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Genes Jan 2020Small-for-gestational-age (SGA) infants are fetuses that have not reached their genetically programmed growth potential. Low birth weight predisposes these infants to an... (Review)
Review
Small-for-gestational-age (SGA) infants are fetuses that have not reached their genetically programmed growth potential. Low birth weight predisposes these infants to an increased risk of developing cardiovascular, metabolic and neurodevelopmental conditions in later life. However, our understanding of how this pathology occurs is currently incomplete. Previous research has focused on understanding the transcriptome, epigenome and bacterial signatures separately. However, we hypothesise that interactions between moderators of gene expression are critical to understanding fetal growth restriction. Through a review of the current literature, we identify that there is evidence of modulated expression/methylation of the placental genome and the presence of bacterial DNA in the placental tissue of SGA infants. We also identify that despite limited evidence of the interactions between the above results, there are promising suggestions of a relationship between bacterial signatures and placental function. This review aims to summarise the current literature concerning fetal growth from multiple avenues and propose a novel relationship between the placental transcriptome, methylome and bacterial signature that, if characterised, may be able to improve our current understanding of the placental response to stress and the aetiology of growth restriction.
Topics: DNA Methylation; Female; Fetal Development; Fetal Growth Retardation; Gene Expression; Gene Expression Regulation, Developmental; Gestational Age; Humans; Infant, Newborn; Infant, Small for Gestational Age; Male; Microbiota; Placenta; Placentation; Pregnancy
PubMed: 31936801
DOI: 10.3390/genes11010080 -
Proceedings of the National Academy of... Mar 2021Invasive trophoblast cells are critical to spiral artery remodeling in hemochorial placentation. Insufficient trophoblast cell invasion and vascular remodeling can lead...
Invasive trophoblast cells are critical to spiral artery remodeling in hemochorial placentation. Insufficient trophoblast cell invasion and vascular remodeling can lead to pregnancy disorders including preeclampsia, preterm birth, and intrauterine growth restriction. Previous studies in mice identified achaete-scute homolog 2 (ASCL2) as essential to extraembryonic development. We hypothesized that ASCL2 is a critical and conserved regulator of invasive trophoblast cell lineage development. In contrast to the mouse, the rat possesses deep intrauterine trophoblast cell invasion and spiral artery remodeling similar to human placentation. In this study, we investigated invasive/extravillous trophoblast (EVT) cell differentiation using human trophoblast stem (TS) cells and a loss-of-function mutant rat model. transcripts are expressed in the EVT column and junctional zone, which represent tissue sources of invasive trophoblast progenitor cells within human and rat placentation sites, respectively. Differentiation of human TS cells into EVT cells resulted in significant up-regulation of and several other transcripts indicative of EVT cell differentiation. Disruption of ASCL2 impaired EVT cell differentiation, as indicated by cell morphology and transcript profiles. RNA sequencing analysis of ASCL2-deficient trophoblast cells identified both down-regulation of EVT cell-associated transcripts and up-regulation of syncytiotrophoblast-associated transcripts, indicative of dual activating and repressing functions. ASCL2 deficiency in the rat impacted placental morphogenesis, resulting in junctional zone dysgenesis and failed intrauterine trophoblast cell invasion. ASCL2 acts as a critical and conserved regulator of invasive trophoblast cell lineage development and a modulator of the syncytiotrophoblast lineage.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cell Lineage; Female; Humans; Placentation; Pregnancy; Rats; Rats, Sprague-Dawley; Stem Cells; Trophoblasts
PubMed: 33649217
DOI: 10.1073/pnas.2016517118 -
Genes Aug 2021Uterine spiral artery remodeling is essential for placental perfusion and fetal growth and, when impaired, results in placental ischemia and pregnancy complications,... (Review)
Review
Uterine spiral artery remodeling is essential for placental perfusion and fetal growth and, when impaired, results in placental ischemia and pregnancy complications, e.g., fetal growth restriction, preeclampsia, premature birth. Despite the high incidence of adverse pregnancies, current treatment options are limited. Accordingly, research has shifted to the development of gene therapy technologies that provide targeted delivery of "payloads" to the placenta while limiting maternal and fetal exposure. This review describes the current strategies, including placental targeting peptide-bound liposomes, nanoparticle or adenovirus constructs decorated with specific peptide sequences and placental gene promoters delivered via maternal IV injection, directly into the placenta or the uterine artery, as well as noninvasive site-selective targeting of regulating genes conjugated with microbubbles via contrast-enhanced ultrasound. The review also provides a perspective on the effectiveness of these technologies in various animal models and their practicability and potential use for targeted placental delivery of therapeutics and genes in adverse human pregnancies affected by placental dysfunction.
