International Journal of Molecular Sciences

Research

Jump to: Review

12 pages, 957 KiB

Open AccessArticle

Effect of Placenta-Derived Mesenchymal Stromal Cells Conditioned Media on an LPS-Induced Mouse Model of Preeclampsia

by Anna Maria Nuzzo, Laura Moretti, Paolo Mele, Tullia Todros, Carola Eva and Alessandro Rolfo

Int. J. Mol. Sci. 2022, 23(3), 1674; https://doi.org/10.3390/ijms23031674 - 31 Jan 2022

Cited by 8 | Viewed by 3393

Abstract

We tested the pro-angiogenic and anti-inflammatory effects of human placenta-derived mesenchymal stromal cells (hPDMSCs)-derived conditioned media (CM) on a mouse model of preeclampsia (PE), a severe human pregnancy-related syndrome characterized by maternal hypertension, proteinuria, endothelial damage, inflammation, often associated with fetal growth restriction [...] Read more.

We tested the pro-angiogenic and anti-inflammatory effects of human placenta-derived mesenchymal stromal cells (hPDMSCs)-derived conditioned media (CM) on a mouse model of preeclampsia (PE), a severe human pregnancy-related syndrome characterized by maternal hypertension, proteinuria, endothelial damage, inflammation, often associated with fetal growth restriction (FGR). At d11 of pregnancy, PE was induced in pregnant C57BL/6N mice by bacterial lipopolysaccharide (LPS) intravenous injection. At d12, 300 μL of unconditioned media (control group) or 300 μL PDMSCs-CM (CM group) were injected. Maternal systolic blood pressure was measured from 9 to 18 days of pregnancy. Urine protein content were analyzed at days 12, 13, and 17 of pregnancy. At d19, mice were sacrificed. Number of fetuses, FGR, fetal reabsorption, and placental weight were evaluated. Placentae were analyzed for sFlt-1, IL-6, and TNF-α gene and protein expressions. No FGR and/or reabsorbed fetuses were delivered by PDMSCs-CM-treated PE mice, while five FGR fetuses were found in the control group accompanied by a lower placental weight. PDMSCs-CM injection significantly decreased maternal systolic blood pressure, proteinuria, sFlt-1, IL-6, and TNF-α levels in PE mice. Our data indicate that hPDMSCs-CM can reverse PE-like features during pregnancy, suggesting a therapeutic role for hPDMSCs for the treatment of preeclampsia. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

21 pages, 7178 KiB

Open AccessArticle

Protease Inhibitor Anti-HIV, Lopinavir, Impairs Placental Endocrine Function

by Camille Fraichard, Fidéline Bonnet-Serrano, Christelle Laguillier-Morizot, Marylise Hebert-Schuster, René Lai-Kuen, Jeanne Sibiude, Thierry Fournier, Marie Cohen and Jean Guibourdenche

Int. J. Mol. Sci. 2021, 22(2), 683; https://doi.org/10.3390/ijms22020683 - 12 Jan 2021

Cited by 12 | Viewed by 2696

Abstract

Protease Inhibitors (PI e.g., ritonavir (RTV) and lopinavir (LPV)) used to treat pregnant mothers infected by HIV induce prematurity and endocrine dysfunctions. The maintenance of pregnancy relies on placental hormone production (human Chorionic Gonadotrophin (hCG) and progesterone (P4)). Those functions are ensured by [...] Read more.

Protease Inhibitors (PI e.g., ritonavir (RTV) and lopinavir (LPV)) used to treat pregnant mothers infected by HIV induce prematurity and endocrine dysfunctions. The maintenance of pregnancy relies on placental hormone production (human Chorionic Gonadotrophin (hCG) and progesterone (P4)). Those functions are ensured by the villous trophoblast and are mainly regulated by the Unfolded Protein Response (UPR) pathway and mitochondria. We investigated, in vitro, if PI impair hCG and P4 production and the potential intracellular mechanisms involved. Term villous cytotrophoblast (VCT) were cultured with or without RTV or LPV from 6 to 48 h. VCT differentiation into syncytiotrophoblast (ST) was followed measuring hCG and P4 secretion. We evaluated the expression of P4 synthesis partners (Metastatic Lymph Node 64 (MLN64), cholesterol side-chain cleavage (P450SCC), Hydroxy-delta-5-Steroid Dehydrogenase and 3 Beta-and steroid delta-isomerase 1 (HSD3B1)), of mitochondrial pro-fusion factors (Mitofusin 2 (Mfn2), Optic Atrophy 1 (OPA1)) and of UPR factors (Glucose-Regulated Protein 78 (GRP78), Activating Transcription Factor 4 (ATF4), Activating Transcription Factor 6 (ATF6), spliced X-box Binding Protein 1 (sXBP1)). RTV had no significant effect on hCG and P4 secretion, whereas lopinavir significantly decreased both secretions. LPV also decreased P450SCC and HSD3B1 expression, whereas it increased Mfn2, GRP78 and sXBP1 expression in ST. RTV has no effect on the endocrine placenta. LPV impairs both villous trophoblast differentiation and P4 production. It is likely to act via mitochondrial fusion and UPR pathway activation. These trophoblastic alterations may end in decreased P4 levels in maternal circulation, inducing prematurity. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Graphical abstract

