Ultrastructure of the human first trimester decidua:
nature and distribution of collagen fibrils in the
extracellular matrix of decidua basalis and parietalis
Sinai Talaulikar V1, Bax BE2, Page N3, Manyonda I1
1
Dept. of Obstetrics and Gynaecology, Division of Clinical Sciences, St. George’s University
of London, Cranmer Terrace, Tooting. London - UK. SW17 0RE
2
Dept. of Child Health, Division of Clinical Sciences, St. George’s University of London,
Cranmer Terrace, Tooting. London - UK. SW17 0RE
3
School of Life Sciences, Kingston University, Penrhyn Road, Kingston Upon Thames,
Surrey - UK. KT1 2EE
Corresponding author
Mr. Isaac Manyonda (Consultant and Hon. Reader), Department of Obstetrics &
Gynaecology, St George’s Hospital and University of London, Cranmer Terrace, Tooting,
London – UK. SW17 0RE Telephone: 00442087253663 Fax: 00442087255958 Email:
imanyond@sgul.ac.uk
Running title: Ultrastructure of extracellular matrix of decidua basalis and parietalis.
Abstract
Background
The human embryo-maternal interface in the first trimester of pregnancy is an area of rapid
tissue remodelling in which the extravillous trophoblast cells of the placenta invade the
uterine decidua basalis and inner third of the myometrium. Collagen is a major constituent of
the extracellular matrix of the placental bed, and successful invasion of decidua basalis and
myometrium by the trophoblast must involve its rapid turnover. We sought to describe the
nature and distribution of collagen fibrils in the first trimester human decidua and look for
any differences between ultrastructure of extracellular matrix of decidua basalis (with
trophoblast invasion) compared to decidua parietalis (without trophoblast).
Methods
Biopsies of the placental bed (decidua basalis with myometrium) and decidua parietalis were
obtained distinctly under direct hysteroscopic vision from 7 healthy women undergoing first
trimester surgical termination of pregnancy. These were subjected to morphological
assessment by light and transmission electron microscopy followed by
immunohistochemistry using mouse monoclonal antibodies against Cytokeratin7 and
Collagen types I, III and V. Scanning electron microscopy images were obtained of the
collagen fibrils surrounding decidual blood vessels.
Results
Collagen fibrils in the stroma and myometrium of decidua basalis were thicker (56.46 +/16.97 nm) as compared to decidua parietalis (45.28 +/- 11.33 nm) between 9 to 12 weeks
gestation (p value <0.0001). There were no differences in fibril diameters across the placental
bed between stroma and myometrium. The distribution of the collagen fibrils varied between
the two decidua – fibrils appeared broken and disintegrated at most places surrounding the
decidual/trophoblast cells and in between the muscle cells in basalis while a uniform regular
arrangement was preserved throughout most of the parietalis tissue. Plenty of amorphous
tissue adjacent to the cells and collagen fibrils in recesses or deep invaginations near cell
surface were a common finding in decidua basalis. Occasional giant and spiny collagen fibrils
were noted in both decidual types. The immunohistochemistry findings were similar in DB
and DP which showed Type I collagen to be the most abundant form found throughout the
stroma and myometrium forming a rich network along with type III collagen fibrils.
Conclusion
Thickness and distribution of collagen fibrils of decidua basalis differ from decidua parietalis
in the first trimester of pregnancy between 9 to 12 weeks. While the ultra structure of decidua
basalis comprises of thicker and disintegrating collagen fibrils within abundant amorphous
tissue, the decidua parietalis maintains a largely uniform distribution of thinner fibrils. These
changes may reflect either an adaptation response by the decidua or a direct effect of the
invading extravillous trophoblast cells within the placental bed and may play an important
role in regulating the depth of trophoblast invasion.
