Placenta 33, Supplement A, Trophoblast Research, Vol.

26 (2012) S92eS98

Contents lists available at SciVerse ScienceDirect

Placenta
journal homepage: www.elsevier.com/locate/placenta

Review: The evolving placenta: Different developmental paths to a hemochorial

relationship
A.C. Enders a, *, A.M. Carter b
a
Department of Cell Biology and Human Anatomy, University of California Davis, School of Medicine, Davis, CA 95616, USA
b
Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

a r t i c l e i n f o a b s t r a c t

Article history: The way in which maternal blood is associated with trophoblast prior to the formation of the different
Accepted 12 October 2011 types of hemochorial placenta may be conveniently grouped into four main patterns: a transitory
endotheliochorial condition; maternal blood released into a mass of trophoblast; maternal blood
Keywords: confined to lacunae; and fetal villi entering preexisting maternal blood sinuses. Although it might be
Comparative placentation considered logical that developing placentas would pass through an endotheliochorial stage to become
Hemochorial placentation
hemochorial, this developmental pattern is seen only as a transient stage in several species of bats and
Trophoblast
sciuromorph rodents. More commonly a mass of trophoblast at the junction with the endometrium
serves as a meshwork through which maternal blood passes, with subsequent organization of a labyrinth
when the fetal vascular component is organized. The initial trophoblast meshwork may be cellular or
syncytial, often leading to a similar relationship in the spongy zone and labyrinth. Old World monkeys,
apes and humans have a lacunar stage prior to establishing a villous hemochorial condition. New World
monkeys lack a true lacunar stage, retaining portions of maternal vessels for some time and initially
forming a trabecular arrangement similar to though differently arrived at than that in the tarsier. In
armadillos, preexisting maternal venous sinuses are converted into an intervillous blood space by
intruding fetal villi. Variations from the major patterns of development also occur. The way in which the
definitive placental form is achieved developmentally should be considered when using placental
structure to extrapolate evolution of placentation.
Ó 2012 Published by IFPA and Elsevier Ltd.

1. Introduction
The hemochorial relationship is the most common arrangement
found in interhemal areas in placentas of eutherian mammals. In its
definitive form there is a great deal of variation in number of layers
of trophoblast, the distribution of syncytial and cellular tropho-
blast, whether the form is villous, trabecular or labyrinthine, and
various modifications that occur in the trophoblast layer fronting
maternal blood [1,2]. The intermediate stages in developing the
hemochorial condition are less well known, making it difficult to
determine the extent to which different means of achieving the
definitive condition are recapitulated.
In species examined to date, there is usually substantial access
to maternal blood prior to formation of the definitive placental
arrangement and usually prior to development of the fetal circu-
lation. These important developmental stages, while allowing
* Corresponding author. Tel.: þ1 530 752 8719; fax: þ1 530 752 8520.
E-mail address: acenders@ucdavis.edu (A.C. Enders).
access to maternal blood, must also confine that blood and allow for
subsequent development of the definitive placenta.
Although there is considerable variation in these early stages,
four quite different patterns of obtaining trophoblast contact with
maternal blood in hemochorial placenta formation can be dis-
cerned, along with some minor variations (Table 1).
2. There is a transitory endotheliochorial condition
It might be thought that the most common way of achieving
a hemochorial condition would be for trophoblast to surround the
maternal vessels in an endotheliochorial relationship, followed by
some method of elimination of the endothelium of these vessels.
This relatively rare approach is found in several bat families [3e5]
and in sciuromorph rodents such as the chipmunk [6]. In these
forming placentas, processes from the outer syncytial trophoblast
layer penetrate the basal lamina underlying maternal endothelium,
dislodging the endothelial cells but retaining a space for much of
the basal lamina within the trophoblast (Fig. 1). The result is an
intratrophoblast lamina and space in a hemomonochorial placenta

0143-4004/$ e see front matter Ó 2012 Published by IFPA and Elsevier Ltd.
doi:10.1016/j.placenta.2011.10.009
 A.C. Enders, A.M. Carter / Placenta 33, Supplement A, Trophoblast Research, Vol. 26 (2012) S92eS98 S93

Table 1
Hemochorial placentation is established in four principal ways (1-4) with some variants on these themes (5-6). Several variants may occur within the same order of mammals.

