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Clinical Epigenetics Apr 2023The placenta is a temporary organ that is essential for supporting mammalian embryo and fetal development. Understanding the molecular mechanisms underlying trophoblast... (Review)
Review
The placenta is a temporary organ that is essential for supporting mammalian embryo and fetal development. Understanding the molecular mechanisms underlying trophoblast differentiation and placental function may contribute to improving the diagnosis and treatment of obstetric complications. Epigenetics plays a significant role in the regulation of gene expression, particularly at imprinted genes, which are fundamental in the control of placental development. The Ten-Eleven-Translocation enzymes are part of the epigenetic machinery, converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). DNA hydroxymethylation is thought to act as an intermediate in the DNA demethylation mechanism and potentially be a stable and functionally relevant epigenetic mark on its own. The role of DNA hydroxymethylation during differentiation and development of the placenta is not fully understood but increasing knowledge in this field will help to evaluate its potential role in pregnancy complications. This review focuses on DNA hydroxymethylation and its epigenetic regulators in human and mouse placental development and function. Additionally, we address 5hmC in the context of genomic imprinting mechanism and in pregnancy complications, such as intrauterine growth restriction, preeclampsia and pregnancy loss. The cumulative findings show that DNA hydroxymethylation might be important for the control of gene expression in the placenta and suggest a dynamic role in the differentiation of trophoblast cell types during gestation.
Topics: Pregnancy; Female; Humans; Animals; Mice; Pregnancy Outcome; DNA Methylation; Placentation; Placenta; 5-Methylcytosine; Abortion, Spontaneous; DNA; Mammals
PubMed: 37095555
DOI: 10.1186/s13148-023-01483-z -
Cellular and Molecular Life Sciences :... Apr 2015The mouse is often used as a model for understanding human placentation and offers multiple advantages, including the ability to manipulate gene expression in specific... (Comparative Study)
Comparative Study Review
The mouse is often used as a model for understanding human placentation and offers multiple advantages, including the ability to manipulate gene expression in specific compartments and to derive trophoblast stem cells, which can be maintained or differentiated in vitro. Nevertheless, there are numerous differences between the mouse and human placentas, only the least of which are structural. This review aims to compare mouse and human placentation, with a focus on signaling pathways involved in trophoblast lineage-specific differentiation.
Topics: Animals; Cell Differentiation; Female; Humans; Mice; Models, Biological; Placentation; Pregnancy; Signal Transduction; Trophoblasts
PubMed: 25430479
DOI: 10.1007/s00018-014-1794-x -
Toxicologic Pathology Jan 2022The use of the mouse as a model organism is common in translational research. This mouse-human similarity holds true for placental development as well. Proper formation...
The use of the mouse as a model organism is common in translational research. This mouse-human similarity holds true for placental development as well. Proper formation of the placenta is vital for development and survival of the maturing embryo. Placentation involves sequential steps with both embryonic and maternal cell lineages playing important roles. The first step in placental development is formation of the blastocyst wall (approximate embryonic days [E] 3.0-3.5). After implantation (∼E4.5), extraembryonic endoderm progressively lines the inner surface of the blastocyst wall (∼E4.5-5.0), forming the yolk sac that provides histiotrophic support to the embryo; subsequently, formation of the umbilical vessels (∼E8.5) supports transition to the chorioallantoic placenta and hemotrophic nutrition. The fully mature ("definitive") placenta is established by ∼E12.5. Abnormal placental development often leads to embryonic mortality, with the timing of death depending on when placental insufficiency takes place and which cells are involved. This comprehensive macroscopic and microscopic atlas highlights the key features of normal and abnormal mouse placental development from E4.5 to E18.5. This in-depth overview of a transient (and thus seldom-analyzed) developmental tissue should serve as a useful reference to aid researchers in identifying and describing mouse placental changes in engineered, induced, and spontaneous disease models.
Topics: Animals; Cell Lineage; Embryo Implantation; Embryo, Mammalian; Female; Mice; Placenta; Placentation; Pregnancy
PubMed: 34872401
DOI: 10.1177/01926233211042270 -
Frontiers in Endocrinology 2023Endocrine-disrupting chemicals (EDCs) or endocrine disruptors are substances that are either naturally occurring or artificial and are released into the natural... (Review)
Review
Endocrine-disrupting chemicals (EDCs) or endocrine disruptors are substances that are either naturally occurring or artificial and are released into the natural environment. Humans are exposed to EDCs through ingestion, inhalation, and skin contact. Many everyday household items, such as plastic bottles and containers, the liners of metal food cans, detergents, flame retardants, food, gadgets, cosmetics, and pesticides, contain endocrine disruptors. Each hormone has a unique chemical makeup and structural attributes. The way that endocrine hormones connect to receptors is described as a "lock and key" mechanism, with each hormone serving as the key (lock). This mechanism is enabled by the complementary shape of receptors to their hormone, which allows the hormone to activate the receptors. EDCs are described as exogenous chemicals or compounds that have a negative impact on organisms' health by interacting with the functioning of the endocrine system. EDCs are associated with cancer, cardiovascular risk, behavioural disorders, autoimmune abnormalities, and reproductive disorders. EDCs exposure in humans is highly harmful during critical life stages. Nonetheless, the effect of EDCs on the placenta is often underestimated. The placenta is especially sensitive to EDCs due to its abundance of hormone receptors. In this review, we evaluated the most recent data on the effects of EDCs on placental development and function, including heavy metals, plasticizers, pesticides, flame retardants, UV filters and preservatives. The EDCs under evaluation have evidence from human biomonitoring and are found in nature. Additionally, this study indicates important knowledge gaps that will direct future research on the topic.