21 pages, 4056 KiB

Open AccessArticle

Transcription Factor PLAGL1 Is Associated with Angiogenic Gene Expression in the Placenta

by Rebekah R. Starks, Rabab Abu Alhasan, Haninder Kaur, Kathleen A. Pennington, Laura C. Schulz and Geetu Tuteja

Int. J. Mol. Sci. 2020, 21(21), 8317; https://doi.org/10.3390/ijms21218317 - 6 Nov 2020

Cited by 8 | Viewed by 3974

Abstract

During pregnancy, the placenta is important for transporting nutrients and waste between the maternal and fetal blood supply, secreting hormones, and serving as a protective barrier. To better understand placental development, we must understand how placental gene expression is regulated. We used RNA-seq [...] Read more.

During pregnancy, the placenta is important for transporting nutrients and waste between the maternal and fetal blood supply, secreting hormones, and serving as a protective barrier. To better understand placental development, we must understand how placental gene expression is regulated. We used RNA-seq data and ChIP-seq data for the enhancer associated mark, H3k27ac, to study gene regulation in the mouse placenta at embryonic day (e) 9.5, when the placenta is developing a complex network of blood vessels. We identified several upregulated transcription factors with enriched binding sites in e9.5-specific enhancers. The most enriched transcription factor, PLAGL1 had a predicted motif in 233 regions that were significantly associated with vasculature development and response to insulin stimulus genes. We then performed several experiments using mouse placenta and a human trophoblast cell line to understand the role of PLAGL1 in placental development. In the mouse placenta, Plagl1 is expressed in endothelial cells of the labyrinth layer and is differentially expressed in placentas from mice with gestational diabetes compared to placentas from control mice in a sex-specific manner. In human trophoblast cells, siRNA knockdown significantly decreased expression of genes associated with placental vasculature development terms. In a tube assay, decreased PLAGL1 expression led to reduced cord formation. These results suggest that Plagl1 regulates overlapping gene networks in placental trophoblast and endothelial cells, and may play a critical role in placental development in normal and complicated pregnancies. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

11 pages, 4251 KiB

Open AccessArticle

Identifying Stabilin-1 and Stabilin-2 Double Knockouts in Reproduction and Placentation: A Descriptive Study

by Soon-Young Kim, Eun-Hye Lee, Eun Na Kim, Woo-Chan Son, Yeo Hyang Kim, Seung-Yoon Park, In-San Kim and Jung-Eun Kim

Int. J. Mol. Sci. 2020, 21(19), 7235; https://doi.org/10.3390/ijms21197235 - 30 Sep 2020

Cited by 7 | Viewed by 3659

Abstract

The placenta undergoes reconstruction at different times during fetal development to supply oxygen and nutrients required throughout pregnancy. To accommodate the rapid growth of the fetus, small spiral arteries undergo remodeling in the placenta. This remodeling includes apoptosis of endothelial cells that line [...] Read more.

The placenta undergoes reconstruction at different times during fetal development to supply oxygen and nutrients required throughout pregnancy. To accommodate the rapid growth of the fetus, small spiral arteries undergo remodeling in the placenta. This remodeling includes apoptosis of endothelial cells that line spiral arteries, which are replaced by trophoblasts of fetal origin. Removal of dead cells is critical during this process. Stabilin-1 (Stab1) and stabilin-2 (Stab2) are important receptors expressed on scavenger cells that absorb and degrade apoptotic cells, and Stab1 is expressed in specific cells of the placenta. However, the role of Stab1 and Stab2 in placental development and maintenance remain unclear. In this study, we assessed Stab1 and Stab2 expression in the placenta and examined the reproductive capacity and placental development using a double-knockout mouse strain lacking both Stab1 and Stab2 (Stab1/2 dKO mice). Most pregnant Stab1/2 dKO female mice did not produce offspring and exhibited placental defects, including decidual hemorrhage and necrosis. Findings of this study offer the first description of the phenotypic characteristics of placentas and embryos of Stab1/2 dKO females during pregnancy, suggesting that Stab1 and Stab2 are involved in placental development and maintenance. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

