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Maternal-embryonic communication

The generation of an individual of the human species begins with the process of fertilization, which occurs in the distal third of the fallopian tube.

From the union between a sperm and an egg arises the diploid monocellular zygote, which through multiple divisions is transformed into a blastocyst that travels to the uterus through the oviduct.

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Both the transfer of the embryo and its implantation in the endometrium require multiple synchronized and harmonic processes that are orchestrated by a dynamic molecular dialogue between the mother and the embryo, and that involves a complex interaction of signals that are essential to successfully conclude the pregnancy.

For a pregnancy to reach term, it needs this continuous molecular dialogue between mother and embryo, and whose language is based on endocrine and paracrinous factors. Despite the knowledge gained, much remains to be discovered regarding how these factors affect genes in the developing organism.

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Estrogen, progesterone, and posterior effectors govern stromal differentiation and endometrial remodeling, making it receptive for implantation. The embryo also sends several signals to the mother, in the form of extracellular vesicles that carry miRNA and other material, to which the mother responds. The exact routes of communication are not well understood and further exploration is needed.

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Endocrine factors

Hormones such as Estradiol E2 and progesterone P4 are crucial from uterine receptivity to implantation, decidualization and birth.

These hormones command the chronological transitions of these events, affecting various growth factors, transcription factors, cytokines, and cell cycle regulators involved in the course of pregnancy.

Studies in mice have shown that epithelial loss of estrogen receptor 1 (Esr1) shows implantation failures and abnormal expression of estrogen-related genes. Mice with a specific epithelial loss of the progesterone receptor(Pgr)donot respond to P4 treatment and are infertile due to defects in embryo adhesion and  decidualization  of stromal cells.

Paracrine: cytokines and chemokines

Little is known about the paracrinous factors that regulate pregnancy. To study these factors, studies have been carried out in murine models where changes at the level of maternal blood signaling molecules throughout pregnancy were analyzed. The greatest change in the levels of signaling molecules occurs in the third trimester, while moderate changes occurred in the first  trimester and relatively few in the second trimester.

 

During the first 7 days of pregnancy, levels of luteinizing hormone (LH) and brain-derived neurotrophic factor (BDNF) increased and decreased respectively. In this period the fusion between sperm and egg occurs, forming the fertilized egg that will move from the oviduct to the uterus sending stimulating signals to prepare the endometrium for the implantation of the blastocyst.

Levels of monocyte chemotactic protein 1 (MCP1), interleukin-10 (IL-10), IL-13, and growth-related oncogene (GRO) have been observed to rise on day 5 (equivalent to the second month of human pregnancy). In addition, maternal inhibition of T helper  1 (Th1) lymphocytes and activation of Th2 lymphocytes occur, in order to inhibit the mechanisms of maternal immunological   rejection. However, by day 7, when the fetal heart is fully developed, the opposite occurs, Th2 is transformed into Th1 (by regulating and expressing transcription factors), with the aim of activating innate immunity in the embryo.

Inaddition, it has been documented that, in mice, more than 30 types of cells are involved in this molecular dialogue demonstrating alterations in the level of signaling molecules in the maternal serum (such as cytokines, chemokines and hormones) at various points in pregnancy, starting from  preimplantation.

 

In humans, colony-stimulating factor-1 (CSF-1)would be promoting the differentiation  of trophoblast cells into syncytiotrophoblast cells and guiding placental lactogen production. Several metalloproteinases are involved in the invasive capacity of the fetal trophoblast, in particular MMP2 and MMP9. Trophoblastic PMPs are regulated in response to tumor necrosis factor alpha(TNFa),IL-1b, IL-1a, leptin, transforming factor b (TGFb),macrophage colony-stimulating factor (MCSF), and endothelial growth factor (EGF), which are secreted at the maternal-fetal interface of different cells. Endometrial extracellular matrix (ECM) remodeling is essential for successful implantation and placentation.

Extracellular vesicles and their charge

It was recently shown that extracellular vesicles (ELs) play a role in paracrine communication between mother and embryo. These ELs comprise a range of membranous compartments that differ in biogenesis, size, and charge, activating surface receptors on target cells, fusing with the cell membrane, and releasing their contents. The charge of ELs (proteins, lipids and miRN)reflect the physiological state of the cell of origin and this property has been exploited in the search for biomarkers of various pathologies.

ETs have become of interest in the growing field of maternal-embryonic communication. Data have accumulated showing key functions before conception, from gamete maturation to implantation and during pregnancy. Studies have shown  that the  internalization of miR30d miRNA by mouse embryos through the trofectoderm, results in an indirect overexpression of genes related to adhesion: Itgb3,  Itga7 and  Cdh,resulting in an increase in embryo adhesion. Conversely, miR30d deficiency results in reduced implantation rates and poor fetal growth. This finding supports the idea that  miRNAs from the maternal endometrium act as transcriptomic  modifiers  of the preimplantation embryo.

Finally, for a pregnancy to be successful, a continuous molecular dialogue between mother and embryo is essential. Language is based on endocrine and paracrinous factors. Despite the knowledge gained, much remains to be discovered regarding how these factors affect genes in the developing organism. Estrogen, progesterone, and posterior effectors govern stromal differentiation and endometrial remodeling, making it receptive for implantation. The embryo also sends several signals to the mother, in the form of extracellular vesicles carrying miRNAs  and other material, to which the mother responds. The exact routes of communication are not well understood and further exploration is needed.