
Acknowledgment The author gratefully acknowledges Shauna Rockson for her artistic contribution to this chapter.
These concepts are further explored in Chap. 16.
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