Key words
Decidua, basalis, parietalis, collagen, extracellular, matrix, trophoblast, ultrastructure
Introduction
Over the last few decades, the role played by extracellular matrix (ECM) components in
maintenance of tissue homeostasis has become increasingly evident. Not only is the ECM
important in providing structural stability to various tissues and organs but its various
components actively participate in and regulate a wide range of physiological/pathological
processes within the human body (Lin CQ and Bissell MJ, 1993; Madri JA and Basson MD,
1992; Haralson MA, 1993). An understanding of early events in human placentation has the
potential to shed light on disorders such as miscarriage, intrauterine growth restriction,
placenta accreta and pre-eclampsia (PE) where defective trophoblast invasion into the
placental bed is thought be the underlying pathology. The role of ECM and its breakdown by
the invading extravillous trophoblast (EVT) has therefore gained wide attention in recent
times especially in relation to the myometrial spiral artery remodelling (Burrows TD et al,
1996). Collagen is a major component of the ECM of the placental bed and the interstitial
EVT cells should overcome this barrier in order to infiltrate the placental bed successfully.
Ethical constraints and technical difficulties associated with human early pregnancy tissue
sampling have hampered research into the differences in ultrastructure of the ECM of human
decidua basalis (DB) in comparison to decidua parietalis (DP). We obtained distinct biopsies
of DB and DP under direct hysteroscopic vision to compare the nature and distribution of
collagen fibrils in the ECM.
Methods
We obtained DB and DP biopsies from 7 healthy women undergoing first trimester surgical
termination of pregnancy (TOP). The research was approved by the South West London
Research Ethics Committee (REC Ref no. 10/H0803/4) and all women gave informed written
consent for the biopsy procedure. Inclusion criteria were gestational age 6 to 12 weeks as
determined by ultrasound scan, singleton pregnancy, absence of any medical disorders in the
patient and patient age 18 years and above. The biopsies were obtained as previously
described using a novel hysteroscopic direct vision technique to ensure accuracy of sampling
of DB and DP (Sinai Talaulikar V et al, 2012). Biopsies were split into two portions and
those destined for light microscopy and immunohistochemistry studies were immediately
fixed in formalin, routinely processed and embedded in paraffin. For electron microscopy, the
samples were fixed in 4 % glutaraldehyde in 0.2 mol/l sodium cacodylate buffer (pH 7.2). A
single blinded investigator (KK) processed the tissue samples and performed the
histology/electron microscopy staining procedures using standard protocols.
Immunohistochemistry with immunoperoxidase method - serial sections (5 microns) cut
on the microtome were stained with haematoxylin and eosin (H&E) to assess the morphology
of the decidua. Picrosirius red staining was carried out to visualise the network of connective
tissue fibres around the decidual glands and vessels. Immunohistochemistry was performed
using an indirect immunoperoxidase method with mouse monoclonal antibodies to identify
trophoblast (anti-cytokeratin 7 and 17, Invitrogen, UK) or various collagen types (anticollagen type I, III and V, Abcam, UK). For immunohistochemistry, sections were
deparaffinised in xylene and rehydrated by sequential rinses in absolute, 90%, 70%, and 50%
ethanol. Endogenous peroxidase activity was exhausted by incubation with 1% hydrogen
peroxide for 30 minutes. Antigen retrieval was performed using enzymatic (trypsin) digestion
for type I collagen and microwave treatment in citrate buffer pH 6.0 (Invitrogen, UK) for
other antigens. Nonspecific binding was sequentially blocked with 3% bovine serum albumin
in Tris buffered saline (TBS) for 30 minutes and Protein Block (DAKO, UK) for 10 minutes.
After blocking, slides were incubated in mouse primary antibody for 4 hours at room
temperature. Slides were washed in TBS and further incubated in secondary biotinylated goat
anti-mouse antibody (Invitrogen, UK) for 30 minutes at room temperature and then in
horseradish peroxidase-streptavidin (Invitrogen, UK) for 15 minutes. Immunostaining was
developed using diaminobenzidine (DAB) and haematoxylin was used as a counterstain.
Non specific IgG staining was used for control slides.
