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Cell Jan 2024Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism... (Review)
Review
Mounting evidence suggests metabolism instructs stem cell fate decisions. However, how fetal metabolism changes during development and how altered maternal metabolism shapes fetal metabolism remain unexplored. We present a descriptive atlas of in vivo fetal murine metabolism during mid-to-late gestation in normal and diabetic pregnancy. Using C-glucose and liquid chromatography-mass spectrometry (LC-MS), we profiled the metabolism of fetal brains, hearts, livers, and placentas harvested from pregnant dams between embryonic days (E)10.5 and 18.5. Our analysis revealed metabolic features specific to a hyperglycemic environment and signatures that may denote developmental transitions during euglycemic development. We observed sorbitol accumulation in fetal tissues and altered neurotransmitter levels in fetal brains isolated from hyperglycemic dams. Tracing C-glucose revealed disparate fetal nutrient sourcing depending on maternal glycemic states. Regardless of glycemic state, histidine-derived metabolites accumulated in late-stage fetal tissues. Our rich dataset presents a comprehensive overview of in vivo fetal tissue metabolism and alterations due to maternal hyperglycemia.
Topics: Animals; Female; Mice; Pregnancy; Diabetes Mellitus; Fetus; Glucose; Placenta; Diabetes, Gestational
PubMed: 38070508
DOI: 10.1016/j.cell.2023.11.011 -
Physiological Reviews Oct 2023The placenta is a unique organ system that functionally combines both maternal and fetal cell types with distinct lineage origins. Normal placentation is critical for... (Review)
Review
The placenta is a unique organ system that functionally combines both maternal and fetal cell types with distinct lineage origins. Normal placentation is critical for developmental progression and reproductive success. Although the placenta is best known for its nutrient supply function to the fetus, genetic experiments in mice highlight that the placenta is also pivotal for directing the proper formation of specific fetal organs. These roles underscore the importance of the placenta for pregnancy outcome and lifelong health span, which makes it essential to better understand the molecular processes governing placental development and function and to find adequate models to study it. In this review, we provide an overview of placental development and highlight the instructional role of the epigenome in dictating cell fate decisions specifically in the placental trophoblast cell lineage. We then focus on recent advances in exploring stem cell and organoid models reflecting the feto-maternal interface in mice and humans that provide much-improved tools to study events in early development. We discuss stem cells derived from the placenta as well as those artificially induced to resemble the placenta, and how they can be combined with embryonic stem cells and with endometrial cell types of the uterus to reconstitute the early implantation site. We then allude to the exciting prospects of how these models can be harnessed in biomedicine to enhance our understanding of the pathological underpinnings of pregnancy complications in a patient-specific manner, and ultimately to facilitate therapeutic approaches of tissue- and organ-based regenerative medicine.
Topics: Pregnancy; Female; Humans; Animals; Mice; Placenta; Trophoblasts; Placentation; Cell Differentiation; Epigenesis, Genetic
PubMed: 37171808
DOI: 10.1152/physrev.00001.2023 -
Advanced Science (Weinheim,... Sep 2023The interaction between trophoblasts, stroma cells, and immune cells at the maternal-fetal interface constitutes the functional units of the placenta, which is crucial...
The interaction between trophoblasts, stroma cells, and immune cells at the maternal-fetal interface constitutes the functional units of the placenta, which is crucial for successful pregnancy outcomes. However, the investigation of this intricate interplay is restricted due to the absence of efficient experimental models. To address this challenge, a robust, reliable methodology for generating placenta villi organoids (PVOs) from early, late, or diseased pregnancies using air-liquid surface culture is developed. PVOs contain cytotrophoblasts that can self-renew and differentiate directly, along with stromal elements that retain native immune cells. Analysis of scRNA sequencing and WES data reveals that PVOs faithfully recapitulate the cellular components and genetic alterations of the corresponding source tissue. Additionally, PVOs derived from patients with preeclampsia exhibit specific pathological features such as inflammation, antiangiogenic imbalance, and decreased syncytin expression. The PVO-based propagation of primary placenta villi should enable a deeper investigation of placenta development and exploration of the underlying pathogenesis and therapeutics of placenta-originated diseases.
