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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 1  |  Issue : 2  |  Page : 100-114

Developmental aspect of decidual patterning


Reproductive Medical Center, The First Affiliated Hospital of Xiamen University; Fujian Provincial Key Laboratory of Reproductive Health Research, Medical College, Xiamen University, Xiamen, Fujian 361102, China

Date of Web Publication17-Oct-2017

Correspondence Address:
Hai-Bin Wang
Reproductive Medical Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.216864

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  Abstract 


In clinical practice, early pregnancy loss has afflicted approximately 15%–25% women of reproductive age worldwide, which is partially attributed to defects associated with the endometrium. During pregnancy, the endometrial stromal cells experience remarkable tissue remodeling and transformation, termed as decidualization, to support embryonic development, placental formation, and the maintenance of normal pregnancy in both mice and human. During this process, a series of dynamic developmental events, including rapid stromal proliferation, increased stromal cell size, enhanced angiogenesis, taken place in a highly-ordered manner under the precise regulation of steroid hormones. Meanwhile, diverse molecules exhibit spatiotemporal-specific expression pattern, implying their unique roles in decidual development. To achieve a more comprehensive understanding of these biological events and explore the underlying causes of early pregnancy disorders, this review emphasizes on the detailed developmental progression of decidual transformation and patterning as well as related pregnancy complications at the early stage of pregnancy.

Keywords: Decidualization; Implantation; Mouse Model


How to cite this article:
Zhou C, Bao HL, Kong SB, Lu JH, Wang HB. Developmental aspect of decidual patterning. Reprod Dev Med 2017;1:100-14

How to cite this URL:
Zhou C, Bao HL, Kong SB, Lu JH, Wang HB. Developmental aspect of decidual patterning. Reprod Dev Med [serial online] 2017 [cited 2020 Jun 6];1:100-14. Available from: http://www.repdevmed.org/text.asp?2017/1/2/100/216864




  Introduction Top


How a new life is produced from the maternal body has been a profound mystery in the history of human civilization. Dating back to the Golden Age of Greece, the maternal uterus was believed to consist of numerous “tentacles” as provisions for intrauterine suckling to ensure that the fetus is proficient at birth. Although ancient people misunderstood the structure of uterus even with no cognition of the ovary, they did realize the vital nurturing function of uterus for supporting fetal growth. After centuries of exploration, now we know that the uterus consists of an outer layer of myometrium, an inner layer of luminal epithelium and the stroma in the middle. Following the fusion of sperm and oocyte in the  Fallopian tube More Details, the newly formed fertilized egg (the zygote) will be transferred into the uterine cavity, where it contacts with the luminal epithelium and anchors into the stroma, termed as implantation. In response to embryo implantation, the endometrial stromal cells undergo rapid tissue remodeling, referred to as “decidualization,” adapting to the settling of the fetus before placental formation. Well-established decidua, characterized by terminal differentiation of the stromal cells and marked uterine angiogenesis, is essential for successful implantation, placentation as well as the maintenance of pregnancy.[1]


  How Does Decidualization Initiate? – the Beginning of the Story Top


The process of decidual reaction occurs predominantly in species that embryo implantation is accompanied by the breakdown of luminal epithelial cells and the penetration by trophoblast cells. In the majority of these species (including the rodents), the presence of embryos has been a prerequisite for the initiation of decidualization. Over evolutionary time, the decidualization of the endometrium evolved to be under maternal control in several species including bats, elephant shrew, apes and human, which means that the transformation of endometrial stromal cells into decidual cells is initiated spontaneously in each cycle, independent of the implanting embryos.[2] Species, possessing spontaneous decidualization, share diverse reproductive characteristics in common, such as spontaneous ovulation, extended mating (not limited to the periovulatory period), and hemochorial placentae.[3],[4] In this part, the initiation of decidualization in both mouse and human will be discussed.

Evoked decidual reaction by blastocysts in mice

The intense tissue remodeling in the mouse uterine stroma will not occur until the embryo implants into the uterine crypts. The embryo at blastocyst stage attaches to the luminal epithelium on gestation day 4.5 postcoitum, eliciting immediate transformation of the uterine stromal cells surrounding the blastocyst, a process termed as decidualization. The typical features of decidualization are composed of the increase in uterine weight and the enlargement in uterine stromal shape. In mice, the process of decidualization initiates at the antimesometrial pole and then spreads to the mesometrial side (the presumed site of placentation) [Figure 1]. In response to embryo implantation, the stromal cells surrounding the implanting blastocyst start to proliferate and differentiate, forming the primary decidual zone (PDZ), which is epithelioid, avascular, and densely packed, on the afternoon of day 5.[5] The PDZ is fully established by day 6, and a secondary decidual zone (SDZ) is established around the PDZ. At this time, the proliferation of decidual stromal cells has been ceased in the PDZ but still continues in the region of SDZ.[6] The SDZ, characterized by terminally differentiated decidual polyploidy with large mono- or binuclei, is fully developed by day 8.[7] In addition to the polyploid stromal cells, the decidual zone also includes a variety of lymphocytes and blood vessels. However, a thin basal layer of undifferentiated quiescent stromal cells builds up a boundary between the myometrium and the decidual zone [Figure 1]. Thereafter, with the development and invasion of trophoblast, the antimesometrial decidua degenerates and ultimately transforms into a thin layer of tissue termed as the decidua capsularis, while the mesometrial decidua gradually thins out to make room for placentation, eventually forming the decidua basalis.[8]
Figure 1: Developmental progression of decidualization in mice. In response to embryo implantation, the stromal cells surrounding the conceptus undergo decidual transformation, forming the PDZ (late day 5). Sequentially, the decidual reaction spreads throughout the antimesometrial region and the SDZ is established by day 8. Thereafter, the process of decidualization expands to the mesometrial pole, the presumed site of placentation. With the development and invasion of trophoblast, the antimesometrial decidua degenerates and ultimately transforms into a thin layer of tissue termed as the decidua capsularis, and the mesometrial decidua gradually thins out and eventually forms the decidua basalis. Meanwhile, an unaltered or boundary layer sets up a border between the decidual capsularis and the myometrium. M: Mesometrium; AM: Anti-mesometrium; PDZ: Primary decidual zone; SDZ: Secondary decidual zone; BV: Blood vessels; G: Glands.

