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Nutritional Influences on Implantation and Placental Development

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Nutritional Influences on Implantation and Placental
Development
James C. Cross, DVM, PhD, and Lindsay Mickelson, BSc
The placenta is critical for nourishing the fetus
throughout pregnancy, and also produces hormones
that alter the metabolic functions of the mother. While
the effects of nutrition on fetal development and long-
term outcome have been very well documented, there
are only a few reports based on studies in rat, sheep,
and guinea pigs on how specific nutrients or general
nutritional status affect the development of the blas-
tocyst, its implantation, and the subsequent placenta.
The data suggest that placental development is highly
adaptable and that many types of compensation are
possible for suboptimal nutrition.
Key words: amino acids, development, glucose, pla-
centa, trophoblast
© 2006 International Life Sciences Institute
doi: 10.1301/nr.may.S12–S18
INTRODUCTION
As mammals, the placenta is something that we
can’t do without during our embryonic and fetal lives,
but which we soon forget about after birth. Even for
clinicians and researchers who are interested in under-
standing complications in fetal growth, the placenta is
often either not included in the analysis or is given
cursory examination—such as by simply weighing it.
This treatment is unjustified, as the placenta is not simply
a selective filter for nutrient transport to the growing
fetus. Rather, it plays several key roles in most mamma-
lian species in regulating the nutritional status of both the
fetus and the mother by: a) forming a highly branched
villous structure that forms the surface area for nutrient
and gas exchange and establishes its own circulation to
Dr. Cross and Ms. Mickelson are with the Genes
and Development Research Group, University of Cal-
gary, Calgary, Alberta, Canada.
Please address all correspondence to: Dr. James
Cross, Genes and Development Research Group, Of-
fice Room 2279 Health Sciences Centre, 3330 Hospi-
tal Drive NW, Calgary, Alberta Canada T2N 4N1;
Phone: 403-220-6876; Fax: 403-270-0737; E-mail:
jcross@ucalgary.ca.
S12
May 2006: (II)S12–S18
connect to the umbilical cord1,2; b) promoting blood flow
to the implantation site and intervillous space by produc-
ing angiogenic factors and promoting vasodilation3; 3)
producing metabolic hormones such as placental lacto-
gens and placental growth hormone,4,5 which alter insu-
lin production and promote insulin resistance in maternal
tissues to increase glucose availability to the fetus, as
well as leptin6 and ghrelin7; 4) accumulating glycogen in
times of glucose surplus8 (Figure 1).
Each of these placental functions is highly regu-
lated and undertaken by a specific compartment of the
placenta. The barrier covering the chorionic villi in the
human and rodent placenta is composed of several cell
layers, including a multinucleated syncytium of tro-
phoblast (syncytiotrophoblast) cells.2 Nutrient trans-
porters are highly expressed to facilitate and regulate
the transfer between the maternal and fetal circulatory
systems. A specialized subtype of trophoblast cell
invades outside of the confines of the villi (these cells
are called extravillous cytotrophoblasts in humans and
trophoblast giant cells in rodents) to encounter uterine
spiral arteries. They replace the endothelial cell lining
of the arteries and therefore lead to the transition into
the trophoblast-lined blood vessels (hemochorial).3
The different placental hormones are produced by the
invasive trophoblast and the syncytiotrophoblast cells.
Finally, glycogen accumulates in both villous and
extravillous trophoblast cells, but is most dramatic in
the rodent placenta in cells designated as glycogen
trophoblast cells.8 They first start to appear in the
latter part of gestation within the middle layer of
placenta called the spongiotrophoblast (often also
called the junctional zone), which is analogous to the
cytotrophoblast columns in the human placenta. After
appearing, they subsequently invade diffusely into the
interstitium of the decidual tissue of the uterus.
The purpose of this review is to discuss the role of
nutrition in regulating these developmental events. Al-
though there is only limited direct experimental evi-
dence, it is clear that some specific nutrients and general
nutritional status can play key roles in altering the de-
velopmental trajectory of the placenta, effects that have
Nutrition Reviews姞, Vol. 64, No. 5
 Figure 1. Structures and essential functions of the human placenta.
direct consequences for the survival of the fetus and the
well-being of the newborn.