Topics: Pregnancy; Humans; Female; Placentation; Placenta; Endocrine Disruptors; Flame Retardants; Pesticides; Hormones
PubMed: 36896182
DOI: 10.3389/fendo.2023.1059854 -
International Journal of Molecular... Sep 2020The placenta undergoes reconstruction at different times during fetal development to supply oxygen and nutrients required throughout pregnancy. To accommodate the rapid...
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.
Topics: Animals; Cell Adhesion Molecules, Neuronal; Endothelial Cells; Female; Fetal Development; Humans; Mice; Mice, Knockout; Oxygen; Placenta; Placentation; Pregnancy; Reproduction; Trophoblasts; Vascular Remodeling
PubMed: 33008099
DOI: 10.3390/ijms21197235 -
Human Reproduction Update Nov 2020The placenta is the active interface between mother and foetus, bearing the molecular marks of rapid development and exposures in utero. The placenta is routinely... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The placenta is the active interface between mother and foetus, bearing the molecular marks of rapid development and exposures in utero. The placenta is routinely discarded at delivery, providing a valuable resource to explore maternal-offspring health and disease in pregnancy. Genome-wide profiling of the human placental transcriptome provides an unbiased approach to study normal maternal-placental-foetal physiology and pathologies.
OBJECTIVE AND RATIONALE
To date, many studies have examined the human placental transcriptome, but often within a narrow focus. This review aims to provide a comprehensive overview of human placental transcriptome studies, encompassing those from the cellular to tissue levels and contextualize current findings from a broader perspective. We have consolidated studies into overarching themes, summarized key research findings and addressed important considerations in study design, as a means to promote wider data sharing and support larger meta-analysis of already available data and greater collaboration between researchers in order to fully capitalize on the potential of transcript profiling in future studies.
SEARCH METHODS
The PubMed database, National Center for Biotechnology Information and European Bioinformatics Institute dataset repositories were searched, to identify all relevant human studies using 'placenta', 'decidua', 'trophoblast', 'transcriptome', 'microarray' and 'RNA sequencing' as search terms until May 2019. Additional studies were found from bibliographies of identified studies.
OUTCOMES
The 179 identified studies were classifiable into four broad themes: healthy placental development, pregnancy complications, exposures during pregnancy and in vitro placental cultures. The median sample size was 13 (interquartile range 8-29). Transcriptome studies prior to 2015 were predominantly performed using microarrays, while RNA sequencing became the preferred choice in more recent studies. Development of fluidics technology, combined with RNA sequencing, has enabled transcript profiles to be generated of single cells throughout pregnancy, in contrast to previous studies relying on isolated cells. There are several key study aspects, such as sample selection criteria, sample processing and data analysis methods that may represent pitfalls and limitations, which need to be carefully considered as they influence interpretation of findings and conclusions. Furthermore, several areas of growing importance, such as maternal mental health and maternal obesity are understudied and the profiling of placentas from these conditions should be prioritized.
WIDER IMPLICATIONS
Integrative analysis of placental transcriptomics with other 'omics' (methylome, proteome and metabolome) and linkage with future outcomes from longitudinal studies is crucial in enhancing knowledge of healthy placental development and function, and in enabling the underlying causal mechanisms of pregnancy complications to be identified. Such understanding could help in predicting risk of future adversity and in designing interventions that can improve the health outcomes of both mothers and their offspring. Wider collaboration and sharing of placental transcriptome data, overcoming the challenges in obtaining sufficient numbers of quality samples with well-defined clinical characteristics, and dedication of resources to understudied areas of pregnancy will undoubtedly help drive the field forward.
