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Pregnancy |
Department of Anatomy, University of Cambridge, Cambridge CB2 3DY, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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decidua, developmental biology, placenta, syncytiotrophoblast, trophoblast
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The zone nearest the chorionic plate is the labyrinth zone (Lz), and in structure, this closely resembles a maze or labyrinth. Within this zone, the maternal and fetal circulations are closely approximated, and so this represents the principal site of hemotrophic exchange [3]. Maternal blood flowing through irregularly shaped spaces (MBS) is separated from fetal blood circulating within the fetal capillaries (FC) by an interhemal membrane (LIM) comprising two layers of syncytial trophoblast and a superficial layer of cytotrophoblast cells. Together these provide a selectively permeable barrier between the two circulations. Due to its obvious importance in fetal survival and development, the Lz is the focus of this article, although brief consideration has been given to other placental zones.
Surrounding the Lz is a layer comprising fetal spongiotrophoblast cells and trophoblast glycogen cells. Together they represent the junctional zone (Jz) of the mouse placenta. The role of this zone is not understood [3], but in its absence, the embryo cannot survive [4]. Initial invasion of the mouse blastocyst into the maternal uterus is controlled in part by the trophoblast giant cells (TG). Initially, these appear as a continuous layer at E12.5 (E1.0 = day of the vaginal plug) but this becomes discontinuous later in development [5]. These cells represent the most distal fetal component of the mouse placenta and abut the maternal decidua basalis (db).
Formation of the chorioallantoic placenta begins just before midgestation in the mouse. In this article, we are not addressing the establishment of the placenta but rather are quantifying the subsequent growth of the different components and estimating the theoretical diffusional properties of the definitive chorioallantoic placenta. Although studies of gene expression are being conducted to elucidate the function of distinct trophoblast lineages [6], the mechanisms underlying development of the placenta and the ways by which its community of cell types interact remain largely unknown. Targeted genetic manipulation is a powerful tool that can contribute to our knowledge of the roles of specific genes [7], but full interpretation of the results requires a detailed consideration of the morphology of the mutant placenta. Despite the growing number of mouse lines with mutant placental phenotypes, little systematic quantitative analysis of the morphology of the normal chorioallantoic mouse placenta has been performed. Such a database would aid researchers studying mouse development by allowing a precise description of structural abnormalities of dysmorphic placentas and relating these to function.
Stereology is a well-established method for generating absolute three-dimensional quantities, such as volumes, surface areas, and lengths of complex tissues from two-dimensional histological sections [8]. It has been designed for the efficient, unbiased, quantitative, and meaningful analysis of biological structures [9]. Its application has been well used in the past for describing tissue composition with a view to increasing knowledge of the physiology and architecture of such organs as the kidney and brain [8]. In the area of human placentology, there has been a plethora of articles that have incorporated stereological techniques in order to compare and describe, quantitatively, normal and abnormal placentas (for a review, see [10]).
Few stereological studies have been conducted on the placentas of small laboratory rodents, and those that have been performed neglected the advantages of resin embedding [11, 12], a practice common in electron microscopy. There are three advantages to this technique. First, the shrinkage associated with this process is negligible, and so the use of assumption-based correction factors for surface and length densities is avoided. Second, the resolution is far greater than for paraffin sections, allowing precise identification of cell boundaries for measurement purposes (Fig. 1). Finally, this improved resolution permits the unambiguous identification of cell types without the need for immunohistochemistry. Unfortunately, however, the exhaustive sectioning necessary for using the Cavalieri principle cannot be performed on resin-embedded material, so absolute volumes of the reference space must be obtained using paraffin sections.