Transmission electron microscopy (TEM) - Small tissue samples were excised and fixed at
room temperature overnight in 4 % glutaraldehyde in 0.2 mol/l sodium cacodylate buffer (pH
7.2). Samples were then washed twice for 30 min in 0.2 mol/l sodium cacodylate buffer
followed by a 2 hr post-fixation in 1% osmium tetroxide in 0.2 mol/l sodium cacodylate
buffer. After a 30 min wash in 0.2 mol/l sodium cacodylate buffer, samples were stained enblock for 30 minutes in 3% alcoholic uranyl acetate. Samples were dehydrated through an
ascending series of ethanol, 35%, 70%, 90% for 30 min each with two 30 min changes in
dried ( held over molecular sieve) absolute ethanol. Tissue was then transferred into
propylene oxide for 30 min followed by overnight infiltration in 50/50 propylene oxide resin
mix ( TAAB low viscosity resin ) followed by twice 1hr infiltration in 100% resin and final
embedding with overnight polymerisation at 60 degrees C.
Semi-thin 2-micron sections were stained with alkaline toluidine blue (1% dye in 1% borax)
to show fixation quality and tissue orientation. Thin sections were cut at 90 nm using a
diamond knife and were mounted on uncoated 200 mesh copper grids, pre-treated with 1%
aquaeous potassium permanganate (KMnO4), stained with uranyl acetate, contrasted with
Sato's lead citrate and viewed in an Hitachi 7100 TEM equipped with GATAN multi scan
digital camera and images were taken with the software program Digital Micrograph.
Each grid was examined in Hitachi electron microscope at 12000x magnification followed by
examination of random areas at 6000x to 150000x magnification. On some occasions the
magnification was increased to 200000x. Measurement callipers provided within the GATAN
software were used and at least four areas at different corners were examined in each grid. 46 measurements were obtained in each of these areas from longitudinal as well as cross
sections of fibrils at a magnification of 150000x and means calculated. Circular or almost
circular profiles of the cross-sectioned fibrils near the centre of the electron micrograph were
chosen for measurement. In fibrils that had irregular profiles, the greatest diameter was
measured. The observations were recorded into Graphpad Prism 5 datasheet and statistical
analysis was performed using unpaired and paired t test with Welch’s correction wherever
required depending on the groups being analysed.
Scanning electron microscopy (SEM) - Fixed tissue was processed for routine wax
embedding and sectioned at 6 microns. Sections were dewaxed and rehydrated through a
series of ascending concentrations of ethanol (50% to 100 %) and stained using picrosirius
red to determine the presence of collagen in the sample. For SEM visualization of collagen,
some of the dewaxed and rehydrated wax sections were impregnated in 1% tannic acid, postfixed in 1% osmium tetroxide, washed in 0.2 mol/l sodium cacodylate buffer, dehydrated
through a series of ascending concentrations of ethanol and critical point dried using an
Emitech K850. Samples were then mounted on stubs and sputter-coated with a thin layer of
gold using a BioRad E5000 sputter coater. Samples were viewed with a Cambridge
Stereoscan 360 and images were taken with the software program Image Access (ver.3).
Results
Biopsies of DB and DP from 7 women between 6+4 weeks to 11+6 weeks of gestation were
utilised in the study. No patient related complications occurred in association with the
hysteroscopic biopsy procedure.
Light microscopy – Typical decidual morphology with arterioles and glands as well as
presence of abundant collagen fibres were confirmed in decidual biopsies using H&E and
picrosirius red staining (Fig. 1 and 2). Presence of cytokeratin 7 positive extravillous
trophoblast was confirmed in DB by immunohistochemistry (Fig. 3). The distribution of
collagen types I, III and V in the decidua was described using immunohistochemistry (Fig. 46). In both DB and DP, type I collagen appeared to be the most abundant form found in the
stroma between glands and vessels along with type III collagen. Type V fibres were mainly
concentrated around the blood vessels.
Transmission electron microscopy (TEM) – Extensive collagen fibril network was
identified in both types of decidua, filling up most of the intercellular spaces within the
decidual stroma and the myometrium (Fig. 7 and 8). Except on rare occasions cross sections
of the collagen fibrils showed regular profiles and longitudinal sections exhibited typical
collagen cross banding (Fig. 9 and 10). A rich investment of collagen fibrils was also noted
surrounding arterioles and glands within the decidua (Fig. 11 and 12).
