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walls.
Despite the eventual continuity of the cardiovascular system™s
tubular network, the components that represent its extremes in size
and function develop independently of one another. In the chicken,
for example (see Fig. 8.1), the two lateral tubes that ultimately fuse
8 ORGANOGENESIS 191


with one another to make the primitive heart begin forming at 25 hr
of development (top panel), by 29 hr (bottom panel) fusion has taken
place and the heart has already begun to beat. In all vertebrate
organisms the initially straight heart tube undergoes ˜˜looping,” con-
version into a curved tube (Fig. 8.2) directed, in the vast majority of
cases, towards the right side of the embryo (though ultimately the
larger half of the mature, asymmetric, heart resides in the left half
of the chest (Manner, 2000; see Fig. 8.2D).
Interestingly, looping and the subsequent development into a mor-
phologically normal heart is a self-organizing property of cardiogenic
mesenchyme that does not require fusion of the parallel tubes shown
in Fig. 8.2A. In embryonic mice carrying a mutation in the gene spe-
cifying the transcription factor Foxp4, no midline fusion of the heart
tubes takes place. Nonetheless, each bilateral heart-forming region is
capable of developing into a four-chambered heart (Li et al., 2004).
Cardiac looping is the ¬rst morphological manifestation of the
left--right asymmetry in body-axis formation discussed in Chapter 7,
although it is preceded by molecular asymmetries. In Xenopus (Breck-
enridge et al., 2001) and zebra¬sh (Chen et al., 1997), for example, car-
diac looping follows a left-predominant expression of the morphogen
BMP4 in the linear heart tube. Taber and coworkers determined that
the looping actually comprises two mechanical motions, a rotation
and a bending to the right (Voronov and Taber, 2002). While the bend-
ing motion may be in¬‚uenced by asymmetric gene expression, Taber
and coworkers found, using video tracking of ¬‚uorescently labeled
live myocardial (developing heart muscle) cells, that the chicken heart
has no intrinsic ability to rotate (Voronov et al., 2004). In a striking
example of the role of physical mechanisms in morphogenesis, these
investigators demonstrated that external forces, exerted by the intra-
embryonic splanchnopleure (the ventrally located layer of mesoderm
and endoderm (Fig. 8.1, top panel) that eventually forms the wall of
the digestive tube, and the veins associated with this layer of tissue),
drive the rotation and determine the directionality of looping in the
initial stages of this process.
During the same period small blood vessels, which will eventu-
ally be part of a completely interconnected network of tubes that
includes the heart, are developing at sites distant from that organ
(Rupp et al., 2003). In the yolk sac (a membranous structure outside
the embryo proper, which in the chicken embryo plays a similar role
to the vegetal pole cells of the frog egg) and in the splanchnopleure,
cords of cells arise that eventually become tubular by a process of
pattern formation referred to as ˜˜cavitation” (Lubarsky and Krasnow,
2003). During cavitation, the cord™s internal core differentiates into
blood cells, thereby becoming subject to ¬‚ow (driven by the beating
of the newly forming heart, once connectivity is established), while
its external layer remains in place, forming a vessel.
In the somatopleure, the dorsally located layer of mesoderm and
ectoderm that eventually forms the body wall (Fig. 8.1, top panel),
192 BIOLOGICAL PHYSICS OF THE DEVELOPING EMBRYO



Head mesenchyme

Ectoderm


Somatopleure


Splanchnopleure


Endoderm
Cardiogenic mesenchyme




Neural tube Notochord




Endocardial
primordia




Myocardium

Foregut


Endocardial tube
Ventral mesocardium
Pericardial cavity




Myocardium
Endocardium




Fig. 8.1 (opposite)
8 ORGANOGENESIS 193



ANTERIOR Fig. 8.2 Fusion of the two heart
B
A
tubes and cardiac looping. (A, B) A
ventral view of fusing heart tubes
in the human embryo at
developmental stages
corresponding to the chicken
Prospective
stages shown in the lowest two
ventricle
panels of Fig. 8.1. (C) The fused
Prospective heart tube in B is viewed from the
atrium
left side at a slightly later stage.
The anterior portion of the tube
bends in a ventral and posterior
direction (C) and, with continued
POSTERIOR
development, rotates slightly to
the right (D). (After Langman,
1981.)
D
C