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In this article, we have designed a method for analyzing physical details of the developing chorioallantoic mouse placenta that are of direct physiological importance. The method encompasses the use of both paraffin- and resin- embedded material and stereological techniques for maximizing the accuracy and precision of the measurements. We have used this method to describe the normal development of the labyrinth zone, and estimate the physical determinants of the interhemal membrane for gaseous exchange at different gestational ages.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The C57BL/6J inbred mouse was chosen, as it is a standard laboratory strain used in genomic analysis and experimental breeding strategies. All experiments were carried out in accordance with the UK Government Home Office licensing procedures. Matings were set up using virgin females (Harlan, Oxon, UK) between 6 and 8 weeks old and housed under controlled laboratory conditions with a 12L:12D photoperiod. One fetus and placenta were taken from each uterine midhorn (avoiding runts at the ovary position and biasing selection of embryos by weight) from at least three litters per stage, in accordance with the findings from early studies [13–15]. Where there were fewer than three or greater than seven fetuses in a horn, no material was taken. Stages E12.5, E14.5, E16.5, and E18.5 were the time points used (E1.0 = day of the vaginal plug). Weights were recorded for all selected embryos and placentas. Placentas were then hemisected using a double-edged razor blade, each half was weighed, and then immediately fixed.
Histology
Half of each placenta was fixed in 4% paraformaldehyde in 0.1 M PIPES buffer, dehydrated, and embedded in paraffin wax. Using a rocking microtome, the placental halves were exhaustively sectioned; 7-µm vertical sections (the chorionic plate providing the theoretical horizontal plane) were cut and transferred to slides. Systematic random sampling [9] was used to select, without bias, sections for analysis. Sections to be analyzed were stained using a standard hematoxylin and eosin (H&E) protocol (Fig. 1) [16].
Corresponding placental halves were fixed for 6 h with 4% glutaraldehyde in 0.1 M PIPES buffer, washed with 0.1 M PIPES buffer, and treated with 1% osmium tetroxide. The postfixed tissue was washed in 0.1 M PIPES buffer and dehydrated. This was followed by washes in propylene oxide, propylene oxide:Spurr resin (1:1), and Spurr resin:propylene oxide (2:1), then overnight flat embedding in 100% Spurr epoxy resin (Taab, Aldermaston, U.K.). Spurr resin was changed three times over 3 days, and the castings were thermally cured at 60°C for 24 h.
Sections, 1 µm thick, close to the placental midline were stained with Methylene blue and used in analysis in conjunction with the paraffin- embedded counterparts (Fig. 1).
Stereology
The Computer Assisted Stereology Toolbox (CAST) 2.0 system from Olympus (Ballerup, Denmark) was used to perform all measurements.
Absolute Placental Volume
To determine the absolute volume of placentas, a 32-point grid was superimposed on vertically orientated paraffin sections viewed using a 1.25x objective lens enabling a view of the complete sample. Points falling on the sample were counted and the Cavalieri principle was applied in order to reach a volume estimate [17]:
 | (1) |
P is the sum of points on sections. Shrinkage during the paraffin-embedding process was assessed by measuring the diameter of 100 randomly selected erythrocytes in placentas at the various stages of gestation and comparing this value to that obtained by measuring fresh maternal erythrocytes to attain a shrinkage factor [18, 19]. Placental volume was corrected accordingly.
Volume of Placental Components
Meander sampling is a function of CAST that allows random fields of view within a sample to be identified. Using the 10x objective lens, 12 fields of view on the sections used for determining the absolute placental volume were selected by meander sampling and measured by point counting to estimate component densities of the three zones (Lz, Jz, and db) using the equation
 | (2) |
Labyrinth Analyses
Resin sections were used to resolve the labyrinth vasculature in detail. A 100x objective lens was used and 12 fields of view within the Lz were selected by meander sampling to determine volume densities, surface densities, length densities, and interhemal membrane thickness. Shrinkage associated with resin embedding was considered insignificant at 1.08% and was assessed by comparing the mean diameter of 100 erythrocytes in the resin-embedded placentas with fresh maternal erythrocytes [21].
Volumes
Volume densities of the MBS, FC, and trophoblasts were obtained using a point grid as described previously. Volume densities were converted to absolute component volumes by multiplying by the volume of the Lz.