Thickness of collagen fibrils - Tables I-IV summarise the results of comparison of mean
diameters of collagen fibrils measured in DB and DP at various gestations. Collagen fibrils in
the stroma of DB were significantly thicker (56.46 +/- 16.97 nm) and showed more variation
in size as compared to DP (45.28 +/- 11.33 nm). The same trend was also noted when
collagen fibrils in myometrium beneath DB were compared to that of DP (56.39 +/- 9.84 nm
versus 48.30 +/- 13.61). However this difference was noted only between the gestational ages
of 9 to 12 weeks. In cases 8 weeks or less, there was no statistically significant difference
when collagen fibril diameters were compared in the stroma and myometrium between DB
and DP (Tables I and II). We did not find any difference in thickness of collagen fibrils
across the placental bed (Table III). There were also no differences in diameters when
perivascular collagen fibrils were compared with the rest of the intervening stroma in DB
(Table IV).
Distribution of collagen fibrils within the ECM - The distribution of the collagen fibrils
varied between the two decidua. While it was common to find broken or disintegrated
collagen fibrils surrounding the decidual/trophoblast cells and in between the muscle cells in
basalis (Fig.13), a uniform or regular arrangement was preserved at most places in the
parietalis tissue (Fig. 14). Plenty of amorphous tissue adjacent to the cells and collagen fibrils
in recesses or deep invaginations of the cell surface were also frequently seen in DB (Fig. 1518).
Other findings – Occasional giant fibrils, spiny collagen fibrils as well as irregular cross
section profiles (spiraled collagen) were noted in both DB and DP (Fig. 19-21). Proteoglycan
particles which were seen as electron dense material surrounding the collagen fibrils were
especially notable in areas where thin collagen fibrils appeared next to decidual cells (Fig.
22).
Scanning electron microscopy (SEM) – The SEM findings confirmed a rich investment of
decidual arterioles by thick collagen fibrils (Fig. 23-28) running in various directions.
Discussion
The haemo-chorial nature of human placentation characterised by trophoblast invasion of the
placental bed makes the embryo-maternal interface in the first trimester of pregnancy, an area
of extensive tissue remodelling. As invasion proceeds, the EVT must overcome the barriers
within the ECM to successfully reach the inner third of the myometrium and transform the
spiral arteries. Collagens are abundant proteins which make up one-quarter of the mammalian
protein mass and form a major component of the ECM. Fibrillar collagens (types I, II, III, IV,
V) are the most abundant collagens and function as structural proteins, but they have roles in
developmental biology and cellular functions like growth, differentiation, adhesion and
migration (Byers PH, 2000). The human uterus shows a gradual and progressive increase in
content of collagen during pregnancy. Quantitative collagen determinations demonstrate an
increase of approximately 800 per cent in the collagen content of the human uterus at term as
compared with the non-pregnant state. Following parturition, there is a rapid resorption of
collagen. The amount of collagen which disappears from the post partum uterus is
approximately 53 gm (Morrione TG and Seifter S, 1962). We compared the collagen fibrils in
decidua basalis versus parietalis to look for any significant differences in their size and
distribution.
Our results showed significantly thicker collagen fibrils in the stroma of DB and myometrium
of placental bed as compared to DP. This difference of 7-10 nm between the fibrils was
observed between 9-12 weeks of pregnancy. When we compared the diameters of fibrils in
the stroma of DB and myometrium within the placental bed, there were no significant
differences. Similarly, a comparison of fibrils in the perivascular region versus rest of the
stroma within the DB also showed no differences. Our findings concur with previous reports
from studies in mice which have demonstrated thick collagen fibrils in the ECM surrounding
decidual cells from the fifth day of pregnancy onwards. The region of mature decidual cells
showed the thickest fibrils reaching 370 nm in diameter (Zorn TM et al, 1986; AlbertoRincon MC et al, 1989). It has been suggested that large decidual collagen fibrils arise by
lateral association of smaller diameter fibrils (Carbone K et al, 2006). We found such
thickening at 9 weeks of gestation and beyond implying that the deposition of thick collagen
fibrils in the DB may be contributing to better support for the growing embryo as the
gestation advances. Alternatively it could be serving the functions of nutrition or formation of
a local barrier from the immune cells within the placental bed. It is also tempting to speculate
that the thick collagen may itself act either as a stimulus for EVT invasion or possibly prevent
over invasion by the interstitial EVT.