Topics: Pregnancy; Female; Humans; Placenta; Chorionic Villi; Placentation; Trophoblasts; Organoids
PubMed: 37438660
DOI: 10.1002/advs.202301565 -
Archives of Gynecology and Obstetrics May 2024Preeclampsia is a major cause of health problems for both pregnant women and unborn babies worldwide. However, the underlying causes of preeclampsia are not fully... (Review)
Review
PURPOSE
Preeclampsia is a major cause of health problems for both pregnant women and unborn babies worldwide. However, the underlying causes of preeclampsia are not fully understood, leading to limited effective treatments. The goal of this study is to enhance our knowledge of its causes, devise prevention strategies, and develop treatments.
METHODS
We performed a systematic literature search. Six models regarding the pathogenesis of preeclampsia are discussed in this review.
RESULTS
This review focuses on the latest advancements in understanding preeclampsia's origins. Preeclampsia is a complex condition caused by various factors, processes, and pathways. Reduced blood flow and oxygen to the uterus and placenta, heightened inflammatory reactions, immune imbalances, altered genetic changes, imbalanced blood vessel growth factors, and disrupted gut bacteria may contribute to its development.
CONCLUSION
Preeclampsia is thought to result from the interplay of these factors.
Topics: Pregnancy; Female; Humans; Pre-Eclampsia; Placenta; Uterus
PubMed: 38421424
DOI: 10.1007/s00404-024-07393-6 -
International Journal of Molecular... Apr 2024We are pleased to present this Special Issue of the , entitled "Physiology and Pathophysiology of Placenta 2 [...].
We are pleased to present this Special Issue of the , entitled "Physiology and Pathophysiology of Placenta 2 [...].
Topics: Humans; Placenta; Pregnancy; Female; Animals; Placenta Diseases
PubMed: 38731805
DOI: 10.3390/ijms25094586 -
Nature Genetics Feb 2024The human placenta has a vital role in ensuring a successful pregnancy. Despite the growing body of knowledge about its cellular compositions and functions, there has...
The human placenta has a vital role in ensuring a successful pregnancy. Despite the growing body of knowledge about its cellular compositions and functions, there has been limited research on the heterogeneity of the billions of nuclei within the syncytiotrophoblast (STB), a multinucleated entity primarily responsible for placental function. Here we conducted integrated single-nucleus RNA sequencing and single-nucleus ATAC sequencing analyses of human placentas from early and late pregnancy. Our findings demonstrate the dynamic heterogeneity and developmental trajectories of STB nuclei and their correspondence with human trophoblast stem cell (hTSC)-derived STB. Furthermore, we identified transcription factors associated with diverse STB nuclear lineages through their gene regulatory networks and experimentally confirmed their function in hTSC and trophoblast organoid-derived STBs. Together, our data provide insights into the heterogeneity of human STB and represent a valuable resource for interpreting associated pregnancy complications.
Topics: Pregnancy; Humans; Female; Placenta; Multiomics; Trophoblasts; Cell Nucleus; Transcription Factors; Cell Differentiation
PubMed: 38267607
DOI: 10.1038/s41588-023-01647-w -
International Journal of Molecular... May 2024This Special Issue comprises original articles in the field of clinical studies whose major topics concern the genetic and immunological aspects of miscarriage and...
This Special Issue comprises original articles in the field of clinical studies whose major topics concern the genetic and immunological aspects of miscarriage and pre-eclampsia, the isolation of decidua macrophages and Hofbauer cells in the placenta for diagnostic purposes, and epigenetic mechanisms that trigger labor [...].
Topics: Humans; Pregnancy; Female; Placenta; Abortion, Spontaneous; Reproduction; Pre-Eclampsia; Macrophages; Decidua
PubMed: 38791171
DOI: 10.3390/ijms25105132 -
Seminars in Perinatology Feb 2024Stillbirth affects a large proportion of pregnancies world-wide annually and continues to be a major public health concern. Several causes of stillbirth have been...
Stillbirth affects a large proportion of pregnancies world-wide annually and continues to be a major public health concern. Several causes of stillbirth have been identified and include obstetrical complications, placental abnormalities, fetal malformations, infections, and medical complications in pregnancy. Placental abnormalities such as placental abruption, chorioangioma, vasa previa, and umbilical cord abnormalities have been identified as causes of death for a significant proportion of stillbirths. In the absence of placental abnormalities, the gross and histologic changes in the placenta in stillbirth are found when secondary to other etiologies. Here we describe both gross and histologic changes of the placenta that are associated with stillbirth.