Developmental type Order Representatives Example

1. Transitory endotheliochorial condition Macroscelidea Elephant shrewsa Rhynchocyon chrysopygus
Rodentia Sciuromorph rodents Tamias quadrivittatus
Chiroptera Vespertilionid bats Myotis lucifugus
Chiroptera Molossid batsb Molossus ater
Chiroptera Pteropodid bats Rousettus leschenaultii
Carnivora Hyenasa Crocuta crocuta
2. Maternal blood released into a mass of trophoblast Afrosoricida Hedgehog tenrecs Echinops telfairi
Afrosoricida Golden moles Amblysomus hottentotus
Hyracoidea Hyraxes Procavia capensis
Rodentia Myomorph rodents Rattus norvegicus
Rodentia Hystricomorph rodents Cavia porcellus
Lagomorpha Rabbits Oryctolagus cuniculus
Dermoptera Colugos Galeopterus variegates
Erinaceomorpha Hedgehogs Erinaceus europaeus
3. Maternal blood confined to lacunae Primates Old World monkeys Macaca fascicularis
Primates Apes Homo sapiens
4. Fetal villi enter maternal blood sinuses Cingulata Armadillos Dasypus novemcinctus
Pilosa Anteaters Tamandua tetradactyla
5. Trabeculae or villi formed without a lacunar stage Primates Tarsiers Tarsius tarsier
Primates New World monkeys Callithrix jacchus
6. Villous and labyrinthine regions formed Afrosoricida Shrew tenrecs Microgale cowani
a
Postulated from the definitive structure.
b
Endotheliochorial and hemochorial placentas briefly coexist.

in the chipmunk Tamias, and a similar structure in the outer
trophoblast layer of the hemodichorial placenta of bats such as the
little brown bat Myotis lucifugus [6]. The intrasyncytial lamina is
replicated as the placenta grows, since the vast majority of the
labyrinth is formed well after initial conversion from the endo-
theliochorial condition [7].
A variation of this structure occurs in molossid bats, in which
cytotrophoblast that surrounds vascular tufts creates the intratro-
phoblast lamina within cytotrophoblast rather than syncytium [4].
Although this species of bat has a well-formed endotheliochorial
placenta that persists for a considerable time, the vascular tufts are
not part of the endotheliochorial placenta. Thus for a part of gesta-
tion there is both an endotheliochorial placenta, the diffuse placenta,
and a hemochorial placenta, the definitive placenta. Both the spotted
hyena Crocuta crocuta [8] and the golden-rumped elephant shrew
Rhynchocyon chrysopygus [9] have an intrasyncytial lamina and
space in hemomonochorial placentas. However, the way in which
these structures are formed needs further study.

Fig. 1. Placenta of a chipmunk (Tamias quadrivittatus) in early pregnancy. A. A fetal capillary containing a nucleated erythrocyte indents the cytotrophoblast in the upper right. The
maternal capillary in the center of the micrograph is surrounded by syncytial trophoblast. B. The syncytial trophoblast is in the process of displacing maternal endothelium
(outlined). Note that the basal lamina of the maternal endothelium is retained within the trophoblast as an intrasyncytial lamina (arrow). Scale bar: 17 mm (A); 0.6 mm (B).
S94 A.C. Enders, A.M. Carter / Placenta 33, Supplement A, Trophoblast Research, Vol. 26 (2012) S92eS98

Fig. 2. Implantation site of a rat (Rattus norvegicus). A. Day 10. Maternal blood has entered spaces within the trophoblast and between trophoblast and decidua. B. Day 13. A spongy
zone and labyrinth have been established. Note that the fetal capillaries with nucleated erythrocytes are just beginning to associate with maternal blood spaces in the forming
labyrinth. Scale bar: 23 mm (A); 13 mm (B).

3. Maternal blood is released into a mass of trophoblast
(cellular or syncytial)
The most frequently observed way of establishing hemochorial
placentation is for some disruption of maternal vessels that leaks
blood into trophoblast, occurring well before fetal connective
tissue and blood vessels form a villous or labyrinthine relationship.
Quite commonly a mass of trophoblast overlies maternal vessels,
the released maternal blood then taking an irregular pathway
through the trophoblast mass (often showing some accumulation
near the chorionic surface). Only after this relationship has
developed do projections from fetal connective tissue extend into