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The physiological interaction of the blastocyst with the uterine luminal epithelium elicits an attachment reaction, which coincides with a localized increase in uterine vascular permeability at the site of attachment, as the implantation sites can be visualized by vein injection of a macromolecular blue dye. The appearance of ptsg2 at the attachment side is believed to be the earliest prerequisite implantation marker.[9],[10]Ptsg2 gene encoded Cyclooxygenase 2 (Cox2) is an inducible rate-limiting enzyme that converts arachidonic acid to prostaglandins (PGs). PGs exert their function by interacting with cell surface G protein-coupled receptors, but they can also serve as ligands for nuclear peroxisome proliferator-activated receptors.[11],[12] The Cox2-derived PGs are critical for the implantation and decidualization based on the findings from genetic knockout mice. In the Cox1 deficiency mouse model, Cox2 compensates for the loss of Cox1 to ensure normal implantation; and Cox2-deleted mice fail to initiate the process of decidualization while the exogenous administration of PGI2 partially restores this defect [13],[14] although this phenomenon occurs in a background-dependent manner.

In addition to the increased vascular permeability at implantation site, the mesenchymal-to-epithelial transition is considered as an another characteristic that the intiated decidualized stromal cells display. Zonula occludens-1 (ZO1) is one of the tight junction proteins localized on the surface of plasma membranes.[15],[16] On the initiation of decidualization, the expression of ZO1 is restricted to epithelial and subepithelial stromal cells and later spreads into the decidualizing stromal cells. These results indicate that the presence of ZO1 in the PDZ may serve as a permeability barrier to regulate the access of immunologically competent maternal cells and/or molecules to the embryo and provide homotypic guidance of trophoblast cells in the endometrium.[17]

The blastocyst-triggered decidual conversion can be simulated artificially by injecting sesame oil through uterine horn. Intraluminal oil injection on day 4 of pseudopregnancy mice (female mice mated with vasoligated males) leads to a robust decidual response throughout the stroma.[18] Scratching uterine wall by needle tip could also induce the uterine decidualization. The artificially induced decidualization exhibits a dramatically increase in uterine size and enlargement and differentiation of the stromal cell layer, the same as the embryo-induced decidualization during normal pregnancy.[19] A recent study reveals that lysophosphatidic acid (LPA), produced at the embryonic-epithelial boundary, activates LPA3 in the luminal epithelial cells, which upregulates epithelial heparin-binding EGF and Cox2 and subsequently induces stromal bone morphogenetic protein (Bmp2) and Wnt4 expression. This highly coordinated and ordered cascade results in the breakdown of luminal epithelium, the proliferation of stroma as well as the enhancement of angiogenesis.[20] The decidual reaction elicited by LPA may explain, to some extent, the machenism by which decidualization can be induced by oil injection.

Spontaneous endometrial transformation during menstrual cycle in human

The endometrium in human is highly dynamic, experiencing cyclically shedding, repairation, regeneration, and remodeling throughout the reproductive life under the coordinated regulation of the steroid hormones estrogen (E2) and progesterone (P4).[21],[22],[23] The increasing progesterone level after ovulation induces extensive remodeling of the estrogen-primed endometrial stroma, which is referred to as decidualization. The process of decidualization involves both morphological and biochemical changes, during which the fibroblast-like endometrial stromal cells become rounded and start to secrete and release diverse factors, including prolactin (PRL), insulin-like growth factor binding protein-1 (IGFBP-1), and tissue factor.[24],[25],[26],[27] Unlike mice and other nonmenstruating species, in which the process of decidualization requires embryo implantation, human and several other primates with menstruation undergo spontaneous decidualization driven by the rising postovulatory progesterone level and increasing local cyclic adenosine monophosphate (cAMP) production during the mid-to-late secretory phase in each menstrual cycle.[2] It seems that the human endometrium is always prepared for the embryo in each menstrual cycle no matter whether they will come or not, guaranteeing the best developmental condition for the possibly arriving embryo. If embryo implantation does not take place, these superficial terminally differentiated decidual cells will be shed during menses in response to the falling progesterone level. However, in case of conception, the decidual reaction becomes intenser, and the decidual cells are capable of facilitating extravillous trophoblasts invasion and spiral artery remodeling, protecting the embryo from maternal immunological rejection,[28] and environmental stress stimuli.[29] An emerging concept suggests that the decidua can sense the quality of embryo and assist the rejection of those with developmental defects.[30]

Abundant experimental and clinical evidence have confirmed the essential role of progesterone in the initiation of decidual transformation. Within endometrium, progesterone functions primarily through the nuclear-receptor, progesterone receptor (PR). On bounded by progesterone, PR undergoes conformational changes, dissociates from its chaperone factors and binds specifically to the progesterone response elements (PREs) in the promoter region of target genes.[31] Indeed, two putative PREs have been found within the promoter of IGFBP-1, a marker of decidualization.[32] Previous studies have revealed that PR serves as a scaffold for the recruitment of several other transcription factors in response to the cAMP signaling,[33] including the signal transducer and activator of transcription 5 (STAT5),[34] CCAAT enhancer-binding proteins,[35] and forkhead box O (FOXO1).[36]