Topics: Pregnancy; Female; Humans; Stillbirth; Placenta; Placenta Diseases; Abruptio Placentae; Public Health
PubMed: 38199875
DOI: 10.1016/j.semperi.2023.151871 -
EBioMedicine Jul 2023Preeclampsia (PE) is a common hypertensive pregnancy disorder associated with shallow trophoblast invasion. Although bone morphogenetic protein 2 (BMP2) has been shown...
BACKGROUND
Preeclampsia (PE) is a common hypertensive pregnancy disorder associated with shallow trophoblast invasion. Although bone morphogenetic protein 2 (BMP2) has been shown to promote trophoblast invasion in vitro, its cellular origin and molecular regulation in placenta, as well as its potential role in PE, has yet to be established. Additionally, whether BMP2 and/or its downstream molecules could serve as potential diagnostic or therapeutic targets for PE has not been explored.
METHODS
Placentas and sera from PE and healthy pregnant women were subjected to multi-omics analyses, immunoblots, qPCR, and ELISA assays. Immortalized trophoblast cells, primary cultures of human trophoblasts, and first-trimester villous explants were used for in vitro experiments. Adenovirus expressing sFlt-1 (Ad Flt1)-induced PE rat model was used for in vivo studies.
FINDINGS
We find globally decreased H3K27me3 modifications and increased BMP2 signalling in preeclamptic placentas, which is negatively correlated with clinical manifestations. BMP2 is derived from Hofbauer cells and epigenetically regulated by H3K27me3 modification. BMP2 promotes trophoblast invasion and vascular mimicry by upregulating BMP6 via BMPR1A-SMAD2/3-SMAD4 signalling. BMP2 supplementation alleviates high blood pressure and fetal growth restriction phenotypes in Ad Flt1-induced rat PE model.
INTERPRETATION
Our findings demonstrate that epigenetically regulated Hofbauer cell-derived BMP2 signalling enhancement in late gestation could serve as a compensatory response for shallow trophoblast invasion in PE, suggesting opportunities for diagnostic marker and therapeutic target applications in PE clinical management.
FUNDING
National Key Research and Development Program of China (2022YFC2702400), National Natural Science Foundation of China (82101784, 82171648, 31988101), and Natural Science Foundation of Shandong Province (ZR2020QH051, ZR2020MH039).
Topics: Pregnancy; Humans; Female; Rats; Animals; Trophoblasts; Histones; Pre-Eclampsia; Bone Morphogenetic Protein 2; Placenta; Cell Movement
PubMed: 37331163
DOI: 10.1016/j.ebiom.2023.104664 -
Clinical Microbiology Reviews Jun 2024SUMMARYViral infections during pregnancy are associated with significant adverse perinatal and fetal outcomes. Pregnancy is a unique immunologic and physiologic state,... (Review)
Review
SUMMARYViral infections during pregnancy are associated with significant adverse perinatal and fetal outcomes. Pregnancy is a unique immunologic and physiologic state, which can influence control of virus replication, severity of disease, and vertical transmission. The placenta is the organ of the maternal-fetal interface and provides defense against microbial infection while supporting the semi-allogeneic fetus via tolerogenic immune responses. Some viruses, such as cytomegalovirus, Zika virus, and rubella virus, can breach these defenses, directly infecting the fetus and having long-lasting consequences. Even without direct placental infection, other viruses, including respiratory viruses like influenza viruses and severe acute respiratory syndrome coronavirus 2, still cause placental damage and inflammation. Concentrations of progesterone and estrogens rise during pregnancy and contribute to immunological adaptations, placentation, and placental development and play a pivotal role in creating a tolerogenic environment at the maternal-fetal interface. Animal models, including mice, nonhuman primates, rabbits, and guinea pigs, are instrumental for mechanistic insights into the pathogenesis of viral infections during pregnancy and identification of targetable treatments to improve health outcomes of pregnant individuals and offspring.
Topics: Pregnancy; Female; Humans; Pregnancy Complications, Infectious; Animals; Virus Diseases; Placenta; Infectious Disease Transmission, Vertical; Disease Models, Animal
PubMed: 38421182
DOI: 10.1128/cmr.00073-23