Morphogen synergisms during antepartum synchronic evolution of

Rom J Leg Med [23] 121-130 [2015]
DOI: 10.4323/rjlm.2015.121
© 2015 Romanian Society of Legal Medicine Morphogen synergisms during antepartum synchronic evolution of placental
hemochorial and pulmonary alveolar-blood biologic barriers in Homo
Sapiens
Petru Razvan Melinte1, Gheorghe S. Dragoi2,*, Ileana Dinca1, Elena Patrascu1
_________________________________________________________________________________________
Abstract: During the ontogenesis of Homo Sapiens there are two systems for the gas exchanges that incites towards the
study of the anatomic characteristics of ecoton areas, that is transition areas between adjacent biocenosis. The microanatomic
analysis of placental hemochorial and pulmonary alveolar-blood biologic barriers was carried out on 9 fetus-placenta systems
with gestational age between 16 and 26 weeks and on 3 embryos of 7 weeks of gestation. The comparative study of these
two biological barriers involved in das exchange, offered arguments for understanding the morphogen synergisms from the
perspective of their structural synchronism. The authors consider that at the base of their morphogenesis, stand the reciprocal
induction and interrelations between epithelium and mesenchyme that generate structures adapted to gas exchange between
different environments: blood-blood antepartum and air-blood postpartum.
Key Words: morphogen synergism, respiratory biologic barrier, placental villi, pulmonary alveoli.
D
uring the epigenesist of placental
hemochorial and pulmonary alveolar-blood
biologic barriers, one can define a certain convergence
for morphogenesis of structures and a divergence for the
different functions in time and space. The synchronism
and significance of phenotype changes undergone by
the structural elements of those biologic barriers have
not been studied properly. The interest for knowing
those barriers is determinant by the search for answers
to numerous problems regarding their functional
anatomy: What are the microanatomic characteristics
of space distribution of blood capillaries networks
inside the structures involved in gas exchanges such as
antepartum placenta and postpartum lung? What are
the consequences for tissue interactions and reciprocal
induction between epithelium and mesenchyme during
the antepartum genesis of placenta hemochorial and
pulmonary alveolar-blood barriers? What is the dynamics
of phenotype changes undergone by chorial villosities
during placenta epigenesist? Why the advent placental
and pulmonary vascular structures belong to the arterial
system (umbilical artery and pulmonary artery) and
the outgoing to the venous system (umbilical vein and
pulmonary veins)? Could the gas exchange through
hemochorial barrier be considered as a phylogenetic
review of branchial respiratory system in fish? Are there
any flow-regulating structures inside placenta vascular
system? What is the contribution of cytotrophoblast in the
genesis ande remodeling of placenta villosities? What are
the determining factors for the decrease of gas exchange
surface in hemochorial and alveolar-blood barriers?
The purpose of this paper is to highlight the
theoretical and practical problems of genesis and
evolution in time and space of placental and pulmonary
1) Univesity of Medicine and Pharmacy of Craiova, Department of Anatomy
2) Romanian Academy of Medical Sciences, Bucharest, Romania
* Corresponding author: Prof.MD, PhD, Email: [email protected]
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Petru Razvan Melinte et al.Morphogen synergisms during antepartum synchronic evolution
respiratory systems from the structural synchronic and
functional diachronic perspectives in Homo Sapiens.
We proposed ourselves to perform a micronatomic
analysis of space distribution and relations between the
structural elements that take part to the formation of
placenta hemochorial and pulmonary alveolar-blood
barriers; they create transition areas between liquid
biocenosis of placental blood and air and liquid biocenosis
in lungs.
MATERIALS AND METHODS
The study was carried out on a set of 9 fetusplacenta systems with gestational age between 16 and
26 weeks and on 3 embryos of 7 weeks of gestation.