The decidual reaction initially occurs in the stromal cells surrounding the spiral arteries approximately 10 days after the increase of the ovarian progesterone level, raising the possibility that the initiation of decidual reaction is unlikely to be under the direct regulation of the progesterone signaling. Accumulated proofs based onin vitro experiments have supported the involvement of cAMP in the evocation of decidualization.[37],[38],[39] The intracellular second messenger cAMP, which contributes to the transmission and amplification of extracellular signals, is processed from adenosine triphosphate by adenylate cyclase. The cAMP signaling can be regulated at different levels, including the activation of adenylate cyclase that leads to increased cAMP production and enhanced cAMP effects, the catabolism of cAMP by phosphodiesterase, the expression level of cAMP-response element modulators as well as coactivators and corepressors.[40] An elevated level of PGE2, which is capable of activating cAMP through its receptors EP2 and EP4,[41] is observed during the secretory phase of the menstrual cycle in the human endometrium.[42] Relaxin, secreted by the endometrium during decidualization,[43] is a natural inhibitor of phosphodiesterase and participates in the initiation of decidual reaction, further reinforcing the critical role of cAMP in decidual induction.[44]


  The Progression of Decidualization – A Highly-Ordered Event Top


Following the establishment of the PDZ in murine uterus, the stromal cells next to the PDZ start to experience immense proliferation and differentiation, forming the terminally differentiated SDZ under the precise control of the progesterone signaling. In addition, a variety of cytokines, growth factors, homeobox (Hox) genes, and other developmental genes are expressed in a spatiotemporal-specific manner and exert their unique functions in different compartments of the uterus.

Progesterone – progesterone-receptor cascades during decidualization

The development of the decidua is accompanied by extensive tissue remodeling and angiogenesis in response to endocrinological variation.[45] The highly regulated progesterone signaling plays a critical role in the initiation and maintenance of decidualization.[46] Following the postovulatory rise of progesterone levels, endometrial stromal cells adjacent to fetus undergo decidual transformation to support embryonic development and maintain normal pregnancy.[47] In both primates and rodents, sustained progesterone, acting through the nuclear-receptor PR, is decisive for proper implantation and decidualization. The nuclear-receptor family is composed of a large number of intracellular proteins with the unique roles in transcriptional regulation and specific location.[48]

PRs are expressed mainly as two protein isoforms, PR-A and PR-B, which are produced from one gene at different transcription start sites. The PR-A and PR-B isoforms differ in that PR-B contains an additional NH2-terminal stretch of about 165 amino acids, which encodes a transactivation domain that specifically binds to PR-B-target gene.[49] Expression of both the two PR isoformsis is observed in the murine uterus, and the PR knockout (PRKO) mice exhibits infertility due to pleiotropic reproduction abnormalities, including behavioral defects, failed ovulation, nonreceptivity uterus, and lack of response to artificial deciduogenic stimulus.[50] Demayo's group has generated mice with ablation of individual PR-A and PR-B, PRAKO and PRBKO, respectively, shedding light on the roles of each isoform in the uterus.[51],[52] The uterine phenotype of PRAKO mouse resembles that of PRKO mouse while PRBKO mouse displays normal fertility but reduced mammary gland morphogenesis, indicating that PR-A is the predominant mediator of P4 signaling in the mouse reproduction tract. Contrary to mouse, PR-B plays a dominant role in human endometrium during decidualization.[53] In addition, previous evidence revealed that the existence of PR-C, which lacks N-terminus region containing DNA binding domain, may contribute to the onset of parturition.[54]

It has been widely-accepted that P4 and PR regulate a great deal of different gene targets,[55] and the appropriate actions of PR rely on the interplay with molecular chaperones. In the absence of P4, PR is located in the cytoplasm and bounded by a complex of immunophilins and heat-shock proteins.[56] The expression of two immunophilins, FKBP4 (FKBP52) and FKBP5 (FKBP51), overlaps with that of PR in the uterine stromal cells. Although Fkbp5 knockout mice do not display any obvious reproductive defects, both male and female mice with Fkbp4 mutaiton are infertile.[57],[58] The defects of Fkbp4-null uterus are due to the complete failure of implantation and decidualization. In agreement with a close functional association of FKBP4 with PR, dramatically reduced transcriptional activity of PR target genes and mediators are observed in the FKBP4-null mice, including Hoxa-10, Indian Hedgehog, and amphiregulin.[59] Supplied with progesterone ligand daily from day 2 and bryond, the Fkbp4-deleted mice could maintain the decidualization properly although in a background-dependent manner.

Once bounded by ligands, the activated PR dissociates from heat-shock proteins and chaperones and then interacts with coactivators and cosuppressors at the promotor/enhancer region of PR target genes, facilitating hormonal regulation of transcription. Among many coregulators, steroid-receptor coactivator p160/SRC family is well-studied mediators, which are composed of SRC-1, SRC-2, and SRC-3. Both SRC-1 and SRC-2 are expressed in the epithelial and stromal cells while SRC-3 expression is undetected in the peri-implantation mouse uterus.[60] SRC-1 has been confirmed as a protein that interacts with PR and enhances its transcriptional activity without affecting the basal activity of other nuclear receptor. The SRC-1 knockout females are fertile but shows a dampened response to exogenous steroid-hormone treatment.[61] The deficiency of SRC-1 also led to reduced stromal differentiation in response to the artificial stimuli. Accordingly, SRC-1 plays important roles in mouse uterus under the regulation of steroid hormones. However, there is no direct evidence that SRC-1 and PR interact together to mediate the uterine decidual response. In contrast to SRC-1, SRC-2 is essential for the maintenance of pregnancy. The SRC-2 null female mice displayed a reduction in fertile ability and partial lethality phenotype.[62],[63] The increased rate of embryonic resorptions results from lowered response to artificial decidualization and placental development, which displays the decreased numbers of trophoblastic trabeculae and embryonic capillaries in the labyrinthine region.[60],[63] To explore the function of SRC-2 in pregnancy, conditional ablation of SRC-2 mouse model are generated by crossing the PR-Cre mice with floxed SRC-2 alleles mice.[64],[65] The SRC-2 knockout mice are infertile and exhibited a reduction in the artificial decidualization reaction.[64] Besides, the crossing between uterine conditional SRC-2 knockout mice and SRC-1 null mice will lead to a complete infertility in female mice for the lack of decidualization, proving that SRC-1 and SRC-2 are necessary for decidualization.[64]