20 pages, 8987 KiB

Open AccessArticle

Endothelial Jagged1 Antagonizes Dll4/Notch Signaling in Decidual Angiogenesis during Early Mouse Pregnancy

by Nicole M. Marchetto, Salma Begum, Tracy Wu, Valerie O’Besso, Christina C. Yarborough, Nuriban Valero-Pacheco, Aimee M. Beaulieu, Jan K. Kitajewski, Carrie J. Shawber and Nataki C. Douglas

Int. J. Mol. Sci. 2020, 21(18), 6477; https://doi.org/10.3390/ijms21186477 - 5 Sep 2020

Cited by 12 | Viewed by 6447

Abstract

Maternal spiral arteries and newly formed decidual capillaries support embryonic development prior to placentation. Previous studies demonstrated that Notch signaling is active in endothelial cells of both decidual capillaries and spiral arteries, however the role of Notch signaling in physiologic decidual angiogenesis and [...] Read more.

Maternal spiral arteries and newly formed decidual capillaries support embryonic development prior to placentation. Previous studies demonstrated that Notch signaling is active in endothelial cells of both decidual capillaries and spiral arteries, however the role of Notch signaling in physiologic decidual angiogenesis and maintenance of the decidual vasculature in early mouse pregnancy has not yet been fully elucidated. We used the Cdh5-Cre^ERT2;Jagged1(Jag1)^flox/flox (Jag1∆EC) mouse model to delete Notch ligand, Jag1, in maternal endothelial cells during post-implantation, pre-placentation mouse pregnancy. Loss of endothelial Jag1 leads to increased expression of Notch effectors, Hey2 and Nrarp, and increased endothelial Notch signaling activity in areas of the decidua with remodeling angiogenesis. This correlated with an increase in Dll4 expression in capillary endothelial cells, but not spiral artery endothelial cells. Consistent with increased Dll4/Notch signaling, we observed decreased VEGFR2 expression and endothelial cell proliferation in angiogenic decidual capillaries. Despite aberrant Dll4 expression and Notch activation in Jag1∆EC mutants, pregnancies were maintained and the decidual vasculature was not altered up to embryonic day 7.5. Thus, Jag1 functions in the newly formed decidual capillaries as an antagonist of endothelial Dll4/Notch signaling during angiogenesis, but Jag1 signaling is not necessary for early uterine angiogenesis. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

18 pages, 6841 KiB

Open AccessArticle

Persistent Human KIT Receptor Signaling Disposes Murine Placenta to Premature Differentiation Resulting in Severely Disrupted Placental Structure and Functionality

by Franziska Kaiser, Julia Hartweg, Selina Jansky, Natalie Pelusi, Caroline Kubaczka, Neha Sharma, Dominik Nitsche, Jan Langkabel and Hubert Schorle

Int. J. Mol. Sci. 2020, 21(15), 5503; https://doi.org/10.3390/ijms21155503 - 31 Jul 2020

Cited by 3 | Viewed by 3795

Abstract

Activating mutations in the human KIT receptor is known to drive severe hematopoietic disorders and tumor formation spanning various entities. The most common mutation is the substitution of aspartic acid at position 816 to valine (D816V), rendering the receptor constitutively active independent of [...] Read more.