Topics: Female; Fetal Growth Retardation; Genetic Therapy; Humans; Liposomes; Nanoparticles; Peptides; Placenta; Placentation; Pregnancy; Uterus
PubMed: 34440429
DOI: 10.3390/genes12081255 -
Biomolecules Mar 2020Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in... (Review)
Review
Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in development and it remains under debate how well they reflect primary trophoblast (TB) cells. The absence of robust protocols to generate TSCs from humans has resulted in limited knowledge of the molecular mechanisms that regulate human placental development and TB lineage specification when compared to other human embryonic stem cells (hESCs). As placentation in mouse and human differ considerably, it is only with the development of human-based disease models using TSCs that we will be able to understand the various diseases caused by abnormal placentation in humans, such as preeclampsia. In this review, we summarize the knowledge on normal human placental development, the placental disease preeclampsia, and current stem cell model systems used to mimic TB differentiation. A special focus is given to the transforming growth factor-beta (TGFβ) family as it has been shown that the TGFβ family has an important role in human placental development and disease.
Topics: Cell Differentiation; Female; Humans; Placentation; Pre-Eclampsia; Pregnancy; Transforming Growth Factor beta; Trophoblasts
PubMed: 32183218
DOI: 10.3390/biom10030453 -
Proceedings of the National Academy of... Sep 2021Directed trophoblast migration toward the maternal mesometrial pole is critical for placentation and pregnancy success. Trophoblasts replace maternal arterial...
Directed trophoblast migration toward the maternal mesometrial pole is critical for placentation and pregnancy success. Trophoblasts replace maternal arterial endothelial cells to increase blood supply to the placenta. Inferior trophoblast invasion results in pregnancy complications including preeclampsia, intrauterine growth restriction, miscarriage, and preterm delivery. The maternal chemotactic factors that direct trophoblast migration and the mechanism by which trophoblasts respond to these factors are not clearly understood. Here, we show that invasive trophoblasts deficient in , a core planar cell polarity (PCP) component, fail to invade in maternal decidua, and this deficiency results in middle-gestational fetal demise. Previously, we have shown that tightly regulated endocannabinoids via G protein-coupled cannabinoid receptor CB1 are critical to the invasion of trophoblasts called spiral artery trophoblast giant cells (SpA-TGCs). We find that CB1 directly interacts with VANGL2. Trophoblast stem cells devoid of and/or show compromised cell migration. To study roles of VANGL2 and CB1 in trophoblast invasion in vivo, we conditionally deleted (coding CB1) and in progenitors of SpA-TGCs using trophoblast-specific protein alpha ()-Cre. We observed that signaling mediated by VANGL2 and CB1 restrains trophoblasts from random migration by keeping small GTPases quiescent. Our results show that organized PCP in trophoblasts is indispensable for their directed movement and that CB1 exerts its function by direct interaction with membrane proteins other than its canonical G protein-coupled receptor role.
Topics: Abortion, Spontaneous; Animals; Arteries; Cannabinoids; Cell Line; Cell Movement; Cell Polarity; Endocannabinoids; Endothelial Cells; Female; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Signal Transduction; Trophoblasts
PubMed: 34521753
DOI: 10.1073/pnas.2108201118 -
Frontiers in Endocrinology 2023Placental dysfunction refers to the insufficiency of placental perfusion and chronic hypoxia during early pregnancy, which impairs placental function and causes... (Review)
Review
Placental dysfunction refers to the insufficiency of placental perfusion and chronic hypoxia during early pregnancy, which impairs placental function and causes inadequate supply of oxygen and nutrients to the fetus, affecting fetal development and health. Fetal intrauterine growth restriction, one of the most common outcomes of pregnancy-induced hypertensions, can be caused by placental dysfunction, resulting from deficient trophoblast syncytialization, inadequate trophoblast invasion and impaired vascular remodeling. During placental development, cytotrophoblasts fuse to form a multinucleated syncytia barrier, which supplies oxygen and nutrients to meet the metabolic demands for fetal growth. A reduction in the cell fusion index and the number of nuclei in the syncytiotrophoblast are found in the placentas of pregnancies complicated by IUGR, suggesting that the occurrence of IUGR may be related to inadequate trophoblast syncytialization. During the multiple processes of trophoblasts syncytialization, specific proteins and several signaling pathways are involved in coordinating these events and regulating placental function. In addition, epigenetic modifications, cell metabolism, senescence, and autophagy are also involved. Study findings have indicated several abnormally expressed syncytialization-related proteins and signaling pathways in the placentas of pregnancies complicated by IUGR, suggesting that these elements may play a crucial role in the occurrence of IUGR. In this review, we discuss the regulators of trophoblast syncytialization and their abnormal expression in the placentas of pregnancies complicated by IUGR.
Topics: Pregnancy; Female; Humans; Placenta; Trophoblasts; Fetal Growth Retardation; Placentation; Oxygen
PubMed: 36798658
DOI: 10.3389/fendo.2023.1107182 -
Oxidative Medicine and Cellular... 2014Oxidative stress (OS) is known to be strongly involved in a large number of fetal, neonatal, and adult diseases, including placental disorders, leading to pregnancy loss... (Review)
Review
Oxidative stress (OS) is known to be strongly involved in a large number of fetal, neonatal, and adult diseases, including placental disorders, leading to pregnancy loss and stillbirths. A growing body of research links OS to preeclampsia, gestational diabetes, obesity, spontaneous abortion, recurrent pregnancy, preterm labor, and intrauterine growth restriction. While a considerable number of miRNAs have been related to physiological functions and pathological conditions of the placenta, a direct link among these miRNAs, placental functions, and OS is still lacking. This review summarizes data describing the role of miRNAs in placental pathophysiological processes and their possible impact on OS damaging responses. As miRNAs can be found in circulation, improving our understanding on their role in the pathogenesis of pregnancy related disorders could have an important impact on the diagnosis and prognosis of these diseases.