MOLECULAR MECHANISMS OF PLACENTAL
DEVELOPMENT
The cellular and molecular mechanisms underlying
the development of the placenta are best understood in
the mouse as a result of studies of experimental embry-
ology, the ability to culture trophoblast stem cells, and
analysis of several mouse mutants that have defects in
placental development usually resulting in embryonic
mortality or intrauterine growth restriction. Whereas we
knew of only a few genes essential for placental devel-
opment a decade ago,9 we now know of approximately
100. These subjects have been recently reviewed in detail
Figure 2. Developmental origins and molecular mechanisms underlying the differentiation of trophoblast cell types in the mouse
placenta.
Nutrition Reviews姞, Vol. 64, No. 5
elsewhere,2,8 but some of the key molecular pathways
regulating placental development are summarized in Fig-
ure 2.
There are several important themes that emerge
from the work to date. First, the placenta normally
achieves the delicate balance of having the correct pro-
portions of the different cell types to achieve its func-
tions. Second, differentiation of the trophoblast compart-
ments of the placenta is regulated by largely independent
molecular mechanisms (Figure 2). Third, primary defects
in one developmental process can lead to secondary
changes in other parts. For example, as is observed in
retinoblastoma (Rb) mutant placentas, failure to properly
form villi can lead to secondary attempts to hypervascu-
larize the villi that do form.10 This suggests that devel-
opment is adaptable to environmental circumstances.
S13
Indeed, the differentiation potential of trophoblast cells is
highly regulated by oxygen levels.11-13 Given this, it
stands to reason that nutrients and nutritional status may
also have similar effects.
EFFECT OF GLUCOSE, AMINO ACIDS, AND
FASTING ON BLASTOCYST DEVELOPMENT
The progenitors of the placenta are established in the
pre-implantation embryo. Many years of culturing mam-
malian embryos have led to a significant understanding
of their metabolism and of the optimal medium for
embryos that allows them to reach the blastocyst stage
and to successfully implant if transferred into a recipient
mother.14 Blastocyst development and subsequent im-
plantation potential are reduced in diabetic mothers,15
and this effect can be mimicked by culturing embryos in
high concentrations of D-glucose.16,17 Amino acid sup-
plementation also affects development. Essential amino
acid supplementation during in vitro culture of pre-
implantation embryos enhances post-implantation fetal
development.14 In addition, a strong beneficial effect of
nonessential amino acid supplementation is observed in
mouse embryos, leading to enhanced blastocyst forma-
tion18 and increased implantation rates.14,18
The beneficial effect of the nonessential amino acids
can be observed in an in vitro model of implantation
called blastocyst attachment and outgrowth. In the ab-
sence of amino acids, blastocysts do not attach but enter
a state of quiescence analogous to delayed implanta-
tion.19 With the addition of amino acids, the trophoblast
cells change their adhesive characteristics and form out-
growths. The effect is mediated by the mTOR signaling
system and can therefore be inhibited with rapamycin.19
Interestingly, blastocysts can be exposed to the attach-
ment-promoting amino acid levels for as little as a
critical 8-hour period. This narrow window implies that
amino acid sensing by blastocysts is a checkpoint mech-
anism for determining whether to continue to develop. If
the blastocyst does not initiate attachment to the uterus,
the maternal-side window of implantation will close and
pregnancy will not be established.
Another potential mechanism by which undernutri-
tion may affect blastocyst development has recently been
suggested. Ghrelin is a hormone first described for its
ability to increase fat deposition by stimulating appetite
and decreasing fat utilization.20 Its expression is stimu-
lated by fasting and insulin-induced hypoglycemia.20
The ghrelin receptor is also expressed by pre-implanta-
tion embryos, and ghrelin treatment significantly reduces
the number of inner cell mass and trophectoderm cells in
blastocysts,21 similar to the effect of a low-protein diet
during the period of blastocyst formation.22
S14
EFFECT OF MATERNAL NUTRITIONAL
STATUS ON VILLOUS PLACENTAL
DEVELOPMENT
While specific nutrients have not been evaluated for
effects on post-implantation placental development, the
effect of feed restriction and overfeeding have been
evaluated in rat, sheep, and guinea pig models. Curi-
ously, at a general level, while the responses in rats and
sheep are similar, the guinea pig appears to show a
different effect. In rats, protein restriction from the time
of mating leads to intrauterine growth restriction (IUGR)
of approximately 10%, but the placentas show enhanced
villous development.23 While the overall volume of the
villous placenta (called the labyrinth in rodents) is not
changed, the villous surface area is enhanced by about
15%, implying that branching had become more elabo-
rate. The underlying molecular mechanism is unclear.