The macroanatomic analysis of placenta was performed
on 3 specimens injected through the umbilical vessels
with a Tehnovit suspension and on 6 specimens fixed
in 5% formaldehyde solution buffered at 7.2 pH. The
microanatomic analysis was performed on embryos and
on fragments of placenta and lung harvested from fetus;
the fragments were included in paraffin using classical
methods. The 5 microns sections were stained using
Hematoxyline-Eosine, Mac Manus and reduced silver
nitrate Gömöri method. The sections were examined
using Nikon Eclipse 80i microscope. The microanatomic
imagery was captured by Nikon Digital Sight DS-Fi1
High Definition Color Camera Head. The macroanatomic
pictures were captured by Digital Camera Eos 1ds Mark II
equipped with Macro Ultrasonic Lens EF 100 mm f/2.8.
RESULTS
A. Microanatomic analysis of space distribution
and relations between the structural elements that take part
to the formation of hemochorial barrier.
Our attention was particularly drawn by: the shape
and structures of the walls of spaces between villosities as
location for arterial maternal blood; by the variable space
distribution of trophoblast inside umbilical blood vessels
that carry fetus venous blood; by the relations of argirofile
collagen fibers with the inter-villi structures and last but
not least by the location and relations of flow-regulating
structures. When examining by 4x objective the serried
sections through placenta fragments harvested from
pregnancies at 24 weeks of gestation, we could identify
the inter-villi space that is crossed by placenta villosities
sectioned under variable angles. The stem villosities
present crenelated margins due to the presence of mature
intermediate villi and of villus terminalis (Fig. 1A).
The examination with the 63x objective of the
walls bordering the inter-villi spaces allowed us to visualize
the relations between conjunctive-vascular stroma and
vascular-syncytial membrane. This membrane is made by
the trophoblast around villi, the walls of villi capillaries and
by a thin layer of villosity stroma interposed between the
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two structures (Fig.2A). At the level of villus terminalis we
visualized a network of sinusoid capillaries that expand to
the periphery of villi; thus, a vascular complex is achieved,
resembling “a bunch of grapes” (Fig. 3A). At the base of
villus terminalis, we could identify fascicles of muscle
cells stained by Hematoxyline-Eosine (Fig. 3 A). When
examining the sectioned processed by reduced silver
nitrate Gomori method, we could easily visualize the
reticular lamina of subtrophoblast subendothelial basal
membrane and the presence of paired argirofile collagen
fibers with spiral trajectories towards the base of villus
terminalis (Fig. 3B).
Neutral mucopolysaccharides visualized by Mac
Mannus method are present in subendothelial basal
membrane area of capillaries within terminal villosities
structure (Fig. no. 3C). Significant changes were observed
in the spatial distribution of perivillous trophoblast,
by formation of syncytial knots which are prominent
outside the villous surface; syncytial sprouts present
during the development of lateral villosities; syncytial
and interfibrinous-villous bridges; the partial absence of
syncytiotrophoblast nuclei which lead to the development
of “vascular-syncytial membrane”. Within this structural
unity, argirofile collagen fibers are present as “reticular
blades” of subtrophoblastic and subendothelial basal
membranes (Fig. 5B). Similarly, we noticed the presence
of perivillous fibrinous substance deposits between
syncytium and cytotrophoblast (Fig. 3 C-E). Rupture of
placental membrane was frequently observed. There was
also noticed the crossing of nucleate fetal red blood cells
into the inter-villi space of the mother. When examining
by 100x objective, terminal villosities are well visualized:
sinusoid capillaries, vascular-syncytial membrane,
subendothelial and subtrophoblastic basal membranes,
trophoblast islands within pericapillar stroma (Fig. 5 A, B).
B. Microanatomic analysis of spatial distribution
and relations of structural elements that participate to the
formation of hemochorial barrier.