Topics: Female; Gene Expression Profiling; Humans; Microarray Analysis; Placenta; Placentation; Pregnancy; Pregnancy Complications; Pregnancy Trimester, First; Trophoblasts
PubMed: 33043357
DOI: 10.1093/humupd/dmaa028 -
Reproduction (Cambridge, England) Jul 2020Appropriate human trophoblast lineage specification and differentiation is crucial for the establishment of normal placentation and maintenance of pregnancy. However,... (Review)
Review
Appropriate human trophoblast lineage specification and differentiation is crucial for the establishment of normal placentation and maintenance of pregnancy. However, due to the lack of proper modeling systems, the molecular mechanisms of these processes are still largely unknown. Much of the early studies in this area have been based on animal models and tumor-derived trophoblast cell lines, both of which are suboptimal for modeling this unique human organ. Recent advances in regenerative and stem cell biology methods have led to development of novel in vitro model systems for studying human trophoblast. These include derivation of human embryonic and induced pluripotent stem cells and establishment of methods for the differentiation of these cells into trophoblast, as well as the more recent derivation of human trophoblast stem cells. In addition, advances in culture conditions, from traditional two-dimensional monolayer culture to 3D culturing systems, have led to development of trophoblast organoid and placenta-on-a-chip model, enabling us to study human trophoblast function in context of more physiologically accurate environment. In this review, we will discuss these various model systems, with a focus on human trophoblast, and their ability to help elucidate the key mechanisms underlying placental development and function. This review focuses on model systems of human trophoblast differentiation, including advantages and limitations of stem cell-based culture, trophoblast organoid, and organ-on-a-chip methods and their applications in understanding placental development and disease.
Topics: Cell Differentiation; Epithelium; Female; Humans; Maternal-Fetal Exchange; Models, Biological; Placenta; Placentation; Pregnancy; Trophoblasts
PubMed: 32485667
DOI: 10.1530/REP-19-0428 -
Reproduction (Cambridge, England) Mar 2021Normal placental development and function is of key importance to fetal growth. Conversely aberrations of placental structure and function are evident in pregnancy... (Review)
Review
Normal placental development and function is of key importance to fetal growth. Conversely aberrations of placental structure and function are evident in pregnancy complications including fetal growth restriction (FGR) and preeclampsia. Although trophoblast turnover and function is altered in these conditions, their underlying aetiologies and pathophysiology remains unclear, which hampers development of therapeutic interventions. Here we review evidence that supports a role for estrogen related receptor-gamma (ESRRG) in the development of placental dysfunction in FGR and preeclampsia. This relationship deserves particular consideration because ESRRG is highly expressed in normal placenta, is reduced in FGR and preeclampsia and its expression is altered by hypoxia, which is thought to result from deficient placentation seen in FGR and preeclampsia. Several studies have also found microRNA (miRNA) or other potential upstream regulators of ESRRG negatively influence trophoblast function which could contribute to placental dysfunction seen in FGR and preeclampsia. Interestingly, miRNAs regulate ESRRG expression in human trophoblast. Thus, if ESRRG is pivotally associated with the abnormal trophoblast turnover and function it may be targeted by microRNAs or other possible upstream regulators in the placenta. This review explores altered expression of ESRRG and upstream regulation of ESRRG-mediated pathways resulting in the trophoblast turnover, placental vascularisation, and placental metabolism underlying placental dysfunctions. This demonstrates that the ESRRG pathway merits further investigation as a potential therapeutic target in FGR and preeclampsia.
Topics: Female; Fetal Growth Retardation; Humans; Placenta; Placenta Diseases; Placentation; Pregnancy; Trophoblasts
PubMed: 33361468
DOI: 10.1530/REP-20-0272 -
Development (Cambridge, England) Jan 2023Hemochorial placentation involves the differentiation of invasive trophoblast cells, specialized cells that possess the capacity to exit the placenta and invade into the...
Hemochorial placentation involves the differentiation of invasive trophoblast cells, specialized cells that possess the capacity to exit the placenta and invade into the uterus where they restructure the vasculature. Invasive trophoblast cells arise from a well-defined compartment within the placenta, referred to as the junctional zone in rat and the extravillous trophoblast cell column in human. In this study, we investigated roles for AKT1, a serine/threonine kinase, in placental development using a genome-edited/loss-of-function rat model. Disruption of AKT1 resulted in placental, fetal and postnatal growth restriction. Forkhead box O4 (Foxo4), which encodes a transcription factor and known AKT substrate, was abundantly expressed in the junctional zone and in invasive trophoblast cells of the rat placentation site. Foxo4 gene disruption using genome editing resulted in placentomegaly, including an enlarged junctional zone. AKT1 and FOXO4 regulate the expression of many of the same transcripts expressed by trophoblast cells, but in opposite directions. In summary, we have identified AKT1 and FOXO4 as part of a regulatory network that reciprocally controls critical indices of hemochorial placenta development.
Topics: Animals; Female; Pregnancy; Rats; Cell Cycle Proteins; Forkhead Transcription Factors; Gene Expression Regulation; Placenta; Placentation; Proto-Oncogene Proteins c-akt; Trophoblasts; Uterus
PubMed: 36607602
DOI: 10.1242/dev.201095 -
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