- Open Access
Intercellular wireless communication network between mother and fetus in rat pregnancy-a study on directed and weighted network
© The Author(s). 2019
- Received: 7 March 2019
- Accepted: 23 April 2019
- Published: 1 May 2019
The maternal body forms a wireless communication system with the embryo through the blood circulation system. Obviously, direct sampling from early embryos is damaging. Therefore, we detected changes in the concentrations of 30 signaling molecules in serum from the pregnant rats at the 14 time points, then the intercellular wireless communication network was established, to explore the regularity of signal communication between mother and fetus.
Method of study
We used liquid chip scanning technology to detect 30 signal molecules at 14 time points. Statistical analysis of the data yielded significant change signal molecules. According to the secretory cells and effector cells involved in signal molecules, the communication network of different stages were drawn by using Biograph software.
The process could be divided into 4 periods including early, middle, late pregnancy, and postpartum. In early pregnancy, two immune transformations occur: (a) interleukin-10 (IL-10), interleukin-13 (IL-13) increased at day 5, which promoted immunoglobin G (IgG) secretion, provided protection through the neonatal Fc receptor for IgG (FcγRn) crossing the placental barrier to reach the embryo, achieved T helper 1 (Th1) transformation into T helper 2 (Th2), reduced maternal innate and cellular immunity, and prevented fetal abortion; (b) the fetal heart was fully developed at day 7, with circulatory system established, which provided a platform for intercellular information exchange. The second transformation corresponded to the maternal immune system providing signaling molecules for the embryo to promote Th2 transformation into Th1, thus activating embryonic innate immune cells, and enabling antibody-mediated immune recognition, response and protection. Days 9–19 was a stable period. After 21 days of pregnancy, the maternal body prepared for delivery. The characteristic signaling molecules in the process were monocyte chemotactic protein-1 (MCP-1), IL-10, IL-13, IL-1ɑ, interferon-inducible protein-10 (IP-10), regulated upon activation normal T cell expressed and secreted (RANTES), thyroid stimulating hormone (TSH), IL-2, IL-6, IL-12p70 and IL-18.
Detection of concentration changes of the factors in maternal serum could provide a tool for monitoring, diagnosis, prediction and treatment of embryo differentiation, development and health.
- Cell–cell communication network
- Communication between mother and fetus
Embryonic development is a process of strict communication between mother and fetus, and healthy fetal development is significant for procreation and reproduction of a population. Studies have shown that mammalians have regulated embryo-fetal development, that is, embryonic stem cells are strictly induced and modulated by signaling molecules, especially cytokines, during differentiation and whole developmental process [1–3]. In other words, maternal body forms a wireless communication system with the embryo through the blood circulation system, so during embryo development, cytokines provided by the maternal body to the fetus are extremely important for fetal growth and development. Obviously, direct sampling from early embryos is damaging; therefore, in the present study, by detecting changes in the concentrations of 30 signaling molecules in serum from the pregnant rats at the 14 time points, a directed and weighted network, an intercellular wireless communication network between mother and fetus, was drawn by a software developed by our research group. Information exchange between mother and fetus should precede development and differentiation of fetal morphology; therefore, fetal differentiation, development and health could be monitored based on changes in the concentrations of characteristic signaling molecules in maternal serum at each time points, which could help achieve timely prevention and treatment.
All animal procedures in this study were approved by the Biomedical Engineering Institute of Academy of Medical Sciences of China in accordance with the guidelines about Animal Care of the Medical Sciences of China. Female and male Sprague-Dawley rats, aged 60 days (weighing 205-221 g), were purchased from the Animal Center of Academy of Military Medical Sciences of People’s Liberation Army. Rats were maintained under controlled lighting (12 h light-12 h dark cycle) and temperature (22 °C) with ad libitum access to food and water. Female were fed a standard rat chow for 2 weeks before being mated with age-matched Sprague-Dawley males fed the same diet. Copulation was confirmed by the presence of sperm in a vaginal flush; the day of copulation was designated as gestational day 1. After copulation, female and male rats were separated.
Experimental design and sampling
1 mL blood was collected from the eye sockets of five female rats before being mated as the control. Blood sample was collected respectively from the five female rats at 3 pm on the gestation days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, and days 1 and 3 after delivery; a total of 14 time points (70 female rats were used). After clottting, the samples were centrifuged at 1000 r/min for 10 min and the serum was separated. Serum samples were stored at − 20 °C for later use.