Spatiotemporal molecular patterns and boundaries in the decidua

During the progression of decidualization, a variety of cytokines, growth factors, Hox genes, and other developmental genes display spatiotemporal expression patterns, some of which even possess the potential function of establishing boundaries within the decidual region, implying their unique roles in different compartments of the uterus [Table 1].
Table 1: Genes critical to decidualization: results from knockout mouse models

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Growth differentiation factor 10 (Gdf10), highly related to Bmp3, is identified as a member of the transforming growth factor-β (TGF-β) superfamily.[103] The expression of Gdf10 appears prominently in the developing skeleton during embryogenesis, as well as in the uterus, adipose tissue, and brain in adult animals,[103],[104] indicating its involvement in the regulation of cell differentiation. With the progression of decidualization, Gdf10 is expressed specifically in a few layers of decidualized stromal cells in the PDZ surrounding the blastocyst on day 7. However, the expression of Gdf10 is undetectable in the deciduoma on day 7 of pseudopregnancy.[5] The unique expression pattern of Gdf10 suggests that it participates in the modulation of PDZ establishment under the influence of embryonic signals.

Pentraxin 3 (Ptx3), also known as the tumor necrosis factor-stimulated gene 14, belongs to the Ptx superfamily. Ptx3 is rapidly produced and released by different types of cells, including mononuclear phagocytes, dendritic cells, fibroblasts, and endothelial cells, in response to inflammatory stimuli.[105] Several studies have accentuated the significance and necessity of Ptx3 in diverse reproductive events. Serving as an essential structural constituent of the cumulus oophorus extracellular matrix (ECM), Ptx3 plays an important role in cumulus-oocyte interaction during ovulation, and Ptx3-/- mice suffer from severe abnormalities of the cumulus oophorus as well as failure of fertilization, leading to infertility.[106],[107] Furthermore, deletion of Ptx3 results in impaired implantation and compromised decidualization, suggesting the involvement of Ptx 3 in these processes during early pregnancy.[98]Ptx3 is reported to display a spatiotemporal-specific expression pattern in the uterus during the period of decidualization.[98] With the formation of PDZ on day 5, Ptx3 is restrictedly expressed in the periphery of PDZ. Later, Ptx3 is observed to specifically localize at the boundary between PDZ and SDZ. The expression of Ptx3 at the border of PDZ and SDZ brings up a hint that this molecule may participate to protect the embryo from the maternal immunologic stimuli since the PDZ barrier gradually undergoes degeneration to make room for the developing embryo on day 7–8. It has been proven that Ptx3 plays an important role in the complement-mediated clearance of apoptotic cells.[105],[108] Thus, it is possible that Ptx3 constitutes a barrier between the regressing PDZ and the proliferating SDZ or controls cell death in the PDZ and cell differentiation of the decidualizing stroma in the SDZ.

BMPs, a member of the highly conserved TGFβ superfamily, are implicated in diverse biological processes including cell proliferation, differentiation, apoptosis, cell fate determination, and morphogenesis. The vertebrate BMPs regulate the development of nervous system, somites, lung, kidney, skin, gonads, and other critical events during the establishment of embryonic body plan.[109] Although plenty of BMPs have been observed in the uterus during pregnancy, only BMP2 is spatiotemporally associated with implantation and decidualization.[110] During early pregnancy, Bmp2 is initially detected in the stromal cells surrounding the implanting blastocyst on day 5. By day 7, the expression of Bmp2 disappears in the postmitotic PDZ, but spreads to the highly proliferating and differentiating SDZ.[110] A uterine-specific deletion of Bmp2 leads to compromised decidual response and thus complete infertility, which cannot be compensated by other members of the BMP family.[68] Moreover, the expression of BMP2 is remarkably increased in human primary endometrial stromal cells during decidualization, reinforcing its critical roles in this process.[111]

Furthermore, the antagonists of BMPs also display temporal and cell-specific expression. Nog, the gene encoding Noggin, appears in the stroma underlying the epithelium at the mesometrial pole with the development of decidua. Dan, belonging to the Dan/Dante BMP antagonist family,[112] is detected in the PDZ on day 6. Crim1, encoding a protein that has the capacity to bind both IGF and BMP,[113] is expressed in the decidua close to the embryo on day 7–8, partially overlapping with the expression of Bmp2.[110] The importance of uterine planar cell polarity signaling has been uncovered during implantation and decidualization in mice since it is responsible for the downregulation of Nog and induction of Bmp2 to ensure proper attachment reaction and decidual transformation at the implantation site.[114]

The Wnt proteins are a family of evolutionarily conserved signaling molecules that participate in various biological events during embryogenesis and tumorigenesis.[115],[116] Wnt proteins bind to their receptors, the Frizzled (Fzd) family which are located on the cell surface, to initiate either the canonical or the noncanonical signaling. In the canonical Wnt pathway, the signal is passed on to β-catenin, which later translocates into the nucleus and activates transcription of Wnt target genes. On the other hand, Wnt proteins may stimulate Wnt/Ca 2+, Wnt/Jun N-terminal kinase, and several other pathways through noncanonical signaling.[117],[118]