Fig. 3. A. Implantation in the macaque (Macaca fascicularis), day 11. Some of the clefts in the syncytial trophoblast (arrows) have opened into lacunae. B. Human lacunar stage. Both
clefts (arrow) and lacunae can be seen in this stage 5c, Carnegie No.7700. Scale bar: 160 mm (A), 65 mm (B).
 A.C. Enders, A.M. Carter / Placenta 33, Supplement A, Trophoblast Research, Vol. 26 (2012) S92eS98 S95

the trophoblast forming the labyrinth, leaving the remaining
portion as a spongy zone. In the lesser hedgehog tenrec Echinops
telfairi, both the trophoblast pad and the labyrinth are composed of
cellular trophoblast [10]. In the Hottentot golden mole Amblyso-
mus hottentotus, the labyrinth is hemodichorial with both outer
syncytial and inner cellular trophoblast layers retained throughout
pregnancy [11].
A similar situation is seen in the rat and mouse in which
the decidua also participates in confining maternal blood
[12,13]. It is further complicated by a fold that both closes the
amnion and creates a separate chorionic layer beneath the
ectoplacental trophoblast before formation of a labyrinthine
hemotrichorial placenta [14]. Again, however, the exposure to
maternal blood is quite early (Fig. 2). In the guinea pig the
amnion is formed by cavitation and the ectoplacental cone
trophoblast forms a syncytial hemomonochorial placenta and
spongy zone [15].
Additionally, this general method of establishing hemochorial
placentation occurs in hyraxes [16], rabbits [17], colugos [18] and
hedgehogs [19].

Fig. 4. Placenta of the nine-banded armadillo (Dasypus novemcinctus). A. Note the clusters of placental villi that have entered endometrial blood sinuses deep in the richly glandular
endometrium early in gestation. B. In midgestation, placental villi have expanded the confluent blood sinuses which they have invaded. The intraluminal inverted yolk sac has
recoiled. Note that it overlies endometrial glands above the sinuses. C. Armadillo villi near term. Note that the general form of the villi is similar to that in the human, despite the
difference in formation. D. Human villi, third trimester. Scale bar: 365 mm (A,B); 50 mm (CD).
S96 A.C. Enders, A.M. Carter / Placenta 33, Supplement A, Trophoblast Research, Vol. 26 (2012) S92eS98
4. Maternal blood is confined to lacunae
The formation of the villous hemochorial placenta in Old World
monkeys and apes (including humans) shows early exposure to
maternal blood, but in a unique fashion, forming a lacunar stage in
which the blood is confined to spaces surrounded by syncytial
trophoblast (Fig. 3). These lacunar spaces form from clefts that
differentiate within syncytial masses [20]. Cleft formation consti-
tutes the differentiation of a polarized microvillous syncytial
trophoblast both before and during expansion of lacunae [21]. Later
cellular trophoblast penetrates into the syncytial trophoblast sep-
tae that partition the lacunar spaces. Subsequent branching and
formation of anchoring villi and trophoblast shell at the junction
with the endometrium result in maternal blood being contained in
an intervillous space within the trophoblast.
5. Fetal villi enter preexisting maternal blood sinuses
In formation of the hemomonochorial placenta of the nine-
banded armadillo Dasypus novemcinctus, fetal villi first enter pre-
existing maternal venous sinuses in the fundic portion of the
endometrium [22,23]. The villi then extend into contiguous sinuses
in the body of the uterus. The proliferating villi expand these
sinuses, leaving the endothelium covering them intact (Fig. 4A,B).
Maternal blood passes in endometrial septae from the basal to the
luminal side of the endometrium before entering the sinuses. The
blood drains through numerous small veins in the myometrium.
Hence fetal villi are contained within the maternal vascular system.
Cytotrophoblast is confined to growing villus tips while villi are
being added, and these cells disappear in late pregnancy, providing
a general conformation of villi similar to that in the human
Fig. 5. Placentation in a tarsier (Tarsius tarsier). A. Forming placenta showing a stem villus intruding from the chorionic plate into a meshwork of syncytial trophoblast that encloses
maternal blood. B. A late gestation placenta of T. tarsier, showing the interconnection of the villi forming a trabecular arrangement. (Hubrecht Collection, Berlin). Scale bar: 100 mm
(A), 120 mm (B).
(Fig. 4C,D). Anteaters (e.g. Tamandua tetradactyla) have similar
placentation and it is established in similar fashion by villi
extending into a preexisting system of uterine blood sinuses
[24,25].
6. Variations of the patterns in development of hemochorial
placentas
As might be expeced there are several variants of the major
patterns. The tarsier and marmoset show differences in formation
of villi. In tarsier Tarsius tarsier, a branched network of apparently
syncytial trophoblast is invaded by fetal villi resulting not in
a labyrinthine but in an initially trabecular arrangement, i.e. villi
with interconnections between them (Fig. 5) [26]. New World
monkeys such as marmosets (Callithrix sp.) also lack a lacunar stage
[27,28]. In the marmoset a dilated anastomotic network of enlarged
maternal vessels is surrounded by trophoblast. While some blood
leaves these vessels fairly early, other branches of the vessels are
retained, including their thickened basal lamina and the hyper-
trophied endothelial cells [28]. For a considerable part of gestation
(as late as day 60) some vessels can be found within the placental
pad (Fig. 6A). When first formed, many of the villi are inter-
connected, i.e. trabecular. However, as is often the case with the
trabecular arrangement, there are fewer interconnections in later
pregnancy, the arrangement becoming more villous.
In the shrew tenrec Microgale cowani, the initial maternal blood
spaces under the chorion are quite large, and the first vascularized
fetal intrusions into these spaces form a series of villi (Fig. 6B) [29].
Subsequently the trophoblast pad through which blood entered the
subchorionic spaces is converted into a labyrinth, providing an
example of a placenta with both villous and labyrinthine regions.
 A.C. Enders, A.M. Carter / Placenta 33, Supplement A, Trophoblast Research, Vol. 26 (2012) S92eS98 S97