Detection of main signaling molecules
The Liquichip workstation liquid protein chip system, a new type of protein research and analysis platform, can be used to simultaneously detect multiple molecules in same sample, as the flexible Muti-Analyte Profiling (xMAP) technology. The Liquichip workstation organically integrates colored microspheres, laser technology, fluidics and the latest mathematical signal processors, and computer programming algorithms. This technology has the characteristics of unparalleled detection specificity, sensitivity and operability.
Abbreviations and full-names correspondence table
the neonatal Fc receptor for IgG
T helper 1
T helper 2
monocyte chemotactic protein-1
regulated upon activation normal T cell expressed and secreted
thyroid stimulating hormone
granulocyte macrophage-colony-stimulating factor
granulocyte colony-stimulating factor
macrophage inflammatory protein 1 alpha
tumor necrosis factor-alpha
vascular endothelial growth-factor
brain derived neurotrophic factor
The SPSS 17.0 was used to pass the normal distribution test (Kolmogorov-Smirnov), and the data conforming to the normal distribution was compared with the control experiment results by the comparative t-test. The non-conformity data was subjected to the nonparametric test, and the 95% confidence interval was selected (As shown in Table 3). All data were expressed as the mean ± standard deviation.
Establishment of an intercellular communication network model
Est represents the communication effect between secretion cells and target cells; s represents whether the cell was able to secrete cytokines i, the value should be 1, or else 0; t represents whether cell was the target cell of cytokines i, the value should be 1, − 1, or else 0; p represents the statistical significance of cytokine (P < 0.05), the value should be 1, or else 0.
Communication effect of the secretion cells on the target cells
Target cells of cytokines
Secretion cells of cytokines
Signaling molecules with significant changes
Signal molecules that showed significant changes during this period
Rate of change in concentration
Statistical analysis method
Changes in the intercellular wireless communication network
Early pregnancy (days 1–7; equivalent to the first trimester of human pregnancy)
Time correspondence between rats and humans in the whole process
The pregnancy stages
The 1st day
The 5th day
The 7th day
The 9th day
The 1st day
Th3 rd day
The 1st month
The 2nd month
The 3rd month
The 4th month
The 5th month
The 6th month
The 7th month
The 8th month
The 9th month
Mid-pregnancy (days 9–19, equivalent to pregnancy months 4–8 in humans)
Late pregnancy (days 21–23, equivalent to pregnancy months 9–10 in humans)
At pregnancy day 23, ACTH and BDNF levels were markedly reduced. As shown in Fig. 5, the activity of maternal nerve cells was inhibited, indicating that the mother was about to give birth.
At 3 days postpartum, the maternal body entered lactation period, and PRL increased significantly, promoting and maintaining maternal lactation.
Characteristic signaling molecules at each time points of pregnancy
At pregnancy day 7, characteristic signaling molecules included IL-1α and IP-10, with rates of concentrations change of 14.4 (P < 0.05) and 5.11 (P < 0.05), respectively. At pregnancy day 7, the fetal heart was fully developed and fetus had circulatory system, which provided a platform for intercellular information exchange. At this time, innate and cellular immune activities in embryo needed to be activated, and maternal IgG molecules were used to mediate the immune response to foreign antigens, thus providing fetal protection. Therefore, maternal body needed to produce Th1-type cytokines, such as IL-1α and IP-10, and to complete Th2 transformation into Th1. In addition, a study demonstrated a mutual promotion effect between IP-10 and IFN-γ to some extent, which can decrease Th2 activity . When these two cytokines are decreased in levels, fetal innate immunity is likely not activated, and the fetus is unable to provide protection for itself, resulting in abortion. During pregnancy, fetal health and development can be monitored and even treated by detecting the concentrations of these two cytokines.
At pregnancy day 19, characteristic signaling molecule with significant increase was TSH; the rate of concentration change was 1.79 (P < 0.01). A study pointed out that TSH content in maternal body in early pregnancy is the lowest, increasing gradually after entering stable period . This might be due to the amounts of thyroid hormone from maternal body increasing as the fetus develops gradually in mid-pregnancy; the negative feedback regulation significantly increases TSH levels in maternal body . By measuring TSH levels in maternal body, we could assess fetal growth and development.