Activating mutations in the human KIT receptor is known to drive severe hematopoietic disorders and tumor formation spanning various entities. The most common mutation is the substitution of aspartic acid at position 816 to valine (D816V), rendering the receptor constitutively active independent of ligand binding. As the role of the KIT receptor in placental signaling cascades is poorly understood, we analyzed the impact of KIT^D816V expression on placental development using a humanized mouse model. Placentas from KIT^D816V animals present with a grossly changed morphology, displaying a reduction in labyrinth and spongiotrophoblast layer and an increase in the Parietal Trophoblast Giant Cell (P-TGC) layer. Elevated differentiation to P-TGCs was accompanied with reduced differentiation to other Trophoblast Giant Cell (TGC) subtypes and by severe decrease in proliferation. The embryos display growth retardation and die in utero. KIT^D816V-trophoblast stem cells (TSC) differentiate much faster compared to wild type (WT) controls. In undifferentiated KIT^D816V-TSCs, levels of Phosphorylated Extracellular-signal Regulated Kinase (P-ERK) and Phosphorylated Protein Kinase B (P-AKT) are comparable to wildtype cultures differentiating for 3–6 days. Accordingly, P-TGC markers Placental Lactogen 1 (PL1) and Proliferin (PLF) are upregulated as well. The results reveal that KIT signaling orchestrates the fine-tuned differentiation of the placenta, with special emphasis on P-TGC differentiation. Appropriate control of KIT receptor action is therefore essential for placental development and nourishment of the embryo. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

18 pages, 2718 KiB

Open AccessArticle

Fractalkine Regulates HEC-1A/JEG-3 Interaction by Influencing the Expression of Implantation-Related Genes in an In Vitro Co-Culture Model

by Ramóna Pap, Gergely Montskó, Gergely Jánosa, Katalin Sipos, Gábor L. Kovács and Edina Pandur

Int. J. Mol. Sci. 2020, 21(9), 3175; https://doi.org/10.3390/ijms21093175 - 30 Apr 2020

Cited by 12 | Viewed by 3267

Abstract

Embryo implantation is a complex process regulated by a network of biological molecules. Recently, it has been described that fractalkine (CX3CL1, FKN) might have an important role in the feto–maternal interaction during gestation since the trophoblast cells express fractalkine receptor (CX3CR1) and the [...] Read more.

Embryo implantation is a complex process regulated by a network of biological molecules. Recently, it has been described that fractalkine (CX3CL1, FKN) might have an important role in the feto–maternal interaction during gestation since the trophoblast cells express fractalkine receptor (CX3CR1) and the endometrium cells secrete fractalkine. CX3CR1 controls three major signalling pathways, PLC-PKC pathway, PI3K/AKT/NFκB pathway and Ras-mitogen-activated protein kinases (MAPK) pathways regulating proliferation, growth, migration and apoptosis. In this study, we focused on the molecular mechanisms of FKN treatment influencing the expression of implantation-related genes in trophoblast cells (JEG-3) both in mono-and in co-culture models. Our results reveal that FKN acted in a concentration and time dependent manner on JEG-3 cells. FKN seemed to operate as a positive regulator of implantation via changing the action of progesterone receptor (PR), activin receptor and bone morphogenetic protein receptor (BMPR). FKN modified also the expression of matrix metalloproteinase 2 and 9 controlling invasion. The presence of HEC-1A endometrial cells in the co-culture contributed to the effect of fractalkine on JEG-3 cells regulating implantation. The results suggest that FKN may contribute to the successful attachment and implantation of embryo. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

20 pages, 5503 KiB

Open AccessArticle

Trophectoderm-Specific Knockdown of LIN28 Decreases Expression of Genes Necessary for Cell Proliferation and Reduces Elongation of Sheep Conceptus

by Asghar Ali, Mark D. Stenglein, Thomas E. Spencer, Gerrit J. Bouma, Russell V. Anthony and Quinton A. Winger

Int. J. Mol. Sci. 2020, 21(7), 2549; https://doi.org/10.3390/ijms21072549 - 6 Apr 2020

Cited by 18 | Viewed by 3895

Abstract

LIN28 inhibits let-7 miRNA maturation which prevents cell differentiation and promotes proliferation. We hypothesized that the LIN28-let-7 axis regulates proliferation-associated genes in sheep trophectoderm in vivo. Day 9-hatched sheep blastocysts were incubated with lentiviral particles to deliver shRNA targeting LIN28 specifically to [...] Read more.