DORSAL


VENTRAL

Ventricle

Atrium




Formation of the chick heart. Top panel: During the same period that neurulation is
occurring (see Fig. 5.13) the mesoderm lateral to the somite-forming segmental plate
splits along the anteroposterior axis into two layers, the parietal and visceral mesoderm.
The parietal layer, along with the ectoderm that lies dorsal to it, forms the
somatopleure, the future body wall. The visceral layer, along with the endoderm beneath
it, forms the splanchnopleure, the future wall of the digestive tube. (The body wall and
digestive tube take up their de¬nitive spatial relationship, the former surrounding the
latter, after the embryonic layers undergo lateral folding and ventral fusion along the
midline, not shown here). Middle panels: The heart starts out as two parallel tubes
arising from the visceral mesoderm, each consisting of an inner, endocardial, layer, and an
outer, myocardial layer. The space separating the two layers is ¬lled with an extracellular
matrix known as cardiac jelly. The endocardium will form the heart™s inner lining,
chamber walls and valves, while the myocardium will form its muscles (bottom panel).
Transverse section through the anteroposterior axis at the heart-forming region of the
chick embryo at (top to bottom panels) 25, 26, 28, and 29 hr. (After Gilbert, 2003.)
194 BIOLOGICAL PHYSICS OF THE DEVELOPING EMBRYO


a population of cells arises that also forms vascular tubes, but, in
contrast with the cells of the yolk sac and splanchnopleure, it does
so without simultaneously giving rise to blood cells. The two vessel-
forming cell populations vascularize distinct regions of the embryo
(the aorta being somewhat exceptional in receiving contributions
from both). These different mechanisms of vasculogenesis (i.e., the de
novo formation of blood vessels) suggest the existence of two distinct
cell types -- the unipotential angioblast of the somatopleure and the
bipotential hemangioblast of the yolk sac and splanchnopleure, al-
though the existence of the hemangioblast as a single precursor
cell type is still speculative (Pardanaud et al., 1996; Pardanaud and
Dieterlen-Lievre, 2000; Eichmann et al., 2002).
Cardiogenesis (i.e., heart formation) and vasculogenesis (i.e., the
formation of capillaries and eventually veins and arteries, Fig. 8.3)
are thus both examples of tube morphogenesis (Fig. 8.4), some other
examples of which we have encountered before. Recall that the ver-
tebrate neural tube was described in Chapter 5 as forming by the
raising and fusing of parallel ridges along the neural plate, a process
that Lubarsky and Krasnow (2003) refer to as ˜˜wrapping.” Cardiogene-
sis and vasculogenesis by cells of splanchnopleural origin, in contrast,
occur by the formation of cell cords followed by cavitation, as de-
scribed above, whereas vasculogenesis by cells of somatopleural origin
occurs by still another mechanism of tube morphogenesis, referred
to as ˜˜cord hollowing” (Lubarsky and Krasnow, 2003). During this pro-
cess (which is similar to the lumen-forming process depicted in Fig.
4.2), the rearrangement of cells without cell loss, within an initially
solid cord, yields the tubular morphology. Finally, some very small
caliber blood vessels form by a process of ˜˜cell hollowing” (Lubarsky
and Krasnow, 2003) in which individual cells arranged in linear
chains undergo a process of cytoplasmic rearrangement and vesicle
fusion such that a continuous channel is formed within the
chain.
All these tube-forming mechanisms depend on the polarized na-
ture of epithelial cells. As we saw in Chapter 4 (see Fig. 4.2), polar-
ized epithelial cells that have non-adhesive molecules on their apical
surfaces will automatically rearrange in such a way that a cavity or
lumen forms, lined by the cells™ non-adhesive surfaces. However, the
energy barrier separating the tubular morphology from the cystic
or closed sac-like morphology is probably not large, as evidenced by
the relatively high frequency in humans of polycystic kidney disease,
a condition in which kidney tubules and ducts frequently take the
form of cysts (Wilson, 2004).
Epithelial sheets can also form tubular structures by extrusion-
type processes, often referred to as evagination or invagination. We
saw examples of the latter in our discussion of amphibian gas-
trulation (Chapter 5) and of the former when we considered the
Mittenthal--Mazo application of the differential adhesion hypothe-
sis to epithelial sheet morphogenesis and the formation of the in-
sect leg (Chapter 4). Extrusion from a preexisting tube, referred to
8 ORGANOGENESIS 195



EMBRYONIC VASCULOGENESIS




ANGIOGENESIS


Non-sprouting

Sprouting




ASSEMBLY AND MATURATION
Mural cell
recruitment Vessel
identity




Network
formation




ORGANOTYPIC DIFFERENTIATION




Fig. 8.3 The hierarchy of morphogenetic events during the development of blood
vessels. Top panel: The primary formation of blood vessels occurs through the
mechanisms of vasculogenesis. Embryonic vasculogenesis results from the coalescence of
mesodermal precursor cells (angioblasts) to form a capillary network. Upper middle
panel: further development of blood vessels by angiogenesis, i.e., the formation of vessels
and vascular networks from preexisting vascular structures. This can occur through
classical sprouting angiogenesis with the formation of interconnected branches or
anastomoses (on the right) or through the mechanisms of nonsprouting angiogenesis (on
the left). Nonsprouting angiogenesis occurs by intussusceptive microvascular growth
(IMG) “ the focal insertion of a tissue pillar “ or by the longitudinal fold-like splitting of a
vessel. Sprouting angiogenesis and intussusception contribute to the increasing
complexity of a growing vascular network. Lower middle panel: as the network
assembles and matures, mural (i.e., outer-wall) cells, which include pericytes and
smooth-muscle cells, are recruited to the surfaces of the vascular tubes, and directional

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