At pregnancy day 21, characteristic signaling molecules with significant increase were IL-2, IL-6, IL-18 and IL-12p70, with rates concentration change of 2.77 (P < 0.05), 0.755 (P < 0.05), 3.33 (P < 0.05), and 1.11 (P < 0.05), respectively. IL-2, IL-6 and IL-18 belong to Th1-type inflammatory cytokine family. Sennstrom suggested that when maternal body is close to delivery, IL-6 amounts are increased significantly, probably because mature expansion of the cervix is a physiological inflammatory reaction . During whole pregnancy, IL-18 amounts were higher, and after childbirth started, it further increased until delivery end, before decreasing thereafter.
Correlation analysis of the whole process at different time points
A significant positive correlation was found at pregnancy days 9, 17 and 19. During this period, GH was altered significantly, with rates of concentration change of 4.05 (P < 0.05), 4.19 (P < 0.05) and 3.72 (P < 0.1), respectively. As mentioned above, during this period (pregnancy days 9–19) embryo grows rapidly, and maternal body must secrete large amounts of GH to promote fetal growth and development. Therefore, fetal growth and development could be monitored by detecting GH in maternal serum. In case of low GH content, fetal growth could be promoted by injection of adequate GH amounts.
There was a highly positive correlation between pregnancy days 1 and 15, and LH changed significantly on both days, i.e. 0.694 (P < 0.05) and − 0.59 (P < 0.05), respectively. In early pregnancy, LH was increased, playing an important role in oocyte maturation and ovulation; at day 15, LH was decreased significantly.
This study showed that communication of signaling molecules (such as cytokines, chemokines, hormones) between mother and fetus mediated the strict interactions of the fetus at various time points of implantation, differentiation, development and delivery, to maintain balance and adaptation of immune and endocrine activities between mother and fetus. In early pregnancy, IL-6 levels were decreased (not significantly), but increased significantly at day 21 of pregnancy. The possible mechanism is that in early pregnancy, IL-6 decreases in order to prevent maternal immune rejection of embryo; however, with pregnancy time, IL-6 amounts in maternal serum increases gradually. In late pregnancy, cervical collagen fibers were swollen, curled and fractured, while the cervix was softened, shortened and relaxed, similar to acute inflammation. These results corroborated Barrat . Sennstrom et al., who found a gradual IL-6 level increase in amniotic fluid as the number of pregnancy days increases .
TNF-α regulates corpus luteum throughout the whole pregnancy, and appropriate amounts of TNF-α in pregnant women can promote catabolism. TNF-α in fetus plays an important role in the proliferation, division and immune protection of embryonic cells [25, 26]. As shown above, with the progression of pregnancy, TNF-α levels in rat serum were gradually decreased, but not significantly in comparison with pre-pregnancy amounts. Monzón-Bordonaba F et al. confirmed that low TNF-α concentration can promote energy metabolism and embryonic development in pregnant women, and improve the synthesis of progesterone and chorionic gonadotropin, which is beneficial to reduction of the extracellular matrix of decidual cells and placental implantation . This plays an important role in the maintenance of pregnancy. Large amounts of TNF-α secreted during pregnancy can stimulate apoptosis in human amniotic cells and syncytiotrophoblasts, leading to thrombosis and inflammatory response, blood vessel injury, and embryonic death . Although without significant difference, the downtrend observed also showed that TNF-α might play a regulatory role in many aspects of the reproductive process.
A study suggested that IFN-γ produced by NK cells during mouse pregnancy is an important factor in the maintenance of normal pregnancy . The present study showed that in late pregnancy, IFN-γ levels in serum were increased gradually as the number of pregnancy days increased. In addition, IFN-γ also enhances apoptosis in amniotic cells and trophoblasts activated by TNF-α, induces the activity of lymphokine-activated killer cells(LAK cells) treated with IL - 2, and promotes interleukin-2 receptor(IL- 2R) expression in T cells, which play an important role in the immune response [30, 31]. It is speculated that the mechanism of action might be a dynamic equilibrium process of maternal and fetal immune response and regulation from pregnancy to delivery. The gradual increase in the level of IFN-γ, as a Thl-type cell factor, plays an immune protection role at delivery.