The distribution patterns of collagen fibrils within the ECM varied between DB and DP. We
observed that collagen fibrils were often found in recesses or deep invaginations of
the decidual cell surfaces throughout the DB, a finding that has also been reported in animal
studies by other investigators (Welsh AO and Enders AC, 1985; Katz SG, 2005). On the
other hand, the parietalis tissue was characterised by large well organised bundles of collagen
fibrils at most places throughout stroma and underlying myometrium. The widespread
disruption of collegen in the ECM in DB could be attributed to the action of matrix
metalloproteinases (MMPs) and other proteases secreted by the decidual cells and
trophoblast. Animal studies and in vitro studies using human trophoblast have also
demonstrated phagocytosis of collagen by decidual cells and extravillous trophoblast, and the
findings in DB could represent an early step during this process (Katz SG, 2005, Choy MY
and Manyonda IT, 1998; Manyonda IT and Choy M, 1999). However it should be born in
mind that any such conclusions about phagocytosis purely based on the morphological
studies alone are inadequate due to possibility of processing/sectioning tissue artefacts and
need conformation by co-culture experiments or immunohistochemistry.
Granular or amorphous deposits and filamentous aggregates in between stromal cells were
another characteristic feature noted in both DB and DP (although much more frequent in DB
than DP). The exact nature of these deposits is unknown but they may represent the residues
left after extracellular degradation of collagen and ground substance by release of various
lysosomal enzymes like MMPs by the decidual cells and EVT.
In both DB and DP, type I and III collagen fibrils formed a rich network within the ECM.
Kisalus et al reported similar findings using immunofluorescence in human first trimester
decidua (Kisalus LL et al, 1987). We also observed that type V fibrils were mainly
concentrated around structures such as blood vessels. Spiess K and Zorn TM used
immunogold localisation to show that both thin and thick collagen fibrils present in the
mouse pregnant endometrium were formed by type I, III and V collagens. Type V collagen
was predominant in the thick collagen fibrils and almost absent in the thin fibrils (Spiess K
and Zorn TM, 2007). Aplin JD et al also reported that type III and type V collagens and
fibronectin were present in endometrial stroma throughout the menstrual cycle as well as in
the human first trimester decidua (Aplin JD et al, 1988). Other studies have shown that type
V collagen is masked by type I collagen in heteropolymeric fibrils and that type V collagen
may regulate the diameter of the major type I collagen fibrils (Fitch JM et al, 1984).
Although we did not observe morphological differences in distribution of proteoglycan
particles in the ECM of DB and DP, it is interesting to consider their possible role in light of
the findings of thicker collagen fibrils described in DB. Collagen fibrillogenesis is a complex
molecular process coordinated by factors such as the types and amounts of
glycosaminoglycans and proteoglycans associated with collagen molecules (Prockop DJ and
Kivirikko KI, 1995; Ghosh AK, 2002). Biglycan and decorin are two small leucine rich
proteoglycans (SLRPs) which are intimately related with collagen organisation and turnover
within the ECM. Immunocytochemical electron microscopy studies have shown that biglycan
is associated with the presence of thick collagen fibrils in mouse decidua while decorin is
associated exclusively with thin collagen fibrils in non-decidualised endometrial areas. (San
Martin S and Zorn TM, 2003). It has been well established that remodelling of ECM during
decidualisation includes alterations in the expression and distribution of four members of the
SLRP family. Close correlations with changes in collagen fibril morphology indicate a
functional association between these proteoglycans and collagen deposition. Some authors
have suggested that decidual proteoglycans influence cell growth and differentiation in
the pregnant uterus directly and modulate local growth factor availability (Sam Martin S et al,
2003). Decorin deficient mice have abnormal morphology of collagen fibrils consisting of
variability in size and irregularity of shape (Danielson KG et al., 1997). In the decorin
knockout mouse, the decidualised stroma of the uterus shows abnormal architecture with
large diameters and irregular contours of the endometrial collagen fibrils (Sanches JC et al,
2010). It is possible that decrease in concentrations of SLRP such as decorin is a prerequisite
to successful trophoblast invasion as it brings about alteration of collagen fibrils within the
decidual ECM. The resulting milieu of reduced decorin with thick disorganised collagen
fibrils may be one of the factors which favours the trophoblast invasion into the decidua DB
and the spiral vessels within it.