Fzd proteins are equipped with a serpentine structure containing seven-transmembrane helical domains and a cytoplasmic carboxy terminal. A group of proteins, homologous with Fzd proteins but without the transmembrane domain, are known as the secreted Fzd-related proteins (sFRPs). It has been proven that sFRPs have the capacity to inhibit Wnt signaling by competitively binding to Wnt ligands or by forming a nonsignaling complex with Fzds.[115] Serving as Wnt antagonists, sFRPs regulate the morphogenetic gradients and zones of the Wnt signaling, through the same mechanism by which BMP gradient is regulated by its antagonists Noggin and Chordin. Wnt and BMP gradients work in close coordination to specify cell fates and tissue boundaries during development.[119]

The expression of Wnt4 first appears in the PDZ surround the blastocyst on day 5, and then expands to the SDZ on day 8. Meanwhile, sFRP4 is observed in the thin layer of undecidualized stromal cells, serving as a barrier separating the decidual cells, and the circular muscle layer.[110],[120] The unique expression pattern of Wnt4 and sFRP4 indicates that activated Wnt4 signaling is to some extent involved in the establishment of a boundary between the SDZ and the myometrium.

As mentioned above, sFRP4 (Wnt antagonist) is specifically expressed in the undecidualized stromal cells. In addition to sFRP4, PRL receptor (PRLR) and Fgf2 also exhibit a similar expression pattern.[94],[110] Besides being synthesized and secreted by the anterior pituitary gland, the expression of PRL has been confirmed in various cells and tissues including the brain, decidua, thymus, spleen, and mammary epithelial cells.[121] Thus, PRL possesses diverse functions in the regulation of growth, development, behavior, immunity, and reproduction through endocrine, paracrine, and autocrine pathways. The biological and physiological functions of PRL are accomplished through its receptor, PRLR, a single-pass transmembrane protein which is a member of the class I cytokine-receptor superfamily.[94],[121] PRLR-deficient mice suffer from multiple reproductive defects. Heterozygous females exhibit lactation failure owing to impaired mammary gland development while homozygous females are infertile resulting from unsuccessful implantation. Furthermore, they show irregular cycles, reduced ovulation, compromised fertilization, and incapability of implantation after blastocyst transfer.[122] On day 6–8 of pregnancy, the expression of PRLR is observed in the undecidualized stromal cells outside the SDZ at the antimesometrial border. Although the implantation and decidualization defects in PRLR-deficient mice are proven to be mediated by ovarian not uterine PRLR,[94] the cell-specific localization of PRLR in the uterus during early pregnancy suggests that uterine PRLR may play a unique role in pregnancy maintenance, which remains speculative. In addition, another member of fibroblast growth factor family, Fgf2, is exclusively expressed outside the decidual zone on day 8, indicating it may participate in the maintenance of this unaltered or boundary layer.[110] Together, this unaltered or boundary layer of mouse uteri, which is sFRP4/PRLR/Fgf2 positive, may act on sustaining the proliferating activity during mouse pregnancy similar with the uterine basal layer in human menstrual cycle. However, whether and how this unaltered or boundary layer acts on the uterine repairment and reestablishment during and/or after mouse pregnancy still needs further explorations.

Polyploidization: Hallmark of decidual cells in mice

The formation of polyploid cells is considered as one of the hallmarks during the progression of decidualization in mice.[7],[123],[124],[125] Cellular polyploidy, a term defined as cells containing two or more sets of genomic chromosomes, represents a unique process of transition from normal cell cycle of uterine stromal cells to endocycle of decidual cells. Endoreplication, a cell cycle variation that generates multinucleated cells with multiple copies of chromosomes through repeated rounds of DNA replication without cytokinesis has been observed widely in plants, protozoa, insects, and higher animals.[7],[126] However, the results from trophoblast giant cells (TGCs) of the rodent placenta reaveled that mouse TGCs do not endoreduplicate their genomes evenly and some region of the genome are underreplicated while the rest are over-replicated up to 1000C.[126] During decidualization in mice, the DNA content of polyploidy cells could be 4N, 8N, or even higher. Decidual polyploidization, as a hallmark of terminally differentiated cells, has been well explored in the rodents in the past decades.[72] Much is known regarding the regulators of transition, but the concrete functions of the polyploid-state cells remain unclear.[127]

With respect to the cell cycle, one interesting characteristic of endocycle is that the same regulatory proteins functioning in the normal cell cycle also participate in the endorelication. The canonical cell cycle consists of G1-S and G2-M phase, which is controlled by the cyclins and cyclin-dependent kinase (CDKs), a family of serine/threonine protein kinases, and CDK inhibitors (CKIs).[128]

Although most cyclins act on the progression of cell cycles, G-type cyclins, consist of cyclin G1 and G2, are the exceptions functioning mainly as the negatively regulator of cell proliferation.[129] Cyclin G1 is constantly expressed throughout the cell cycle while the appearance of cyclin G2 fluctuates during the cell cycle with a peak level in the late S phase.[130] During the early pregnancy (day 1–8), the action of cyclin G1 is mainly linked to the stromal cell proliferation and differentiation whereas cyclin G2 is associated with the process of terminal differentiation and apoptosis of luminal epithelial and PDZ cells.[72],[129]

By interacting with specific CDKs, the cyclins, accumulating during the G1 phase.[131] Cyclin B1 has been reported to participate in the mitotic entry in late G2 phase.[132] Groisman et al. also show cyclin B1 is localized to spindles in Xenopus embryos and Drosophila, playing important role in the integrity of mitotic apparatus and cell division.[133],[134] Cyclin B1 is expressed specifically in the proliferating stromal cells during the peri-implantation period, as the marker lining the range of decidual cells.