Interestingly, though, the underlying vasculature does
not undergo a proportional expansion. This implies that
the trophoblast cells alter their development, perhaps in
an attempt to compensate for the protein restriction.
IUGR may have occurred because the response was
inadequate or because, in the absence of a proportional
increase in vascularization, the uptake efficiency of the
placenta may not have been sufficient.
The effect of overall energy restriction on placental
development and structure in rats has not been docu-
mented, and this is significant since it is obviously
unclear if the ability of the placenta to compensate (or
what type of compensation occurs) is dependent on the
specific type of nutrient deprivation. Maternal iron re-
striction before and during pregnancy also leads to an
increase in villous surface area but, again, with a failure
in vascular adaptation.24 This model leads to anemia, and
the response indicates that trophoblast-branching mor-
phogenesis and differentiation can be regulated by tissue
oxygenation. This is consistent with previous findings
with knockout mice lacking hypoxia-inducible factor
(HIF).11 Most other animal models of IUGR use feed
restriction rather than protein restriction.
In sheep, overall caloric intake has been tested as a
model and, interestingly, both feed restriction and over-
feeding can lead to IUGR.25-28 The placenta in sheep is
distributed over about 100 separate cotyledons, and nu-
trient status can affect both the number of cotyledons that
form and their subsequent size and vascularity. Tropho-
blast proliferation25 and the expression of angiogenic
factors27,28 are reduced by overfeeding during the first
and second trimesters, leading to smaller cotyledons that
are relatively poorly vascularized. By focusing on shorter
intervals, Wallace et al.26 have been able to show that
cotyledon number is most affected by overnourishment
during the first trimester, whereas final cotyledon size is
Nutrition Reviews姞, Vol. 64, No. 5
most affected by nutritional status in the second and third
trimesters. This coincides with the fact that cotyledons
are formed during the first trimester, and implies that
once the number is established, the placenta has only a
limited ability to compensate through increasing the size
of the remaining cotyledons.
In guinea pigs, a feed restriction model has been
widely used as a model of IUGR. In this model, pregnant
dams are fed only 50% to 70% of the normal ad libidum
intake and birth weights are reduced by about 30%. By
term, the labyrinth layer of placenta is reduced in overall
size,29,30 and the villous surface area is also dramatically
reduced.30 The response of the placental structure is
significantly different than that in the rat models dis-
cussed above. It is not clear whether this reflects a
species difference, differences in response to protein
only versus total diet restriction, or is due to the fact that
the guinea pig model involves a more significant chal-
lenge to the pregnancy. Insulin-like growth factor (IGF)
I and II expression, and the ratio of the IGFs to IGF-
binding proteins is reduced in the guinea pig model.31-34
Moreover, IGF levels appear to be correlated with the
extent of villous branching in the labyrinth and are
inversely correlated with the trophoblast barrier thick-
ness.32,33 These observations are interesting, because
IGF-II mutant mice have defects in the extent of villous
branching in the labyrinth and the barrier thickness is
increased.35,36
EFFECT OF GLUCOCORTICOIDS ON
PLACENTAL DEVELOPMENT AND FUNCTION
In rats, glucocorticoid treatment of pregnant dams
during the second half of gestation results in IUGR. The
expression of several hormone and nutrient transporter
genes has been reported to be altered in this model.37-41
Notably, though, placental weight is also dramatically
smaller in this model, and the decrease in placental size
is associated with an increase in apoptotic cell death41
that occurs in both the labyrinth and junctional zone,
though the specific cell type(s) have not be defined.42
Therefore, the data on gene expression should be inter-
preted with caution, since it is not clear if the changes
simply reflect a change in cell composition or a physio-
logical change in expression. Ain et al.41 have addressed
the point by conducting a microarray experiment focused
on the family of prolactin-related hormone genes, and
then performing in situ hybridization to determine the
relative number and spatial patterns of expressing cells.