Topics: Female; Humans; MicroRNAs; Oxidative Stress; Oxidoreductases; Placenta; Placentation; Pregnancy; Pregnancy Complications; Reactive Oxygen Species
PubMed: 24790700
DOI: 10.1155/2014/103068 -
American Journal of Reproductive... Oct 2010Endogenous retroviruses (ERVs) are present in the genome of all vertebrates and originated from infections of the germline of the host by exogenous retroviruses. ERVs... (Review)
Review
Endogenous retroviruses (ERVs) are present in the genome of all vertebrates and originated from infections of the germline of the host by exogenous retroviruses. ERVs have coevolved with their hosts for millions of years and are recognized to contribute to genome plasticity, protect the host against infection of related pathogenic and exogenous retroviruses, and play a vital role in development of the placenta. Consequently, some ERVs have been positively selected and maintained in the host genome throughout evolution. This review will focus on the critical role of ERVs in development of the mammalian placenta and specifically highlight the biological role of sheep JSRV-related endogenous betaretroviruses in conceptus (embryo and associated extraembryonic membranes) development.
Topics: Animals; Embryonic Development; Endogenous Retroviruses; Female; Humans; Jaagsiekte sheep retrovirus; Placenta; Placentation; Pregnancy; Sheep; Trophoblasts
PubMed: 20528833
DOI: 10.1111/j.1600-0897.2010.00860.x -
Kidney International Aug 2014Pre-eclampsia is a pregnancy-specific hypertensive disorder that may lead to serious maternal and fetal complications. It is a multisystem disease that is commonly, but... (Review)
Review
Pre-eclampsia is a pregnancy-specific hypertensive disorder that may lead to serious maternal and fetal complications. It is a multisystem disease that is commonly, but not always, accompanied by proteinuria. Its cause(s) remain unknown, and delivery remains the only definitive treatment. It is increasingly recognized that many pathophysiological processes contribute to this syndrome, with different signaling pathways converging at the point of systemic endothelial dysfunction, hypertension, and proteinuria. Different animal models of pre-eclampsia have proven utility for specific aspects of pre-eclampsia research, and offer insights into pathophysiology and treatment possibilities. Therapeutic interventions that specifically target these pathways may optimize pre-eclampsia management and may improve fetal and maternal outcomes. In addition, recent findings regarding placental, endothelial, and podocyte pathophysiology in pre-eclampsia provide unique and exciting possibilities for improved diagnostic accuracy. Emerging evidence suggests that testing for urinary podocytes or their markers may facilitate the prediction and diagnosis of pre-eclampsia. In this review, we explore recent research regarding placental, endothelial, and podocyte pathophysiology. We further discuss new signaling and genetic pathways that may contribute to pre-eclampsia pathophysiology, emerging screening and diagnostic strategies, and potential targeted interventions.
Topics: Adaptive Immunity; Animals; Carbon Monoxide; Carrier Proteins; Endothelin-1; Endothelium, Vascular; Epigenesis, Genetic; Female; Heme Oxygenase (Decyclizing); Humans; Immunity, Innate; Neovascularization, Physiologic; Nitric Oxide; Placenta; Placentation; Podocytes; Pre-Eclampsia; Pregnancy; Receptors, Notch; Renal Insufficiency, Chronic; Signal Transduction
PubMed: 24573315
DOI: 10.1038/ki.2014.17 -
Cellular and Molecular Life Sciences :... Sep 2007Formation of extraembryonic tissues, and in particular the placenta, is an absolute necessity to ensure growth and survival of the embryo during intrauterine development... (Review)
Review
Formation of extraembryonic tissues, and in particular the placenta, is an absolute necessity to ensure growth and survival of the embryo during intrauterine development in mammals. To date, an intriguing number of genes have been identified that are essential for development of extraembryonic structures. However, the underlying genetic information must be interpreted by a set of epigenetic instructions to both establish and maintain lineage- and cell type-specific expression profiles. Based on accumulating data in particular from studies in the mouse, this article is aimed at highlighting the epigenetic machinery required for differentiation of extraembryonic cell types and formation of the placenta. An overview of knockout models reveals key stages in extraembryonic development that are particularly sensitive to alterations in the chromatin environment. The article also summarizes the importance of complex epigenetically controlled mechanisms for placental development, such as imprinted gene expression and imprinted X chromosome inactivation. These investigations of the epigenetic regulation of transcriptional states will provide valuable insights into the dynamic chromatin environment that is specific to extraembryonic tissues and determines gene expression patterns required for normal trophoblast differentiation.
Topics: Animals; DNA Methylation; Embryo, Mammalian; Epigenesis, Genetic; Female; Gene Expression Regulation, Developmental; Mice; Placentation; Pregnancy; Trophoblasts
PubMed: 17585370
DOI: 10.1007/s00018-007-7113-z