Surface Areas
Vascular surface densities for the MBS and FC were obtained using a grid formed of cycloid arcs placed over each field of view and intercepts between maternal blood space boundary and fetal capillary boundary were counted. The following equation was used to determine surface areas:
 | (3) |
I(struct) is the total number of intersections of the cycloid arcs with the structure, P(ref) is the total number of points that hit the reference space, and I(p) is the length of the test line associated with each point in the grid [22]. All surface area densities were converted to absolute surface areas by multiplying by the volume of Lz. Mean Capillary Length and Diameter
Capillary length densities were obtained using a counting frame with two contiguous forbidden lines [23] and the 60x objective lens. The number of capillary profiles observed was recorded and so the numerical density of capillary profiles per unit area of labyrinth QA could be determined. From this, the length density of fetal capillaries Lv(cap) could be derived as
 | (4) |
The mean capillary cross sectional area could be calculated from
 | (5) |
 | (6) |
Interhemal Membrane Thickness
Thickness of the interhemal membrane of the Lz was obtained with a line grid to establish a random start point for measuring distances between fetal capillaries and the closest maternal blood space by the method of orthogonal intercepts [24].
Harmonic mean thickness (Th) requires one to produce a reciprocal of the mean of the reciprocals of the intercept distance across a membrane, and to multiply by the correction factor (8/3)
to correct for plane of sectioning [25].
Morphometric Diffusing Capacity of the Interhemal Membrane
The theoretical diffusion capacity for the interhemal membrane was calculated using the equation
 | (7) |
Statistical Analysis
The results from each litter were averaged, and data were subsequently analyzed on a litter basis. One-way ANOVA followed by Fisher protected least significant difference post hoc test was used to test for significant differences between the different gestational ages and to identify homogenous groups that are represented by asterisks on all the graphs (significant P values range from <0.05 to <0.0001). Mean data are expressed ± SEM.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Placental weight reaches a maximum by E16.5, whereas fetal weight increases exponentially between E12.5 and E18.5 from 38 to 942 mg (Table 1).
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Volumes of the Developing Mouse Placenta
Absolute placental volume mimics placental weight through gestation, and by E16.5, the maximum volume of the placenta has been reached (0.104 cm3). This is not necessarily the case for all the components within the placenta (Table 2). Expansion of the Lz increases its volume by 
4 times between E12.5 and 18.5, with most of this increase occurring in the first two time periods (Table 2). The proportion of the placenta that the Lz represents continues to increase up to E18.5 (Fig. 2).
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Volume expansion of the Jz is not as dramatic as that of the Lz, although there is a doubling from E12.5 to E16.5. There then follows a significant reduction in the Jz volume from 0.030 cm3 to 0.025 cm3 at E18.5 (Fig. 2 & Table 3), and this is reflected in a fall in the volume fraction from 29% to 24% between E16.5 and E18.5 (Fig. 2).
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There is no significant change in the volume of the decidua over the time points analyzed.
Development of the Maternal Blood Spaces in the Placental Labyrinth
Most of the expansion in MBS volume occurs between E14.5 and E16.5, with a doubling from 0.0034 to 0.0078 cm3. There is no difference in volume between E12.5 and E14.5 and equally no difference between E16.5 and E18.5. (Table 2).
The surface area of the MBS correlates with its volume. Between E12.5 and E14.5, MBS surface area is constant at 7 cm2, followed by a three-fold expansion between E14.5 and E16.5, with the value reaching 23.41 cm2, after which no further significant increase takes place (Table 4). Viewing the surface densities of the MBS, one can clearly see a period of dramatic surface expansion taking place between E14.5 (267 cm2/cm3) and E16.5 (489 cm2/cm3) (Table 3).
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Development of the Fetal Vasculature in the Placenta
The dynamics of fetal capillary angiogenesis are different from those of MBS development. Between E12.5 and E14.5, fetal capillary volumes are not significantly different, and hence there is an initial quiescent first phase. From E14.5 however, volume expansion occurs in a linear fashion until E18.5 (from 0.0040 cm3 to 0.0139 cm3) (Table 2).
FC surface area expansion is continuous throughout the time points. There is a statistically significant threefold increase in surface area between E12.5 (2.44 cm2) and E14.5 (9.32 cm2). FC surface area then doubles to 20.1 cm2 by E16.5, followed by a further significant expansion of surface area to 27.0 cm2 by E18.5 (Table 4).