We acknowledge some of the shortcomings of our study. Our sample size was small,
therefore larger numbers will be needed in future studies to confirm the differences in fibril
diameters between DB and DP. We also did not differentiate the samples based on age and
ethnicity but both these factors could affect the results due to differences in nature of collagen
in these subtypes.
Modifications of decidual ECM and pathological pregnancies
ECM has been expected to play a significant role in embryo implantation and development
(Kadler K, 2004; Aplin JD, 2008). It is likely that any disturbance in the normal development
of the decidual matrix in the early pregnancy can have a significant impact on the success or
failure of the pregnancy. The human EVT encounters the collagen in the ECM and has to
negotiate this macromolecule to invade the placental bed to a sufficient depth in order to
transform the myometrial spiral arteries. The interactions between EVT and collagen
therefore appear important in following situations –
1) Pre-eclampsia (PE): Research in PE has been focused on defective trophoblast invasion
of maternal spiral arteries leading to failure of physiological widening of the vessels and
consequent resistance to the blood flow. It is not known what causes the deficient trophoblast
invasion. We believe that the nature or distribution of collagen fibrils in the ECM and
adventitia of the spiral vessels in DB may be one of the determining factors.
A number of observations from research and epidemiological studies lend support to this
hypothesis –
i) It is know that PE does not recur in all pregnancies (recurrence rate of about 15% in
second pregnancy). The overall risk of having proteinuric PE diminishes in a second
pregnancy suggesting that the protection conferred by the first pregnancy was effective
against repeat PE (Makkonen N et al, 2000). Women who have PE late in pregnancy towards
term often have no recurrence or mild disease in subsequent pregnancies. Higher recurrence
rates are seen in women with a previous preterm PE and those who develop early onset
severe PE (Mostello D et al, 2008; Hernandez-Diaz S et al, 2009) It is possible that the
women who develop PE late in first pregnancy often have the advantage conferred by the
distension of uterus at term (stretching of decidua and myometrium) that alters the orientation
of collagen fibres and thus favours a better trophoblast invasion in the future pregnancies.
While women with early onset severe PE often develop the need to be delivered at preterm
gestations, and thus may escape the benefit of uterine distension and collagen fibril
reorientation, only to recur in a severe form in a subsequent pregnancy. Interestingly, the
protective effect of a previous pregnancy seems to abate with long inter-pregnancy interval
(Trogstad L et al, 2011) which again is compatible with the suggestion that the collagen in
the uterus undergoes gradual reorganisation over the years and modifies the risk of PE.
ii) PE is very severe when it recurs and black women are affected more than white or
Hispanic women (Mbah AK et al, 2011). Among nulliparous women, black women have a
risk of PE that is twice as high as that of white women (Trogstad L et al, 2011). Studies have
also shown that keloids are more common in Asians (5.2%) and in African Americans (7.1%)
than in whites (0.5%) (Tulandi T et al, 2011). Both these observations suggest underlying
differences in collagen structure and modifications in different ethnic groups.
iii) In a large population-based retrospective cohort study in Canada, multiple regression
analysis showed that one single prior abortion was associated with a slightly decreased risk of
PE (adjusted odds ratio 0.84; 95% CI 0.72 to 0.97) suggesting that decidual scarring (altered
collagen) may favour trophoblast invasion in future pregnancy (Xiong X et al, 2002).
Another study into the effect of previous induced abortions and recurrent miscarriages on
incidence of PE in 20,846 primiparous women participating in the Norwegian Mother and
Child Cohort Study also found that two or more induced abortions reduced the risk of PE
significantly (odds ratio 0.36; 95% CI 0.18 to 0.73) (Magnus P et al, 2006).
iv) The content of decorin, biglycan and versican in the umbilical cord vein wall is elevated
in PE in comparison to the corresponding control vessel. These alterations may affect the
mechanical properties of this vessel and disturb foetal blood circulation. (Gogiel T et al,
2007).
v) Not only is decorin concentration in decidua determinant of collagen diameters and
profiles, but decorin itself negatively regulates proliferation, migration and invasiveness of
human extravillous trophoblast (EVT) cells in a TGF beta independent manner (Iacob D et al,
2008).