LIN28 inhibits let-7 miRNA maturation which prevents cell differentiation and promotes proliferation. We hypothesized that the LIN28-let-7 axis regulates proliferation-associated genes in sheep trophectoderm in vivo. Day 9-hatched sheep blastocysts were incubated with lentiviral particles to deliver shRNA targeting LIN28 specifically to trophectoderm cells. At day 16, conceptus elongation was significantly reduced in LIN28A and LIN28B knockdowns. Let-7 miRNAs were significantly increased and IGF2BP1-3, HMGA1, ARID3B, and c-MYC were decreased in trophectoderm from knockdown conceptuses. Ovine trophoblast (OTR) cells derived from day 16 trophectoderm are a useful tool for in vitro experiments. Surprisingly, LIN28 was significantly reduced and let-7 miRNAs increased after only a few passages of OTR cells, suggesting these passaged cells represent a more differentiated phenotype. To create an OTR cell line more similar to day 16 trophectoderm we overexpressed LIN28A and LIN28B, which significantly decreased let-7 miRNAs and increased IGF2BP1-3, HMGA1, ARID3B, and c-MYC compared to control. This is the first study showing the role of the LIN28-let-7 axis in trophoblast proliferation and conceptus elongation in vivo. These results suggest that reduced LIN28 during early placental development can lead to reduced trophoblast proliferation and sheep conceptus elongation at a critical period for successful establishment of pregnancy. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Graphical abstract

12 pages, 3535 KiB

Open AccessArticle

Downregulation of Placental Amino Acid Transporter Expression and mTORC1 Signaling Activity Contributes to Fetal Growth Retardation in Diabetic Rats

by Jie Xu, Jiao Wang, Yang Cao, Xiaotong Jia, Yujia Huang, Minghui Cai, Chunmei Lu and Hui Zhu

Int. J. Mol. Sci. 2020, 21(5), 1849; https://doi.org/10.3390/ijms21051849 - 7 Mar 2020

Cited by 9 | Viewed by 5016

Abstract

Alterations in placental transport may contribute to abnormal fetal intrauterine growth in pregnancies complicated by diabetes, but it is not clear whether the placental amino acid transport system is altered in diabetic pregnancies. We therefore studied the changes in the expressions of placental [...] Read more.

Alterations in placental transport may contribute to abnormal fetal intrauterine growth in pregnancies complicated by diabetes, but it is not clear whether the placental amino acid transport system is altered in diabetic pregnancies. We therefore studied the changes in the expressions of placental amino acid transporters in a rat model of diabetes induced by streptozotocin, and tested the effects of hyperglycemia on trophoblast amino acid transporter in vitro. Our results showed that the expressions for key isoforms of system L amino acid transporters were significantly reduced in the placentas of streptozotocin-induced diabetic pregnant rats, which was associated with the decreased birthweight in the rats. A decreased placental efficiency and decreased placental mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activity were also found in the rat model. In addition, hyperglycemia in vitro could inhibit amino acid transporter expression and mTORC1 activity in human trophoblast. Inhibition of mTORC1 activity led to reduced amino acid transporter expression in placental trophoblast. We concluded that reduced placental mTORC1 activity during pregnancy resulted in decreased placental amino acid transporter expression and, subsequently, contributed to fetal intrauterine growth restriction in pregnancies complicated with diabetes. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

13 pages, 1834 KiB

Open AccessArticle

Fetuin-A Inhibits Placental Cell Growth and Ciliogenesis in Gestational Diabetes Mellitus

by Chia-Yih Wang, Mei-Tsz Su, Hui-ling Cheng, Pao-Lin Kuo and Pei-Yin Tsai

Int. J. Mol. Sci. 2019, 20(20), 5207; https://doi.org/10.3390/ijms20205207 - 21 Oct 2019

Cited by 6 | Viewed by 2802

Abstract

Gestational diabetes mellitus (GDM) is a type of unbalanced glucose tolerance that occurs during pregnancy, which affects approximately 10% of pregnancies worldwide. Fetuin-A is associated with insulin resistance, and the concentration of circulating fetuin-A increases in women with GDM, however, the role of [...] Read more.

Gestational diabetes mellitus (GDM) is a type of unbalanced glucose tolerance that occurs during pregnancy, which affects approximately 10% of pregnancies worldwide. Fetuin-A is associated with insulin resistance, and the concentration of circulating fetuin-A increases in women with GDM, however, the role of fetuin-A in the placenta remains unclear. In this study, we enrolled placental samples from twenty pregnant women with GDM and twenty non-GDM pregnant women and found that the abundance of fetuin-A was upregulated in terms of mRNA and protein levels. Fetuin-A inhibited placental cell growth by inducing apoptosis and inhibiting S phase entry. Irregular alignment of mitotic chromosomes and aberrant mitotic spindle poles were observed. In addition, centrosome amplification was induced by fetuin-A treatment, and these amplified centrosomes nucleated microtubules with disorganized microtubule arrays in placental cells. Furthermore, fetuin-A inhibited autophagy, and thus blocked the growth of the primary cilium, a cellular antenna that regulates placenta development and differentiation. Thus, our study uncovered the novel function of fetuin-A in regulating placental cell growth and ciliogenesis. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