Two further parameters of the capillaries are considered here. These are total capillary length and mean capillary diameter. The results for early fetal capillary development show that there is little increase in capillary length between E12.5 and E14.5. Elongation becomes significant by E16.5, when there is a significant 59 m increase in total capillary length. Like other fetal parameters, the total capillary length continues to increase significantly from E16.5 to E18.5, when it reaches almost 154 m (Table 4).
Mean capillary diameter is derived from surface area and volume, and assumes that the vessels take the form of uniform cylinders. It can thus only give an approximation of the true situation. Nonetheless, a dramatic change can clearly be seen with gestational age. The mean capillary diameter initially remains steady between E12.5 and E14.5 at 14 µm, but from E14.5 to E16.5, capillary remodeling reduces the mean diameter such that, after this period, the mean diameter remains steady at 11 µm (Table 4).
Development of the Labyrinth Interhemal Membrane
The volume of the labyrinth interhemal membrane (LIM) (expressed as trophoblast volume) increases as the placenta develops. Between E12.5 and E16.5, there is a significant increase in the volume of the LIM from 0.011 cm3 to 0.031 cm3. After E16.5, when total placenta volume ceases to expand further, the LIM volume remains unaltered (Table 2).
Another parameter critical to placental physiology is the thickness of the interhemal membrane. The harmonic mean barrier thickness emphasizes the presence of thin areas of the LIM that are of key importance for the effective diffusion of solutes. The barrier is most dynamic between E12.5 and E16.5, with a statistically significant reduction in Th of about 50% during this period. By E16.5, the final thickness of 4.4 µm is reached and no further reduction occurs (Table 4).
Theoretical and Specific Diffusing Capacity of the Interhemal Membrane
The theoretical diffusion capacity indicates the potential of the labyrinth interhemal membrane for passive diffusion. In our calculation, we have used the Krogh diffusion coefficient for oxygen, but the value for other gases or solutes can be easily substituted into the formula. There is a significant increase in the theoretical diffusion capacity from E12.5 to E18.5 (Table 4 and Fig. 3), reflecting the changes in both surface area and thickness.
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The specific diffusion capacity calculated here is a measure of how effective the interhemal membrane of the placenta is at meeting fetal needs. There is a clear initial steady phase between E12.5 and E14.5 without significant alteration in membrane conductance. The architecture of the interhemal membrane then changes such that it is achieving its maximum specific diffusion capacity at E16.5 (0.021 cm2 min–1 kPa–1 g–1). By E18.5, however, the diffusion capacity of the membrane per gram of fetus has fallen by 50% (Table 4 and Fig. 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In terms of surface area and volume, most development of the MBS occurs between E14.5 and E16.5, preceded and succeeded by relatively quiescent periods. Discounting changes in maternal blood pressure and hence rate of flow, the volume of maternal blood that can circulate through the placenta is therefore maximal by E16.5. This suggests that MBS development is sufficient at this stage to allow the necessary maternal blood flow through to term. In contrast, expansion of FC volume continues until at least E18.5, suggesting a need for continually greater volumes of fetal blood to exchange with the maternal circulation in order to obtain enough nutriment and oxygen for fetal growth. The capillary expansion is illustrated first by the earlier linear expansion of fetal capillary surface area and subsequently by the increasing total capillary length. The latter suggests either elongation or branching of the capillary network, but one cannot distinguish between these two effects based on the measurements performed here. A further indication of fetal vascular remodeling is supported by the reduction in mean capillary diameter between E14.5 and E16.5.
Thin barriers with large surface areas minimize the diffusion distance and maximize the area for passive exchange. An example of an organ, the function of which relies on these principles, is the mammalian lung. These functional requirements have to be balanced, however, with the structural requirements for maintaining the integrity of the organ. The lining of the alveoli of the lung is therefore uneven, providing support and surfactant production via thick areas and optimum diffusion distance via thin areas [28]. In the same way, one can associate increased Lz surface area and decreased interhemal membrane thickness with an increased diffusion capacity necessary for exponential growth of embryonic tissues. It has been shown experimentally by Smith et al. that the diffusing capacity of the guinea pig placenta is a function of its surface area [29]. Harmonic mean thickness is a more critical determinant of the diffusion capacity of the placenta, and even slight decreases in membrane thickness can have a positive effect that cannot be achieved by a comparable change in surface area or volume [30].