2) Morbidly adherent placenta (MAP): It is believed that in placenta accreta, there is
defective interaction between maternal tissues and migratory trophoblast in the early stages of
placentation resulting in deep trophoblast penetration into the uterus. The following
observations strongly suggest a role for scarring or altered collagen and associated SLRPs in
pathogenesis of MAP –
i) Although there is debate whether a defective decidua or abnormal trophoblast is the
primary factor in placenta accreta, the strong association of placenta acreta with a history of
prior caesarean sections and endometrial curettage suggests a role for uterine scarring. A
localised decidual defect resulting from surgical intervention is thought to be the rationale for
the increased incidence of placenta accreta in such women (Wu S et al, 2007).
ii) Case reports of placenta accreta following pelvic or whole body irradiation or following
chemotherapy, (Pridjian G et al, 1990; Norwitz ER et al, 2001; Van Thiel DH et al, 1972)
which most likely would affect the decidualisation process or the vasculature in the placental
bed point to a primary defect in decidualisation.
iii) A recent study demonstrated that induced decidual injury significantly increased the
invasion potential of trophoblastic cells compared with intact decidua. Complete
reapproximation of the incised edges of the decidual slice reversed this effect in vitro (Garmi
G et al, 2011) suggesting an association between decidual trauma and trophoblast invasion.
iv) Yet another study demonstrated that ECM thickness modulates morphology and
proteolytic activity of the trophoblast (Kliman HJ and Feinberg RF, 1990).
v) The results of a histopathology study of normal, normotophic and hypertrophic/keloid
scars showed that compared with all three types of scars, the collagen orientation index was
significantly lower in normal skin, which indicated that scars are organized in a different
albeit more parallel manner (Verhaegen PD et al, 2009).
vi) Studies have shown that hypertrophic scar tissue from burn patients contains abnormally
reduced amounts of decorin in comparison with normal dermis or mature scar (Honardoust D
et al, 2011). The lack of decorin may account for the poor organization of collagen fibrils in
the nodular areas of these scars.
vii) The striking feature of placenta accreta is the finding of the larger radial and arcuate
arteries showing pregnancy-induced changes, a morphological change usually confined to the
smaller spiral arteries – this finding again suggesting overinvasion by trophoblast (Khong TY
and Robertson WB, 1987; Tantbirojn P et al, 2008).
It appears that the type and architecture of components of the decidual and myometrial
extracellular matrix as well as loss of inhibitory molecules may be central to pathogenesis of
placenta accreta. All the above observations suggest that a change in decidual collagen fibril
size and arrangement due to scarring accompanied by altered SLRPs concentrations can
influence or control the depth of trophoblast invasion.
‘Over-invasion’ versus ‘under-invasion’ by the trophoblast – Morbid adherent
placentation represents one extreme of trophoblast invasion where by the EVT infiltrate the
uterine wall beyond physiological limits. One could speculate that relative decorin deficiency
and altered organisation or size of collagen fibrils due to decidual scarring could play an
important role attracting an ‘over-invasion’ by the EVT. On the other hand, persistence of
decorin and thin collagen fibrils may have the opposite effect where the EVT will fail to
invade to a sufficient physiological depth into the placental bed leading to ‘under-invasion’–
a situation present in preeclampsia. The relative expression SLRPs such as decorin at various
stages of the gestation could hold a key to the ECM composition and thus indirectly regulate
the trophoblast invasion.
Conclusion
Decidual ECM undergoes considerable modifications during pregnancy and the interactions
between the trophoblast and ECM are important in early pregnancy when the trophoblast
growth and invasion must be critically controlled. The ability to obtain accurate distinct
biopsies of DB and DP allowed us to study the differences in collagen size and distribution in
the extracelluar matrix of human first trimester deciduas in details. While the ultra structure
of decidua basalis comprises of thicker and disintegrating collagen fibrils within abundant
amorphous tissue, the decidua parietalis maintains a largely uniform distribution of thinner
fibrils between 9-12 weeks. These changes may reflect either an adaptation response by the
decidua or a direct effect of the invading extravillous trophoblast cells within the placental
bed and may play an important role in regulating the depth of trophoblast invasion.
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