Seriate sections of 7 weeks embryos and of
harvested fragments from fetuses lungs aged 16, 20, 24
and 38 gestation weeks, revealed a great variability of
air-ducts shape and structure and also a heterogeneity of
epithelial-mesenchymal interrelations and differentiation
of periductal and perialveolary capillary networks. When
examining by 4x objective, sections through 7 weeks
embryos, it is easily noticeable the presence of bronchial
ducts system, which forms a pseudoglandulary structure
(Fig. 3 E). Examination of seriate sections of pulmonary
fragments from 16 and 20 gestation weeks fetuses, allowed
a microanatomic visualization of bronchi and bronchioles
lumen and also the presence of per bronchial capillaries
(Fig. 3G). In 24 gestational weeks fetuses we concluded
that each terminal bronchiole branches off into two or
more alveolar sacks (primitive alveoli) (Fig. 3 H). When
examining with the x63 objective the alveolar sacks walls,
we noticed the presence of a flat epithelium consisting
Romanian Journal of Legal Medicine Vol. XXIII, No 2(2015)
Figure 1. A. Location and relations of hemochorial barrier, at the level of placental villosities; 24 weeks of gestation. B. Spatial
distribution of pulmonary blood vessels, alveolar ducts and alveolar sacks in the lung of a 24 antepartum week fetus.1. Spatium
intervillosum; 2. Branch of umbilical artery; 3. Mature intermediate villus; 4. Villus terminale; 5. Branch of pulmonary artery; 6.
Alveolar sack; 7. Alveolar duct; 8. Respiratory bronchiole. Paraffin sections. Hematoxyline-Eosin Stain. Macrophotographs taken
with Nikon Digital Sight DS-Fi1 High Definition Color Camera Head x 28 (A, B).
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Petru Razvan Melinte et al.Morphogen synergisms during antepartum synchronic evolution
Figure 2. A. Shape and limits of intervillous space in placenta at 24 weeks of gestation. B. Shape, location and communication
of alveolar ducts and sacks within fetal lung at 24 weeks antepartum. 1. Vascular-syncytial membrane; 2. Spatium intervillosum;
3. Alveolar duct; 4. Alveolar sack; 5. Type I pneumocyte; 6. Type II pneumocyte. Paraffin sections. Hematoxyline- Eosin stain.
Macrophotographs taken with Nikon Digital Sight DS-Fi1 High Definition Color Camera Head x 420 (A, B).
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Figure 3. Spatial distribution and relations of capillaries with argirofile collagen fibers and mucopolysaccharide within the
structure of placental terminal villosities (A-C). Relations of fibrinoid substance with syncytial bridges and trophoblastic buds (C,
D); Stages of evolution. Antepartum evolution stages of epithelio-mesenchymal relations within pseudoglandulary structure of
lung in 12 weeks old fetus (E). Canalicular structure in a lung from a 16 weeks old fetus (F, G); saccular structure in a lung from a
24 weeks old fetus (H); vascular networks within lung capillaries, in new-born (I).1. Muscle cells fascicles; 2. Syncytiotrophoblast;
3. Sinusoid capillaries inside terminal villosities shaped as “grapes”; 4. PAS-positive basal membrane; 5. Argirofile collagen fibers
fascicles, in the area of a “debit regulatory structure”; 6. Subendothelial basal membrane; 6. Trophoblastic bud; 7. Terminal
villosities; 8. Syncytial bridge; 9. Substantia fibrinoidea; 10. Lung with pseudoglandulary structure; 11. Perialveolar capillary
networks, injected with China ink; 12. Branch of pulmonary artery.Paraffin sections. Hematoxylin-Eosin stain (A; D-H). Reduced
Silver Nitrate Gomori Method (B). Toluidin Blue (C); China ink injection (I). Paraffin sections. Hematoxyline- Eosin stain.
Macrophotographs taken with Nikon Digital Sight DS-Fi1 High Definition Color Camera Head x 70 (D, F, I).; x 140 (A, B, E, H);
x 280 (C, G).
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Petru Razvan Melinte et al.Morphogen synergisms during antepartum synchronic evolution
Figure 4. Microanatomic structural adaptations of biologic membrane to the respiratory system in liquid environment: branchial
for aquatic environment (fishes) (A, B) and placental-hemochorial for blood (C-H). 1. Branchial filaments, with “fan-like”
disposition; 2. Branchiospines; 3. Branches of umbilical arteries; 4. Affluent branches of umbilical vein; 5. Dissected chorial blade;
6. Penetration spots of umbilical vessels branches, into subchorial compartment; 7. Lobular branch of umbilical blood vessels; 8.