The D-type cyclins act as the positive regulatory factors in the transit of cell cycle phase, and overexpression of D-type cyclins shortens G1 phase and allows rapid entry into S phase. D-type cyclins are constantly expressed throughout the cell cycle, of which cyclin D3 is restricted to the stroma to be performing decidualization. With the initiation of implantation, cyclin D3 is located at the decidualizing stroma surrounding the blastocyst on day 5, after that increased expression of cyclin D3 is found outside the PDZ until day 8. On day 8, the signaling in the antimesometrial stroma drops off but rises in at the mesometrial pole.[7] As the reports by Das, cyclin D3 usually interact with CDK4 or CDK6 for cell cycle process.[135] While the expression of CDK4 is low at the stroma on day 4, it is upregulated and later decreases gradually in the stroma surrounding the blastocyst at the mesometrial and antimesometrial poles on day 5, revealing that the cyclin D3/CDK4 complex is crucial for the cell proliferation.[7] In the antimesometrial stroma of day 8, the expression of CDK4 drops while CDK6 increased, showing that a switch from CDK4 to CDK6 happens in the differentiation process and it is cyclin D3/CDK6 complex that plays important roles in the differentiation of stromal cells. Overall, cyclin D3 associates with CDK4/CDK6 to regulate the uterine stromal cells proliferation and polyploidization.[5],[7]

As previously reported, CDKs can be inhibited by directly binding to CKIs, and the treatment of CKIs is capable of blocking mitosis and triggering endocycle. CKIs consist of CDKN2A and CDKN1A, and the latter is composed of CDKN1A (p21) and CDKN1B (p27) and CDKN1C. P21 is a CKI regulated by the tumor-suppressor p53 and is hypothesized to mediate G1 arrest.[136] Overexpression of P21 will lead to the arrest of cell cycle in G1.[136] As been reported by Tan, the CKIs, both p21 and p27, are expressed differentially in the mouse uterus in the peri-implantation.[7] The expression pattern of p21 seems to be compensated with CDKs.

Accompanied by the reduced cell proliferation and increased p21 expression in PDZ, both cyclin D3 and CDK4 are also reduced in the PDZ, suggesting p21 takes part in guiding cyclin D3 in the proliferating and differentiating stroma. However, the deepened expression of cyclin D3 and p21 in combination with CDK6, but not CDK4, indicates that the associated complex of cyclin D3/CDK6/p21 participates in the polyploidization of uterine stromal cells.[7] The coordinate expression of cyclin D3 with p21 and CDK6 could drive the progression of polyploidy during stromal cell decidualization.[72] Overall, p21 is involved in the proliferation and differentiation of stromal cell through combining cyclin D3 with CDK4 and CDK6, respectively.

Hoxa-10 belongs to the developmentally conserved abdominal B class Hox gene, and the ablation of Hoxa-10 in mice leads to defective decidualization.[137] During embryogenesis, the expression of Hoxa-10 displays a sharp anterior boundary in the paramesonephric duct at the transition between the future uterus and oviduct.[137] Based on previous experimental data that Hoxa-10 shows a specific spatiotemporal pattern in the uterus, we propose that uterine Hoxa-10 also exhibits unique localization at the boundary between the decidualizing stromal cells and the undifferentiated cells next to the myometrium. Consistant with this point of view, the region-specific expression of CDK4 at the mesometrial side and CDK6 at the antimesometrial pole is entirely lost in the Hoxa-10 deficient uterus. Moreover, unusual nuclear staining of CDK4 is observed in the hoxa-10 null mice compared to the cytoplasmic location in the wild-type mice.[5] In addition, other cell cycle regulators, including cyclin G1 and cyclin G2, which normally function as the inhibitory factors in the cell cycle circuitry, reveal aberrant expression in the Hoxa-10 null uteri.[129]


  Decidual Expansion Toward Mesometrial Side for Placentation Top


As early as the implantation takes place, the site of placental formation has already been decided by the location and orientation of embryo resulting from the close coordination of embryo and uterus.[46],[138] In mice, the blastocyst attaches with the luminal epithelium and implants in the antimesometrial side of uterus while the inner cell mass (ICM) toward the mesometrial pole. The polar trophectoderm next to the ICM will differentiate to the extraembryonic ectoderm and ectoplacental cone, leading to the development of a placenta proximal to the blood vessel from maternal mesometrium.[139] Along with the initial formation of placenta, the uterine decidua tissue, expanding from the antimesometrial side to the mesometrial pole on day 9, undergoes prominently tissue remodeling and vasculogenesis and angiogenesis to advance maternal blood flow [Figure 1].[140]

Various factors associated with vasculogenesis and angiogenesis expressed in the decidua have been proved to be essential for the appropriated decidualization and upcoming placetation, such as Cox2, the expression pattern of which changes in accordance with the expansion of decidualization toward the mesometrial side. First, Cox2 is expressed in the luminal epithelium and subepithelial stromal cells at the antimesometrial pole exclusively around the implanting blastocyst in mice.[9] Later, it is localized around the embryo and shows higher expression level at the mesometrial side on day 8, where the trophoblast layer invades into the maternal decidua to form the functional placenta,[141] indicating that Cox2 may participate in the decidual tissue remodeling or angiogenesis. Previous study has shown that Cox2-derived PGs are involved in uterine vascular permeability, placental formationand angiogenesis throughout pregnancy.[142],[143],[144] The compromised implantation and decidualization in Cox2-/- mice partially results from the impaired vascular permeability and decidual cell reaction, as shown by the decreased endothelial cell marker, CD31.[95] The defects in the Cox2-deleted mice are primarily owing to the dysregulated VEGF signaling rather than the angiopoietin system.[95],[145] In addition, Cox-2 has been proved to function in the occurrence of preeclampsia, a human pregnancy-specific disorder.[146]