It is evident from this work that at least some of the gene
expression changes induced by glucocorticoids, includ-
ing the placental lactogens and IGF-II, are physiological
and due to cellular expression levels rather than to the
pathological loss of cell types. This type of work clearly
Nutrition Reviews姞, Vol. 64, No. 5
needs to be expanded to leptin expression and particu-
larly to the glucose transporters GLUT1 and GLUT3,
since both increases and decreases in their expression
have been reported.37,38 However, in a food restriction
model of IUGR in rats, GLUT expression levels did not
correlate with endogenous glucocorticoid levels, perhaps
suggesting that glucocorticoids may not directly regulate
GLUT expression.43
MODULATION OF PLACENTAL HORMONE
PRODUCTION BY MATERNAL NUTRIENT
STATUS
The placenta produces a number of metabolically
important hormones. The placenta in many mammalian
species has been reported to produce placental-specific
members of the prolactin/growth hormone superfamily.
In humans, both placental lactogen44 and placental
growth hormone45,46 are produced. In rodents, a placen-
tal growth hormone is not made but a huge cluster of
over 25 prolactin-related genes that have been amplified
during evolution are expressed in the placenta, largely by
trophoblast giant cells.47 The functions of most of the
prolactin-related genes are unknown. Four placental lac-
togen I (PL-I)-related proteins and a single PL-II all
work through the prolactin receptor,4 and as such can
potentially mediate several important maternal adapta-
tions to pregnancy that are attributed to prolactin.48
These include mammary development and lactogenesis,
pancreatic islet hyperplasia and the associated increase in
insulin production, as well as insulin resistance. There is
very little information about what regulates the synthesis
and release of the PLs. PL-I expression is suppressed by
progesterone.49 PL-II expression is reduced by IL-6,50
and has been found to be expressed in a circadian
rhythm.51 PL-II is suppressed by melatonin, which is
also expressed in the placenta.51
The placenta also produces leptin52 and ghrelin,20
hormones that suppress and stimulate appetite, respec-
tively, and regulate other metabolic processes as
well.6,20,53 While they no doubt contribute to metabolic
control during pregnancy, there are few insights into the
specific function of the placentally derived hormones.
Leptin is expressed by syncytiotrophoblast cells under
the control of the Gcm1 transcription factor.6,39,54,55
Leptin receptors are also expressed in the placenta,
suggesting an autocrine or negative feedback func-
tion.39,40 Ghrelin expression in the placenta has only
recently been described, but the site of the expression has
not been identified. Interestingly, while fasting leads to
increased levels of ghrelin in circulation during preg-
nancy,56 placental expression is not altered by fasting in
pregnant rats.7
S15
PLACENTAL DEPOSITS OF GLYCOGEN
In addition to transporting glucose from the maternal
to the fetal circulation, the placenta can also store it in the
form of glycogen. Glycogen deposits are a common
pathological finding in different tissues, but placental
accumulation occurs in all pregnancies and appears to be
highly regulated, which suggests that it may be physio-
logical. In mice, glycogen accumulation is limited to the
latter half of gestation, and specifically occurs in a subset
of cells in the spongiotrophoblast layer after embryonic
day 12.5.57 Thereafter, the cells appear to massively
invade the wall of the uterus.57 The extent of glycogen
accumulation is increased in diabetic pregnancies,58,59
but is stimulated by insulin.60 By contrast, glycogen
content is reduced in IGF-II mutant placentas,61 suggest-
ing that IGF-II may act in a paracrine manner within the
placenta to regulate glucose uptake and synthesis of
glycogen, perhaps through the insulin receptor. Gluca-
gon has also been reported to diminish glycogen content
in the placenta in one study,60 but in another study had
no effect.62 While the ability of the placenta to store and
mobilize glycogen is interesting, it is unclear to what
extent it contributes to the energy balance of the fetus
and/or mother.
CONCLUSION
The effects of specific nutrients and general nutri-
tional status on placental development, structure, and
function have been largely ignored by most researchers.
However, from the limited data that do exist, it is clear
that placental development is highly regulated and also
highly adaptable. In particular, villous morphogenesis
can alter to change the maternal-fetal surface area and
barrier thickness across which nutrients pass. In addition,
the extent of vascularization within the villi is adaptable
and may be orchestrated by trophoblast cell expression
of angiogenic factors. In addition to the development of
the basic structure, placental functions (endocrine, active
nutrient transporters, and glycogen storage) are also
highly adaptable and can change either in response to the
maternal environment or to defects within the placenta
itself.
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Nutrition Reviews姞, Vol. 64, No. 5
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