“Fan-like” distribution of subchorial branches of umbilical vessels; 9. Lobular distribution of umbilical vessels.Macrodissection
of branchial system in trout (A, B). Macrodissection of umbilical vessels subchorial distribution (D, E, F). Visualization, after
Technovit injection, of umbilical (C) and subchorial (G, H) vessels. Macrophotographs taken with Canon EOS 1ds Mark II Digital
Camera. Macro Ultrasonic Lens EF 100mm, F/2,8.
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Romanian Journal of Legal Medicine Vol. XXIII, No 2(2015)
Figure 5. Tissue interrelations within placental terminal villosities in third gestational trimester. Relations of blood capillaries
with trophoblastic cells mesenchyme (A); Spatial distribution of argirofile collagen fibers within subtrophoblastic and
subendothelial basal membranes. 1. Vascular-syncytial membrane; 2. Cytotrophoblast; 3. Capillaries with sinusoid trajectory; 4.
Syncytiotrophoblast; 5. Subtrophoblastic basal membrane; 6. Subendothelial basal membrane. Parrafin sections. HematoxylinEosin Stain (A). Reduced Silver Nitrate Gomori Method (B). Microphotographs taken with Nikon Digital Sigh DS-Fi1 High
Definition Color Camera x 420 (A, B).
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Petru Razvan Melinte et al.Morphogen synergisms during antepartum synchronic evolution
of alveolar cells type 1 and from point to point, clear
cytoplasm cells, such as alveolar cells type 2. Capillary
network is well visible around alveolar sacks. This network
was visualized per alveolar, after injecting China ink to a 3
weeks newborn (Fig. 3 I).
C. Mesoscopic anatomic analysis of branchial
respiratory system in fish.
Branchial structures in fish were visualized after
sectioning the operculum at the level of implantation basis
(Fig. 4 A). Underneath each operculum, we visualized four
branchial arches. Each branchial arch consists of a bone
which inserts through “branchiospines”, branchial blades
dispose in fan-shape and contain highly vascularized
filaments (Fig. 4 B).
DISCUSSION
During the ontogenesis of human bio system the
respiratory gas exchanges are achived by two independent
organs – placenta and lungs – that are specially adapted
from anatomic and functional point of view to transfer
oxygen and carbon dioxide between the two identical
or different biocenosis. Placenta presents the respiratory
hemochorial barrier that plays an important role as the
embryo-fetus lung and is known as an “eco-ton area”
between the two liquid blood biocenosis, maternal and
fetal. It separates the maternal blood from the inter-villi
spaces, from the fetus blood inside the blood capillaries
of chorial villosities, and does not allow direct contact
between them. Lungs present the alveolar-blood barrier
and they are equally an “eco-ton area” between two
different biocenosis: air from pulmonary alveoli and blood
inside pulmonary vessels. Morphogenesis of lung takes
place in two successive stages: antepartum for the system
of alveolar sacs and postpartum for the alveolar system
that triggers the respiratory function. The antepartum
stage is contemporary with the morphogenesis and plain
function of placental structures. Their identification and
evaluation was difficult and controversial in the history
of knowledge regarding the functional anatomy of fetusplacenta system.
The first important observations on placenta
have been recorded in antique Greece. Diogenes from
Apollonia (around 480 BC) was the first to consider this
structure as a nutrition organ for the fetus. Aristotel (384322 BC) [1] signaled the presence of fetal membranes
and used the terms such as chorion and amnion. Galenus
(180-201) [2]believed there is a direct communication
between the maternal and fetus blood vessels. Anyway
the term of placenta was introduced later by Matteo
Renaldo Colombo (Columbus) (1559) [3]. Remarkable
progress in the knowledge of the functional structure
and relations regarding uterus-placenta and fetusplacenta systems was achieved after the diversification
of the research instruments and methods: dissection
of pregnant uterus (Leonardo da Vinci – 1492-1519)
128
[4];Andreas Vesalius (1543;1555) [5]; GiulioCezarAranzi
(1584)[7]); experimental methods for the understanding
of blood circulation (William Harvey (1628) [8]) and the
gas exchanges during respiration (John Mayow (1674) [9];
Joseph Priestly 1772) [10]; Antoine Lavoisier (1778) [11]);
the injection of blood vessels with marked substances
( William Hunter (1774) [12]; John Hunter (1786) [13];
Fillipo Civinni (1839) [14]); the invention of photonic
microscopy (Antony von Leewenhoeck ( 1632-1732)
[15]; Robert Hooke 1665) [16]); the visualization of blood
capillaries (Marcello Malpighi (1661) [17] – established
the anatomic basis regional arterial and venous blood
circulation).