Vascular endothelial growth factor (VEGF), originally identified as a vascular permeability factor for its capability to stimulate vascular permeability, also serves as a mitogen for endothelial cells and a regulator of angiogenesis.[147] Targeted deletion of the Vegf gene on one allele leads to embryonic lethality during midgestation with compromised vascular formation.[147],[148] During the process of decidualization, VEGF and its receptors, FLK1 and FLT1, represent a spatial and temporal expression in the uterus. VEGF is accumulated in the luminal epithelial and stromal cells surrounding the blastocyst after the initiation of implantation and expands in both the mesometrial and antimesometrial decidua. In human tissue, VEGF and its antagonist, soluble fms-like tyrosine kinase (sFLT1) but not full-length Flt1, present at the decidual-placental interface, while VEGF locates in maternal decidual cells and sFLT1 is expressed in adjacent extravillous trophoblasts.[149] Increased VEGF and sFLT1 expression are tested in preeclamptic women, demonstating that balanced interaction between VEGF and sFLT1 is important for the normal placentation.[149]

Angiopoietins, another class of angiogenic factors, play an essential role in complementing and coordinating the biological and physiological functions of VEGF.[12],[24] While VEGF functions in the early stages of vessel development as mentioned above, angiopoietins mainly act to stimulate vessel maturation, stabilization, and leakiness.[150],[151] Ang1 and Ang2 serve as agonist and antagonist, respectively to control and balance the process of angiogenesis through the endothelial cell-specific tyrosine kinase receptor Tie2.[152] The function of Ang3 is to inhibit the Ang1 activation of Tie2, similar to Ang2.[153]

The spatiotemporal expression of Ang1, 2, 3 and Tie2 in the uterus during decidualization has been reported, and among these angiopoietins, Ang2 shows the dynamic expression from anti-mesometrial to the mesometrial pole.[95] On day 1–5, Ang2 is undetectable in any uterine cell types except for the highly expression in the stromal cells underlying luminal epithelium surrounding the implanted blastocys. On day 8, the expression pattern of Ang-2 from anti-mesometrial to the mesometrial pole is similar with that of Cox2. The overlapping location of Ang2 and Cox2 in all the mesometrial stroma seems to play a part in the decidua prepared for the placentation. Tie2, the receptor of angiopoietins, share similar expression pattern with Flk1 during the period of decidualization. Since VEGF and its receptor Flk1 are proven to participate in uterine vascular permeability and angiogenesis before and during embryo attachment, angiopoietins, and their receptor Tie2 cooperate with VEGF to regulate uterine angiogenesis during decidualization.[95]

Except those factors associated with vasculogenesis and angiogenesis, various components of the ECM experience remodeling during the period of decidualization.[154] Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have been confirmed to play essential roles in the regulation of matrix remodeling and degradation.[155],[156] With the progression of decidualization, Mmp2 is localized in the SDZ at both mesometrial and antimesometrial poles. On day 7–8, the expression becomes more intense in the mesometrial decidua, where placentation takes place. With respect to Mmp9, the expression is observed in a small population of stromal cells at the implantation site on day 5 of pregnancy, and in the TGCs on day 8.[157] MMP2 and MMP9 are capable of digesting a diversity of ECM components, such as type IV collagen, laminin, fibronectin, proteoglycans, and entactin.[157] The spatiotemporally-specific expression of MMP2 and MMP9 suggests they may participate in early decidualization and placentation. Meanwhile, TIMP1, 2, 3 serve as inhibitors of MMP2,9 to ensure normal decidual reaction and trophoblast invasion. TIMP1 and TIMP2 shared similar localization on day 5–8 of pregnancy. The expressions of both the two molecules are limited to the decidualizing stromal cells on day 5 and expand to the SDZ on day 6–8.[157]

All these factors linked to tissue remodeling, vasculogenesis, and angiogenesis are expressed from antimesometrial to mesometrial and are indicated to take part in the proper decidual tissue remodeling, preparation for the upcoming placenta, and overall pregnancy success.


  Decidual Defects and Early Pregnancy Loss Top


Early pregnancy loss, also known as miscarriage or spontaneous abortion, is defined as clinically-recognized pregnancy loss before 20 weeks of gestation or the loss of embryo less than 400g if gestational age is unclear.[158] Early pregnancy loss occurs in 15%–25% of pregnancies, and the incidence increases in step with the rising maternal age.[159]

Recurrent implantation failure

With the rapid development and widespread application of assisted reproductive technology (ART), an emerging pathophysiological phenomenon in which patients fail to establish pregnancy repeatedly after embryo transfer, also known as recurrent implantation failure (RIF), has been a distressing and frustrating problem duringin vitro fertilization/intracytoplasmic sperm injection procedures. However, no consensus has been reached on the exact definition of RIF.[160],[161]

A wide variety of factors may contribute to the occurrence of RIF, including anatomic abnormalities of the uterus, genetic defects of the embryo, hormonal and metabolic disorders, infections, immunological factors, along with other uncommon causes.[162] Among these, maternal decidual defects play unnegligible roles in the pathogenesis of RIF.

The postovulatory increase of progesterone elicits profound tissue remodeling in the endometriual stroma known as decidualization. One unique characteristic of human decidualization is that this decidual transformation initiates spontaneously in each cycle, preparing for the arrival of embryos, implying the necessity of proper decidual establishment for successful implantation. PGs are secreted by decidual cells, and previous study has shown that the production of PGs is impaired at both mRNA and protein level in RIF patients on days 21–24 of the cycle. Furthermore, sPLA2-IIA and Cox2, both of which participate in the synthesis of PGs, are significantly downregulated in 85% of RIF cases.[163] These results reinforce the relationship between decidual defects and RIF.

Recurrent pregnancy loss

Recurrent pregnancy loss (RPL), commonly appears as a kind of early pregnancy loss, has been considered as an important reproductive health issue worldwide. The exact definition of RPL remains controversial. According to the European Society for Human Reproduction and Embryology and the Royal College of Obstetricians and Gynaecologists, RPL is defined as three consecutive miscarriages. Nevertheless, based on the American Society for Reproductive Medicine, it refers to two or more clinically recognized pregnancy failures.[164] Due to the various criteria used, the prevalence of RPL varies greatly among reports.

The chromosomal abnormalities within the preimplantational embryo may, no doubt, contribute to the pathology whereas defects associated with the endometrium or decidua are inevitably involved in the pathogenic mechanisms of miscarriages. Indeed, accumulated evidence has revealed that RPL is associated with compromised differentiation and transformation of endometrial stromal cells into decidual cells.[165] Teklenburg et al. put forward a concept that the decidua is capable of detecting and evaluating the quality of the embryo penetrating through the luminal epithelium. If the development of the embryo is compromised, the decidua will facilitate maternal rejection of the fetus by eliciting menstruation-like tissue breakdown and shedding.[165],[166]

Endometriosis

Besides RPL, reproductive disorders including endometriosis/adenomyosis, endometrial cancer, uterine fibroids, and polycystic ovary syndrome (PCOS) may exert adverse influence on the pregnancy outcome from embryo implantation to parturition. The pathogenic factors contributing to these pregnancy-related diseases comprise hormonal dysregulation, metabolic disorders, inflammation, endometrial/decidual, and vascular aberrations. Among these, defects associated with endometrial stroma and decidua are responsible for impaired uterine receptivity, embryo implantation, placental development and therefore, pregnancy loss and infertility in women with endometrial cancer, endometriosis/adenomyosis and PCOS.[167],[168]

Endometriosis, affecting approximately 10% of women at reproductive age, is a benign, chronic, and inflammatory gynecological disease. Endometriosis is characterized by the presence of endometrium (both epithelium and stroma)-like tissue outside the uterine cavity, resulting in dysmenorrhea, dyspareunia, chronic pelvic pain, and even increased risk of implantation failure as well as infertility.[169],[170] There are three well-defined clinically-distinct forms of endometriosis: (1) peritoneal endometriosis, in which ectopic decidua tissue takes root on the surface of pelvic peritoneum; (2) endometriomas, manifested as the cysts lined by endometrioid mucosa on the ovary; (3) rectovaginal nodule, a solid mass consisting a cocktail of endometriotic decidual tissue, adipose, and fibromuscular tissue, existing between the vigina and the rectum.[171] Many hypotheses have been proposed regarding the pathogenic mechanisms of endometriosis, among which the retrograde menstruation theory raised in 1927 is widely-accepted. During the period of menses, fragments of the shedding decidual cells, along with the blood, pass retrograde through the fallopian tubes into the peritoneal cavity, subsequently implant on the surface of peritoneum or ovaries and grow into endometriotic lesions. Thereafter, endometriotic tissue mainly consists of the abnormal transferred decidual cells of human functionalis. Nevertheless, this hypothesis remains controversial, for more than 90% of woman of reproductive age have experienced reflux menstruation, but only 5%–10% suffer from endometriosis, indicating other factors including hormonal alteration, immune aberration, and genetic abnormality are involved in the pathogenesis of this disease.[171]

The incidence of endometriosis is commonly accompanied with pregnancy failure and obstetric complications, in either spontaneous pregnancy or ART. Patients suffering from endometriosis are faced with a higher risk of placenta previa, placental complications, miscarriage, and preterm birth (PTB).[172] It is noteworthy that women with endometriosis are more likely to experience gestational diabetes mellitus, premature preterm rupture of membranes, and PTB in their first pregnancy.[173]

Findings based on experimental and clinical research have confirmed the critical roles of steroid hormones estrogen and progesterone in the pathology of endometriosis. Previous studies have revealed that women with endometriosis show altered expression of steroid nuclear receptors, leading to dysfunctional endometrium, impaired trophoblast decidual interaction/invasion and thus adverse pregnancy outcome. Furthermore, since patients with endometriosis display abnormal ER- and PR-signaling particularly progesterone resistance,[174],[175] and in case of Fkbp52-/- mice, which is characterized by inefficient progesterone responsiveness, decidualization is compromised and unable to support and maintain pregnancy,[176],[177] the phenomenon of progesterone resistance in women with endometriosis may impede normal decidual reaction and thus result in early pregnancy loss.

In addition to hormonal impact, increased local and systemic inflammatory responses and accumulated reactive oxygen species are considered to contribute to poor pregnancy outcomes in women with endometriosis.[178] The hyperinflammatory state in the case of endometriosis influences the decidua/trophoblast interactions during early pregnancy period that might induce the occurrence of PTB later.[179],[180],[181]


  What Lies in Front of Us? Top


Early pregnancy losses are linked to incompletely-developed endometrium and defect decidualization in most cases. Well-established decidua, across which the maternal blood comes to the placenta through spiral arteries, is essential to support fetal growth and regulate placental formation. Impaired decidualization may contribute to infertility and placenta-associatied diseases in women, such as endometriosis and preeclampsia. However, many questions remain unclear and need to be further elucidated. What is the accurately mechanism by which decidual cells affect the proper invasion of placental trophoblast cells and balance at the interface between the decidua and placenta? What is the predominate regulator controlling these region-specific expressed molecules? Is there any new molecules expressed in the mesometrial pole participating the preparation for placentation? What unique roles do these patterning molecules play in different layers of the uterus?

Acknowledgments

The work incorporated in this review article was supported in parts by National Key R&D program of China (2017YFC1001402 to H.W.), and the National Natural Science Foundation (81330017 and 81490744 to H.W., 81601285 to S.K., and 31600945 to J.L.) and Fujian Natural Science Foundation (2017J01071 to J.L.).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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