7. Summary and conclusions

Despite considerable variation, it is convenient to group the

ways of obtaining trophoblast contact with maternal blood prior to
formation of a definitive hemochorial placenta into four major
patterns: 1. a transitory endotheliochorial condition; 2. maternal
blood released into a mass of trophoblast; 3. maternal blood
confined to lacunae; 4. fetal villi entering maternal blood sinuses.
The conditions under which maternal blood is released are such
that there is probably extremely poor circulation. Although blockage
of some maternal vessels can occur early, for the most part modifi-
cation of the major uteroplacental arteries occurs later as part of the
establishment of an orderly intraplacental circulation of maternal
blood. Considering the relatively anaerobic conditions in early
development, maternal blood within trophoblast at these stages is
probably more significant for its nutritive effect than for respiration.
The developmental patterns show little phylogenetic relation-
ship above the level of suborders and families. The considerable
differences in how the villous condition is achieved in the macaque
monkey as opposed to the nine-banded armadillo, for example, fit
well with their belonging in different clades. On the other hand, the
similarity in method of achieving the hemochorial condition in
some bats and sciuromorph rodents belies their inclusion in
different clades.
Several attempts have been made to describe the evolution of
placentation based on current knowledge about mammalian
systematics [30e34]. In these treatments a single term e hemocho-
rial placentation e is used to describe the various types of placenta
mentioned above. As explained by Martin [31], there have been
multiple conversions between endotheliochorial and hemochorial
placentation. Consideration of the diverse ways in which hemocho-
rial placentation is achieved leads us to a similar conclusion.
Because developmental series are available for few mammals,
placental evolution tends to be described in terms of the definitive
placenta. No consideration is given to the rate at which the placenta
reaches the definitive state. A particular difficulty arises where the
placenta is endotheliochorial for a substantial part of gestation
overlapping with a hemochorial placenta which is the definitive
structure. This coexistence of two chorioallantoic placentas occurs
in several bats [4,35], such that the same species may be scored as
endotheliochorial in one study [36] and hemochorial in another
[34].
Curiosity about the evolution of placentation dates back to
Hubrecht [19] and beyond and is a consistent theme in comparative
studies. This is perhaps admirable in itself. In recent years, however,
evolutionary biologists have sought to find correlations between
placental characters and variables such as maternal investment in
pregnancy [37]. In order to make such correlations, very different
types of placentas are assigned to the same character state such as
discoid (shape), villous (interdigitation) and hemochorial (inter-
hemal barrier). In addition to using more precise information, the
way in which the definitive placenta is formed developmentally
should be considered when using placental structure to extrapolate
evolution of placentation.

Conflict of interest

Fig. 6. A. Placenta of a marmoset (Callithrix jacchus). A maternal vessel with hyper-

The authors do not have any potential or actual personal,
trophied endothelium is surrounded by a thick interstitial lamina (isl), but also has
openings that bring maternal blood into contact with trophoblast of the developing political, or financial interest in the material, information, or
trabeculae. Day 60 of a gestation period of 144 days, photographed from the Harris techniques described in this paper.
collection, Center for Trophoblast Research, Cambridge. B. Early placenta of a shrew
tenrec (Microgale cowani), stained for cytokeratin. Villi are present in the outer portion
Acknowledgments
of the placenta. A giant cell layer separates them from a trophoblast pad that in later
placentas is organized into a labyrinth. Scale bar: 160 mm (A), 50 mm (B).
We thank Carolyn Jones and Tom Blankenship for collaboration
on several papers contributing to this study. We also acknowledge
S98 A.C. Enders, A.M. Carter / Placenta 33, Supplement A, Trophoblast Research, Vol. 26 (2012) S92eS98
the following collections and their curators: Harris Collection
(Centre for Trophoblast Research, Cambridge); Hubrecht Collection
(Museum fur Naturkunde, Berlin).
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