Two problems have been on top of the list for
researchers: the relations between fetus-placenta and
mother-placenta blood vessels on one hand, and on the
other hand, the structure of placental villosities and the
functional evaluation of inter-villi spaces.The hypothesis
stated by Galenus that described a direct communication
between fetus and maternal blood vessels was resumed and
repelled by many scientists. Based on anatomic studies on
pregnant uterus, Leonardo da Vinci [4] sustained the idea of
no such thing as direct communication. While dissecting,
Alexander Mauro-Primus (1734) [18] observed that there
is no continuity regarding uterus and placenta vessels. He
noticed that the extremity of fetus blood vessels expand
beyond the base of placenta and pass inside depressions
of uterine decidua where they just touch maternal blood
vessels. In 1674, John Mayow [9] raised the problem of gas
exchanges inside placenta that he named as “uterine lung”.
After examining the anatomical specimens injected with
marked substances (red or blue wax), William Hunter
[12], John Hunter [13] and Fillipino Civinni [14] reached
to the same conclusion. Willian Turner (1872) [19] proved
that maternal blood circulates inside inter-villi spaces.
William Campbell (1833) [20] noticed that placenta must
be included in the fetus circulatory system; he makes a
parallel between cardiopulmonary circulation and cadiacfetus-placenta one.
The evaluation of placenta structural anatomy
was possible after the invention of photonic microscopy
(Antony van Leewenhoeck [15]; Robert Hooke [16]. Ernst
Heinrich Weber (1832) [21]was the first to describe the
microanatomic structure of placental villosities and to
notice that they contain branches of fetus blood vessels.
Mathias Duval (1892) [22] demonstrated the invasion of
uterus by placental tissue and its erosion by the trophoblast
of uterine spiral arterioles. Otto Grossen in 1909 and 1927
[23, 24], proposed the structural classification of placenta
after number and type of cellular layer which separates
maternal blood from fetuses one into: epitheliochorial,
syndesmochorial, endotheliochorial and hemochorial.
In 1870 and 1882 Langhans [25;26] demonstrated the
presence of two layers at the periphery of chorial villosities:
a peripheric one represented by syncytiotrophoblast and
an internal one represented by cytotrophoblast (“Langhans
Romanian Journal of Legal Medicine layer”). Harland Mossman [27, 28] in 1926 and 1987
demonstrated, from anatomic and functional point of
view, the existence of a reverse flow of maternal and fetal
circulations. March and Simon in 2011 [29] elaborated the
“turn-over” concept of trophoblastic cells and noticed the
role of apoptosis in placental morphogenesis.
Langhans [26], Wolska [30], Rohr [31] and
Nitabuch [32] draw attention over the fact that fibrinoid
substance is an important structural component of
placenta by its role in the phenotypic transformations
during placental epigenesis. Fose and Sebire [33] in 2007
proposed a placental lesions classification into four classes:
1. lesions determined by disturbances of blood flow
towards placenta via fetal-placental circulatory system;
2. lesions caused by disturbances of maternal blood flow
towards inter-villi spaces; 3. retroplacental hematoma and
non-vascular lesions.
Placental hemochorial and respiratory alveolarblood barriers impress by their structural simplicity, as
well as by time and space variability of structural elements
relations. Anatomic antepartum formation and evolution
of these barriers depends on interrelations and reciprocal
inductions between epithelium and mesenchyme.
Comparative microanatomic study of these two barriers
offers the argument in understanding the morphogen
synergisms, from the structural synchronal perspective.