During normal pregnancy, Th1/Th2 has a Th2 pattern shifted to humoral immunity, the so-called “Th2 phenomenon”, which means that maternal body during pregnancy tends to develop humoral immunity with the involvement of Th2-type cytokines, avoiding cellular immunity with the involvement of Th1-type cytokines . When this ratio shifts in favor of Th1-type cytokines, damage of placental trophoblast cells and fetus might occur, leading to abortion . Recent studies have found that in a variety of pathological pregnancies, such as pregnancy-induced hypertension syndrome and recurrent spontaneous abortion (RSA), the Th1/Th2 pattern in peripheral blood and placenta of patients is shifted to Th1 [34, 35]. Successful pregnancy is associated with increased levels of Th2-type cytokines secreted by lymphocytes [36–38]. This indicates that local immunity at the mother-fetal interface and the Th1/Th2 balance in maternal immune system play important roles in maintaining immune balance during normal pregnancy. IFN-γ, TNF-α and IL-6 belong to Th1-type cytokines . By analyzing changes in serum IFN-γ, TNF-α and IL-6 amounts in pregnant rats, this study found that as the number of pregnancy days increased, IFN-γ, TNF-α and IL-6 amounts were significantly decreased in comparison with control levels, which fully demonstrates that the process of pregnancy is indeed dominated by Th2-type cytokines.
A series of physiological changes occurred in NK cells during pregnancy, which play an immunomodulatory role in endometrium by secreting a variety of cytokines, and participate in embryo implantation, growth and development, as well as early placental formation. A study found that the number of NK cells increases from the 1st week of pregnancy, peaking in the 3rd month of pregnancy, and gradually decreases, indicating that maternal cellular immune function during pregnancy is in a certain degree of inhibitory state . In addition, Matsubayashi et al. found that the killing activity of NK cells in maternal peripheral blood is negatively correlated with pregnancy outcome ; the stronger the killing activity of NK cells in maternal peripheral blood before pregnancy, the higher the abortion odds, indicating that appropriate inhibition of the killing activity of NK cells in maternal peripheral blood during pregnancy is beneficial to the maintenance of pregnancy, as shown in this study that the total activity of NK cells increases in early pregnancy, and decreases in mid- and late pregnancy [42, 43].
In a word, changes in the concentrations of 23 cytokines and 7 hormones in serum samples from pregnant rats at the 14 time points were detected in this study, and variation trends of levels of all cytokines and hormones before and during pregnancy, as well as antenatal and postpartum were obtained. A directed and weighted network was used to quantitatively evaluate changes in intercellular wireless communication network between mother and fetus. This network could clearly reveal the process and pattern of wireless communication between mother and fetus through the placenta. In addition, by introducing parameters such as the output strength (Sout), input strength (Sin) and total strength (Stotal) of nodes, as well as overall network strength (Snet), the wireless communication between mother and fetus during the whole pregnancy could be quantitatively described. Monitoring, diagnosis and treatment of fetal growth, development, differentiation and health based on changes in characteristic signaling molecules in maternal body at various time points could provide a new method and tool for maintaining maternal and embryonic health during pregnancy, ensuring normal delivery.
In early pregnancy, two important immune transformations occur. The first occurs at day 5, i.e. Th1 transformation into Th2. In order to prevent fetal abortion, maternal innate and cellular immunity are inhibited, and embryo implantation as well as subsequent development and differentiation are protected; therefore, humoral immunity is enhanced significantly, which promotes the secretion of IgG, which crosses placental barrier through FcγRn and is transported to fetus, providing fetal protection. At day 7, the fetal heart is fully developed, and fetus has circulatory system which provides a platform for cellular signal communication. At this time, the second transformation occurs: the maternal immune system provides a signaling molecule for the embryonic circulatory system to promote Th2 transformation into Th1 as well as the development and differentiation of fetal innate and cellular immune cells, playing roles in immune recognition, response, and protection of embryonic innate immune cells mediated by maternal IgG (ADCC).
Characteristic signaling molecules throughout whole pregnancy were MCP-1, IL-10 and IL-13 (day 5), IL-1ɑ and IP-10 (day 7), RANTES (day 17), TSH (day 19), IL-2, IL-6, IL-12p70 and IL-18 (day 21). These findings indicated that diagnosis, prevention and treatment of fetal growth, development, differentiation and health could be monitored by detecting changes in concentrations of specific signaling molecules in maternal serum at various time points. However, further investigation is required to explore whether these findings are applicable to humans.
This research was financially supported by “The National Science Foundation of China (31671857, 31371773)”.
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
MZ and TL performed the experiments and acquired the data. MZ performed the data analysis and revised the manuscript. All authors read and approved the final manuscript.
All animal procedures in this study were approved by the Biomedical Engineering Institute of Academy of Medical Sciences of China in accordance with the guidelines about Animal Care of the Medical Sciences of China.
Consent for publication
The authors declare that they have no competing interests.
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