Surface area and thickness of the interhemal membrane are distinct in their development. There is initially a progressive reduction in barrier thickness that ceases by E16.5. After E14.5 and until E16.5, there is an expansion in surface area, which is continuous through fetal capillary remodeling. This is an interesting finding which might be explained by the difference in growth pattern of the fetus and placenta. During the period from E12.5 to E14.5, the fetus is still relatively small and therefore has a small total blood volume. If the surface area of the interhemal membrane and capillary volume were first to increase (rather than the membrane thinning), this would necessitate a far greater extracorporeal circulation for the fetal heart to perfuse. The way in which FC network develops may thus prevent strain on the developing fetal heart. Furthermore, if the interhemal membrane remained thick at first, this would perturb diffusion of substances to the fetus. Thus, our results show continuous surface area expansion occurring after barrier thinning begins. This is due to FC remodeling to provide a larger passive exchange area and perhaps a larger area to accommodate more molecular transporters to meet fetal growth demands after E14.5.
Here the theoretical diffusion capacity of the trophoblast membrane was calculated. This does not equate with true placental diffusing capacity, as it does not take into account oxygen dissociation from the maternal erythrocytes, uptake by the fetal erythrocytes, and diffusion across the relevant plasma interfaces [23, 30]. However, calculations reveal that the interhemal membrane accounts for approximately 90% of the overall resistance to transplacental diffusion, and thus represents the major determinant of diffusing capacity [30]. No experimental data on placental diffusion capacity are available for the mouse, so we are unable to compare our calculations with physiological data. However, work on the guinea pig, in which placental diffusion capacity for carbon monoxide was measured physiologically as well as stereologically, provides a good correlation between the two types of measurement [31].
Expressing the theoretical diffusion capacity per gram of fetal tissue allows one to compare the ability of the placenta to support fetal growth at different gestational ages and is standard practice in the field of placental stereology [32]. Our results indicate that the maximum ability is achieved at E16.5, but that this then falls by approximately 50% by E18.5. In the past, the concept of a placental reserve has been much discussed [33], and in pathological situations, considerable loss of placental tissue can occur without impact on fetal growth. It is possible, therefore, that the reduction in specific diffusion capacity (taking into account fetal mass) represents a reduction in this reserve capacity. This applies to diffusional transfer only, and for materials transported by active processes the situation may be different. The continual increase in fetal capillary surface area could provide space for more transporter proteins on the fetal side of the membrane, sustaining fetal growth. Nonetheless, one might expect a greater imbalance between placental supply and fetal requirements for oxygen toward term, leading to fluctuations in local concentrations and placental oxidative stress [34]. It is notable that we have recently reported immunohistochemical evidence of oxidative stress within the labyrinth zone that is first observed at day E17 and is compatible with a hypoxia-reoxygenation-type injury [35].
One further striking feature emerges when comparing the specific diffusing capacity of the interhemal membrane of the mouse placenta at E18.5 (0.01 cm2 min–1 kPa–1 g–1) with that of the lowland human placenta at term (0.0096 cm2 min–1 kPa–1 g–1) [36]. Although the placentas have a very different structure, labyrinthine versus villous and hemotrichorial versus hemomonochorial, the results indicate that they have the potential to operate with almost identical efficiency. This again indicates the value of quantitative data describing structural parameters of physiological importance rather than making assumptions based on gross morphology alone.
This is the first study to provide extensive quantitative structural data describing development of the definitive mouse placenta. The methodology presented here outlines the structural framework for materno-fetal exchange against which physiological measurements could be performed. They also provide the basis for further investigation and elucidation of the effects of specific genes on the development and growth of the definitive placenta. This in turn will provide insights into the regulation of physiological processes in the placentas of mice and man.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence. FAX: 01223 333786; gjb2{at}cam.ac.uk
Received: 13 October 2003.
First decision: 5 November 2003.
Accepted: 12 January 2004.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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