In the morphogenesis of the two respiratory models
in human, there are stages during which epithelialmesenchymal interactions occur, which represent the
basis of ramification process: in lungs - ramification
of airways system by the participation of endodermic
epithelium and of pulmonary mesenchyme which assures
morphologic differentiation of collagen fibers fascicles
and the formation of perialveolar capillaries networks;
in placenta - ramification of chorionic villous system
due to the contribution of trophoblastic epithelium in
implantation process inside uterine tissue and delimitation
of inter-villi space, and due to the extraembryonary
mesenchyme implication in genesis and differentiation
of extracellular matrix and of vascular capillary network
inside villi. These interactions assure the antepartum
formation of respiratory system structures: placenta,
adapted to gas exchange between blood-liquid biocenosis
and pulmonary, adapted to the gas exchange between two
different biocenosis - air and blood - liquid that becomes
functional in postpartum.
Saunders et al. [34] in 1957 observed that
mesenchyme is responsible for induction specificity into
competent ectoderm. Competence represents the capacity
to respond to an inductive signal (Wadington, 1940) [35].
Experimental embryogenesis researches, performed by
Alescio and Casini (1962) [36] allowed the assessment of
mesenchyme major role in the formation of pulmonary
sprouts. During respirator pulmonary system, regional
specificity of mesenchyme induction has an important
role (Dragoi et al. 2010) [37]. Signal molecules involved
Vol. XXIII, No 2(2015)
in these dynamic and reciprocal interactions between
epithelium and mesenchyme are poorly known. It
appears that FGF10 is a signal molecule correlated to the
formation of bronchus branches; it is expressed inside me
mesenchyme located above the developing buds (Bellusci
et al., 1997) [38].
The respiratory biologic barriers from the structure
of placenta and lungs are the consequence of reciprocal
induction and interrelations epithelium-mesenchyme
during the antepartum part of morphogenesis (Dragoi et
al. 2007) [39].
The pulmonary alveolar-blood barrier is part
of the structure of pulmonary alveoli. The structures
derived from mesenchyme forming the alveolar wall
– blood capillaries and type IV argirofile collagen
fibers – can be found inside this barrier. Collagen fibers
participate to the formation of capillary subendothelial
and sub-pneumocyte basal membrane and they are part
of common septal space. It continues to the conjunctive
sheath of bronchi and blood vessels. Blood capillaries
are incorporated inside the alveolar wall after the fusion
of their basal membrane to the subendothelial basal
membrane. Thus, the alveolar-capillary membrane or
alveolar-blood barrier is formed; inside its structure one
can easily identify epithelial structures (pneumocytes),
endothelial structures (capillary endothelium) and the
two basal membranes subendothelial and subepithelial,
reunited as a double basal membrane.
The placental hemochorial barrier is part of
the structure of terminal placental villi; similar to the
pulmonary alveolar wall, one can find trophoblast
epithelial cells, endothelial cells inside the walls of villi
sinusoid capillaries and type IV collagen fibers that
can be observed using reduced silver nitrate Gömöri
method; collagen fibers appear as sub-trophoblast and
sub-endothelial basal membranes that fuse in the subtrophoblastic area (Fig. 5).
Comparative analysis of placental respiratory
system in human to the branchial respiratory system in
fish draws the attention to a functional similarity between
the human placental villosities structure and filaments of
branchial lamellas in fish (Fig. 4).
Conclusions
1. The comparative study of the epigenesis of
hemochorial and alveolar-blood respiratory barriers
brings arguments for understanding the synergisms
during its morphogenesis.
2. The convergence of genesis and antepartum
evolution of these biological barriers is synchronous to
their functional divergence.
3. The placental hemochorial barrier represent an
adaptation for surviving in a blood liquid environment
and in Homo Sapiens, it represents the equivalent of
branchial respiratory system in fish.
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Petru Razvan Melinte et al.Morphogen synergisms during antepartum synchronic evolution
4. The pulmonary alveolar-blood barrier
represent an adaptation for surviving in air environment
and consequently it does not function antepartum.
5. The structural elements of respiratory barriers
take part in achievement of their morphologic and
functional homeostasis.
6. Blood capillaries networks have different
locations inside the two barriers: inside villi in placenta
and around alveoli in lungs.
7. The pattern for conjunctive-vascular relations
is identical in the two types of barriers and it is determined
by the reciprocal induction between epithelium and
mesenchyme.
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