Review

Jump to: Research

19 pages, 907 KiB

Open AccessReview

Placental Dysfunction in Assisted Reproductive Pregnancies: Perinatal, Neonatal and Adult Life Outcomes

by Claudio Manna, Valentina Lacconi, Giuseppe Rizzo, Antonino De Lorenzo and Micol Massimiani

Int. J. Mol. Sci. 2022, 23(2), 659; https://doi.org/10.3390/ijms23020659 - 8 Jan 2022

Cited by 26 | Viewed by 5718

Abstract

Obstetric and newborn outcomes of assisted reproductive technology (ART) pregnancies are associated with significative prevalence of maternal and neonatal adverse health conditions, such as cardiovascular and metabolic diseases. These data are interpreted as anomalies in placentation involving a dysregulation of several molecular factors [...] Read more.

Obstetric and newborn outcomes of assisted reproductive technology (ART) pregnancies are associated with significative prevalence of maternal and neonatal adverse health conditions, such as cardiovascular and metabolic diseases. These data are interpreted as anomalies in placentation involving a dysregulation of several molecular factors and pathways. It is not clear which extent of the observed placental alterations are the result of ART and which originate from infertility itself. These two aspects probably act synergically for the final obstetric risk. Data show that mechanisms of inappropriate trophoblast invasion and consequent altered vascular remodeling sustain several clinical conditions, leading to obstetric and perinatal risks often found in ART pregnancies, such as preeclampsia, fetal growth restriction and placenta previa or accreta. The roles of factors such as VEGF, GATA3, PIGF, sFLT-1, sEndoglin, EGFL7, melatonin and of ART conditions, such as short or long embryo cultures, trophectoderm biopsy, embryo cryopreservation, and supraphysiologic endometrium preparation, are discussed. Inflammatory local conditions and epigenetic influence on embryos of ART procedures are important research topics since they may have important consequences on obstetric risk. Prevention and treatment of these conditions represent new frontiers for clinicians and biologists involved in ART, and synergic actions with researchers at molecular levels are advocated. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

26 pages, 1131 KiB

Open AccessReview

PlGF Immunological Impact during Pregnancy

by Loredana Albonici, Monica Benvenuto, Chiara Focaccetti, Loredana Cifaldi, Martino Tony Miele, Federica Limana, Vittorio Manzari and Roberto Bei

Int. J. Mol. Sci. 2020, 21(22), 8714; https://doi.org/10.3390/ijms21228714 - 18 Nov 2020

Cited by 23 | Viewed by 5427

Abstract

During pregnancy, the mother’s immune system has to tolerate the persistence of paternal alloantigens without affecting the anti-infectious immune response. Consequently, several mechanisms aimed at preventing allograft rejection, occur during a pregnancy. In fact, the early stages of pregnancy are characterized by the [...] Read more.

During pregnancy, the mother’s immune system has to tolerate the persistence of paternal alloantigens without affecting the anti-infectious immune response. Consequently, several mechanisms aimed at preventing allograft rejection, occur during a pregnancy. In fact, the early stages of pregnancy are characterized by the correct balance between inflammation and immune tolerance, in which proinflammatory cytokines contribute to both the remodeling of tissues and to neo-angiogenesis, thus, favoring the correct embryo implantation. In addition to the creation of a microenvironment able to support both immunological privilege and angiogenesis, the trophoblast invades normal tissues by sharing the same behavior of invasive tumors. Next, the activation of an immunosuppressive phase, characterized by an increase in the number of regulatory T (Treg) cells prevents excessive inflammation and avoids fetal immuno-mediated rejection. When these changes do not occur or occur incompletely, early pregnancy failure follows. All these events are characterized by an increase in different growth factors and cytokines, among which one of the most important is the angiogenic growth factor, namely placental growth factor (PlGF). PlGF is initially isolated from the human placenta. It is upregulated during both pregnancy and inflammation. In this review, we summarize current knowledge on the immunomodulatory effects of PlGF during pregnancy, warranting that both innate and adaptive immune cells properly support the early events of implantation and placental development. Furthermore, we highlight how an alteration of the immune response, associated with PlGF imbalance, can induce a hypertensive state and lead to the pre-eclampsia (PE). Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Graphical abstract

13 pages, 1033 KiB

Open AccessReview

Go with the Flow—Trophoblasts in Flow Culture

by Beatrice A. Brugger, Jacqueline Guettler and Martin Gauster

Int. J. Mol. Sci. 2020, 21(13), 4666; https://doi.org/10.3390/ijms21134666 - 30 Jun 2020

Cited by 17 | Viewed by 7130

Abstract

With establishment of uteroplacental blood flow, the perfused fetal chorionic tissue has to deal with fluid shear stress that is produced by hemodynamic forces across different trophoblast subtypes. Amongst many other cell types, trophoblasts are able to sense fluid shear stress through mechanotransduction. [...] Read more.

With establishment of uteroplacental blood flow, the perfused fetal chorionic tissue has to deal with fluid shear stress that is produced by hemodynamic forces across different trophoblast subtypes. Amongst many other cell types, trophoblasts are able to sense fluid shear stress through mechanotransduction. Failure in the adaption of trophoblasts to fluid shear stress is suggested to contribute to pregnancy disorders. Thus, in the past twenty years, a significant body of work has been devoted to human- and animal-derived trophoblast culture under microfluidic conditions, using a rather broad range of different fluid shear stress values as well as various different flow systems, ranging from commercially 2D to customized 3D flow culture systems. The great variations in the experimental setup reflect the general heterogeneity in blood flow through different segments of the uteroplacental circulation. While fluid shear stress is moderate in invaded uterine spiral arteries, it drastically declines after entrance of the maternal blood into the wide cavity of the intervillous space. Here, we provide an overview of the increasing body of evidence that substantiates an important influence of maternal blood flow on several aspects of trophoblast physiology, including cellular turnover and differentiation, trophoblast metabolism, as well as endocrine activity, and motility. Future trends in trophoblast flow culture will incorporate the physiological low oxygen conditions in human placental tissue and pulsatile blood flow in the experimental setup. Investigation of trophoblast mechanotransduction and development of mechanosome modulators will be another intriguing future direction. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

29 pages, 1281 KiB

Open AccessReview

Preimplantation Genetic Testing: Where We Are Today

by Ermanno Greco, Katarzyna Litwicka, Maria Giulia Minasi, Elisabetta Cursio, Pier Francesco Greco and Paolo Barillari

Int. J. Mol. Sci. 2020, 21(12), 4381; https://doi.org/10.3390/ijms21124381 - 19 Jun 2020

Cited by 63 | Viewed by 14755

Abstract

Background: Preimplantation genetic testing (PGT) is widely used today in in-vitro fertilization (IVF) centers over the world for selecting euploid embryos for transfer and to improve clinical outcomes in terms of embryo implantation, clinical pregnancy, and live birth rates. Methods: We report the [...] Read more.

Background: Preimplantation genetic testing (PGT) is widely used today in in-vitro fertilization (IVF) centers over the world for selecting euploid embryos for transfer and to improve clinical outcomes in terms of embryo implantation, clinical pregnancy, and live birth rates. Methods: We report the current knowledge concerning these procedures and the results from different clinical indications in which PGT is commonly applied. Results: This paper illustrates different molecular techniques used for this purpose and the clinical significance of the different oocyte and embryo stage (polar bodies, cleavage embryo, and blastocyst) at which it is possible to perform sampling biopsies for PGT. Finally, genetic origin and clinical significance of embryo mosaicism are illustrated. Conclusions: The preimplantation genetic testing is a valid technique to evaluated embryo euploidy and mosaicism before transfer. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

20 pages, 1862 KiB

Open AccessReview

Endometrial Decidualization: The Primary Driver of Pregnancy Health

by Shu-Wing Ng, Gabriella A. Norwitz, Mihaela Pavlicev, Tamara Tilburgs, Carlos Simón and Errol R. Norwitz

Int. J. Mol. Sci. 2020, 21(11), 4092; https://doi.org/10.3390/ijms21114092 - 8 Jun 2020

Cited by 174 | Viewed by 24920

Abstract

Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the establishment of the pregnancy at the time of endometrial decidualization. Humans are one of only a few mammalian [...] Read more.

Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the establishment of the pregnancy at the time of endometrial decidualization. Humans are one of only a few mammalian viviparous species in which decidualization begins during the latter half of each menstrual cycle and is therefore independent of the conceptus. Failure to adequately prepare (decidualize) the endometrium hormonally, biochemically, and immunologically in anticipation of the approaching blastocyst—including the downregulation of genes involved in the pro- inflammatory response and resisting tissue invasion along with the increased expression of genes that promote angiogenesis, foster immune tolerance, and facilitate tissue invasion—leads to abnormal implantation/placentation and ultimately to adverse pregnancy outcome. We hypothesize, therefore, that the primary driver of pregnancy health is the quality of the soil, not the seed. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

20 pages, 2224 KiB

Open AccessReview

The Role of LIN28-let-7-ARID3B Pathway in Placental Development

by Asghar Ali, Gerrit J. Bouma, Russell V. Anthony and Quinton A. Winger

Int. J. Mol. Sci. 2020, 21(10), 3637; https://doi.org/10.3390/ijms21103637 - 21 May 2020

Cited by 40 | Viewed by 5727

Abstract

Placental disorders are a major cause of pregnancy loss in humans, and 40–60% of embryos are lost between fertilization and birth. Successful embryo implantation and placental development requires rapid proliferation, invasion, and migration of trophoblast cells. In recent years, microRNAs (miRNAs) have emerged [...] Read more.

Placental disorders are a major cause of pregnancy loss in humans, and 40–60% of embryos are lost between fertilization and birth. Successful embryo implantation and placental development requires rapid proliferation, invasion, and migration of trophoblast cells. In recent years, microRNAs (miRNAs) have emerged as key regulators of molecular pathways involved in trophoblast function. A miRNA binds its target mRNA in the 3ʹ-untranslated region (3ʹ-UTR), causing its degradation or translational repression. Lethal-7 (let-7) miRNAs induce cell differentiation and reduce cell proliferation by targeting proliferation-associated genes. The oncoprotein LIN28 represses the biogenesis of mature let-7 miRNAs. Proliferating cells have high LIN28 and low let-7 miRNAs, whereas differentiating cells have low LIN28 and high let-7 miRNAs. In placenta, low LIN28 and high let-7 miRNAs can lead to reduced proliferation of trophoblast cells, resulting in abnormal placental development. In trophoblast cells, let-7 miRNAs reduce the expression of proliferation factors either directly by binding their mRNA in 3ʹ-UTR or indirectly by targeting the AT-rich interaction domain (ARID)3B complex, a transcription-activating complex comprised of ARID3A, ARID3B, and histone demethylase 4C (KDM4C). In this review, we discuss regulation of trophoblast function by miRNAs, focusing on the role of LIN28-let-7-ARID3B pathway in placental development. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Graphical abstract

30 pages, 2375 KiB

Open AccessReview

Molecular Signaling Regulating Endometrium–Blastocyst Crosstalk

by Micol Massimiani, Valentina Lacconi, Fabio La Civita, Carlo Ticconi, Rocco Rago and Luisa Campagnolo

Int. J. Mol. Sci. 2020, 21(1), 23; https://doi.org/10.3390/ijms21010023 - 18 Dec 2019

Cited by 114 | Viewed by 16287

Abstract

Implantation of the embryo into the uterine endometrium is one of the most finely-regulated processes that leads to the establishment of a successful pregnancy. A plethora of factors are released in a time-specific fashion to synchronize the differentiation program of both the embryo [...] Read more.

Implantation of the embryo into the uterine endometrium is one of the most finely-regulated processes that leads to the establishment of a successful pregnancy. A plethora of factors are released in a time-specific fashion to synchronize the differentiation program of both the embryo and the endometrium. Indeed, blastocyst implantation in the uterus occurs in a limited time frame called the “window of implantation” (WOI), during which the maternal endometrium undergoes dramatic changes, collectively called “decidualization”. Decidualization is guided not just by maternal factors (e.g., estrogen, progesterone, thyroid hormone), but also by molecules secreted by the embryo, such as chorionic gonadotropin (CG) and interleukin-1β (IL-1 β), just to cite few. Once reached the uterine cavity, the embryo orients correctly toward the uterine epithelium, interacts with specialized structures, called pinopodes, and begins the process of adhesion and invasion. All these events are guided by factors secreted by both the endometrium and the embryo, such as leukemia inhibitory factor (LIF), integrins and their ligands, adhesion molecules, Notch family members, and metalloproteinases and their inhibitors. The aim of this review is to give an overview of the factors and mechanisms regulating implantation, with a focus on those involved in the complex crosstalk between the blastocyst and the endometrium. Full article

(This article belongs to the Special Issue Embryo Implantation and Placental Development)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Embryo Implantation and Placental Development

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (17 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI