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Nature Apr 2023The relationship between the human placenta-the extraembryonic organ made by the fetus, and the decidua-the mucosal layer of the uterus, is essential to nurture and...
The relationship between the human placenta-the extraembryonic organ made by the fetus, and the decidua-the mucosal layer of the uterus, is essential to nurture and protect the fetus during pregnancy. Extravillous trophoblast cells (EVTs) derived from placental villi infiltrate the decidua, transforming the maternal arteries into high-conductance vessels. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia. Here we have generated a spatially resolved multiomics single-cell atlas of the entire human maternal-fetal interface including the myometrium, which enables us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to infer the possible transcription factors mediating EVT invasion and show that they are preserved in in vitro models of EVT differentiation from primary trophoblast organoids and trophoblast stem cells. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We predict the cell-cell communication events contributing to trophoblast invasion and placental bed giant cell formation, and model the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provide a comprehensive analysis of postimplantation trophoblast differentiation that can be used to inform the design of experimental models of the human placenta in early pregnancy.
Topics: Female; Humans; Pregnancy; Cell Movement; Multiomics; Placenta; Pregnancy Trimester, First; Trophoblasts; Decidua; Maternal-Fetal Relations; Single-Cell Analysis; Myometrium; Cell Differentiation; Organoids; Stem Cells; Transcriptome; Transcription Factors; Cell Communication
PubMed: 36991123
DOI: 10.1038/s41586-023-05869-0 -
Nature Communications Oct 2022Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year overall survival rate. Patients with PDAC display limited benefits after undergoing chemotherapy or...
Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year overall survival rate. Patients with PDAC display limited benefits after undergoing chemotherapy or immunotherapy modalities. Herein, we reveal that chemotherapy upregulates placental growth factor (PlGF), which directly activates cancer-associated fibroblasts (CAFs) to induce fibrosis-associated collagen deposition in PDAC. Patients with poor prognosis have high PIGF/VEGF expression and an increased number of PIGF/VEGF receptor-expressing CAFs, associated with enhanced collagen deposition. We also develop a multi-paratopic VEGF decoy receptor (Ate-Grab) by fusing the single-chain Fv of atezolizumab (anti-PD-L1) to VEGF-Grab to target PD-L1-expressing CAFs. Ate-Grab exerts anti-tumor and anti-fibrotic effects in PDAC models via the PD-L1-directed PlGF/VEGF blockade. Furthermore, Ate-Grab synergizes with gemcitabine by relieving desmoplasia. Single-cell RNA sequencing identifies that a CD141 CAF population is reduced upon Ate-Grab and gemcitabine combination treatment. Overall, our results elucidate the mechanism underlying chemotherapy-induced fibrosis in PDAC and highlight a combinatorial therapeutic strategy for desmoplastic cancers.
Topics: Female; Humans; Cancer-Associated Fibroblasts; Vascular Endothelial Growth Factor A; Placenta Growth Factor; Single-Chain Antibodies; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Receptors, Vascular Endothelial Growth Factor; Antineoplastic Agents; Fibrosis
PubMed: 36272973
DOI: 10.1038/s41467-022-33991-6 -
Cureus Sep 2022Conjoined twins are described as having been physically fused during pregnancy and delivery. They were first mentioned a long time ago when there was not much known... (Review)
Review
Conjoined twins are described as having been physically fused during pregnancy and delivery. They were first mentioned a long time ago when there was not much known about this. They share some organs that are vital for survival, like the heart; these twins are almost impossible to save, but there are some cases wherein there is evidence of their survival. The article aims to present a unique discussion on conjoined twins. This article talks about the formation of conjoint twins, their types and nomenclatures, embryological concepts, past history/traditional tales, case studies, and the medical enhancements happening in this area. Both fission and fusion are thought to contribute to the disease. A monozygotic twin pregnancy cleaves when it occurs more than thirteen days after fertilization. There is just one placenta and one womb for conjoined twins (one amniotic sac). The twins that are born and stay alive after delivery usually stay alive for a few days or weeks. It's pretty rare for them to live a long prosperous life, but this article shows the otherwise, too, like the Siamese twins, which is a unique example of conjoint twins who lived for a long time. This kind of pregnancy is a complex procedure that needs to be managed by a team of professionals.
PubMed: 36312620
DOI: 10.7759/cureus.29526 -
WormBook : the Online Review of C.... Jan 2006Selective cell fusion is a natural part of development. It is found in sexually reproducing organisms that require fertilization to propagate and in muscles, placenta,... (Review)
Review
Selective cell fusion is a natural part of development. It is found in sexually reproducing organisms that require fertilization to propagate and in muscles, placenta, bones, lens of the eye and stem cells. Cell fusion is particularly important in the development of C. elegans: in addition to 300 sperm and oocytes that fuse during fertilization, 300 of the 1090 somatic cells born, fuse throughout development. Studies of cell fusion in C. elegans have shown that although different types of cells fuse, cell membrane merger is initiated through a common mechanism involving the action of one gene, eff-1. In worms with mutations that inactivate eff-1, almost none of the 300 somatic cells that normally fuse do so, but appear to differentiate, attach and behave in the same way as fusing cells. Such worms develop and survive but have numerous morphological, behavioral and fertility defects associated to cell fusion failure in the epidermis, pharynx, male tail, vulva and uterus. Cell fusion in embryonic dorsal epithelial cells has been analyzed in great detail by confocal microscopy using membrane fluorescent probes, apical junction markers and cytoplasmic aqueous fluorescent probes allowing the direct observation of membrane disappearance, pore expansion and cytoplasmic content mixing. The complete elimination of the membranes between two fusing cells takes about 30 min and involves vesiculation of the fusing membranes. Genetic and cell biological evidence indicates that eff-1 activity is both necessary and sufficient to fuse epithelial and myoepithelial cells in vivo. Based on electron microscopic analyses of intermediates of cell fusion in eff-1 mutants, it appears that eff-1 is required for both initiation and expansion of fusion pores, similar to the fusogen of Influenza virus. While only one gene encoding a novel candidate component of the cell membrane fusion machinery has been found, the nematode's cell fusion program is under the control of many cell-specific transcriptional regulators. A large number of these conserved regulators prevent cell fusion by repressing eff-1 activity. For example, if either ceh-16/engrailed or the GATA factor EGL-18/ELT-5 is inactivated, the lateral epidermal cells that normally do not fuse in the embryo will fuse causing embryonic lethality. And if either the Hox protein lin-39/Deformed or its cofactor ceh-20/Extradenticle is inactivated, the ventral epidermal vulval precursor cells that normally do not fuse in the larvae will fuse and the hermaphrodite will have no vulva. In addition, there is evidence for coordinated and complex regulation of lin-39 in the ventral epidermis by Ras, Wnt, Rb/E2F, NuRD and lin-15 pathways. It appears that in many cells that normally do not fuse, specific transcription complexes repress eff-1 expression preventing cell fusion. ref-2 (REgulator of Fusion-2) encodes a Zn-finger protein that is required to generate ventral Pn.p cells and to keep them unfused both in males and hermaphrodites. ref-2 is necessary, but not sufficient, to maintain Pn.p cells unfused. This review shows that far from cell fusion being an unusual phenomenon, there is the clear prospect that animal cells in all tissues are intrinsically programmed to fuse, and are only prevented from fusing by transcriptional and post-transcriptional control mechanisms. There are three major questions that remain open for future research: (1) How does eff-1 fuse cells? (2) How do Ras, Wnt, Rb, NuRD, E2F, heterochronic and other pathways control cell fusion? (3) What are the implications of cell fusion beyond worms?
Topics: Animals; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Cell Fusion; Cell Membrane; Giant Cells; Humans; Membrane Fusion; Membrane Glycoproteins
PubMed: 18050486
DOI: 10.1895/wormbook.1.52.1 -
MBio Jun 2022Fusobacterium nucleatum, an anaerobic Gram-negative bacterium frequently found in the human oral cavity and some extra-oral sites, is implicated in several important...
Fusobacterium nucleatum, an anaerobic Gram-negative bacterium frequently found in the human oral cavity and some extra-oral sites, is implicated in several important diseases: periodontitis, adverse pregnancy outcomes, and colorectal cancer. To date, how this obligate anaerobe copes with oxidative stress and host immunity within multiple human tissues remains unknown. Here, we uncovered a critical role in this process of a multigene locus encoding a single, fused methionine sulfoxide reductase (MsrAB), a two-component signal transduction system (ModRS), and thioredoxin (Trx)- and cytochrome (CcdA)-like proteins, which are induced when fusobacterial cells are exposed to hydrogen peroxide. Comparative transcriptome analysis revealed that the response regulator ModR regulates a large regulon that includes , , and many metabolic genes. Significantly, specific mutants of the locus, including , are sensitive to reactive oxygen species and defective in adherence/invasion of colorectal epithelial cells. Strikingly, the mutant is also defective in survival in macrophages, and it is severely attenuated in virulence in a mouse model of preterm birth, consistent with its failure to spread to the amniotic fluid and colonize the placenta. Clearly, the MsrAB system regulated by the two-component system ModRS represents a major oxidative stress defense pathway that protects fusobacteria against oxidative damage in immune cells and confers virulence by enabling attachment and invasion of multiple target tissues. F. nucleatum colonizes various human tissues, including oral cavity, placenta, and colon. How this obligate anaerobe withstands oxidative stress in host immune cells has not been described. We report here that F. nucleatum possesses a five-gene locus encoding a fused methionine sulfoxide reductase (MsrAB), a two-component signal transduction system (ModRS), and thioredoxin- and cytochrome -like proteins. Regulated by ModRS, MsrAB is essential for resistance to reactive oxygen species, adherence/invasion of colorectal epithelial cells, and survival in macrophage. Unable to colonize placenta and spread to amniotic fluid, the mutant failed to induce preterm birth in a murine model.
Topics: Animals; Carrier Proteins; Colorectal Neoplasms; Cytochromes c; Female; Fusobacterium nucleatum; Humans; Infant, Newborn; Methionine Sulfoxide Reductases; Mice; Oxidative Stress; Pregnancy; Premature Birth; Reactive Oxygen Species; Thioredoxins; Virulence
PubMed: 35420473
DOI: 10.1128/mbio.03022-21 -
The Journal of Biological Chemistry 2021Formations of myofibers, osteoclasts, syncytiotrophoblasts, and fertilized zygotes share a common step, cell-cell fusion. Recent years have brought about considerable... (Review)
Review
Formations of myofibers, osteoclasts, syncytiotrophoblasts, and fertilized zygotes share a common step, cell-cell fusion. Recent years have brought about considerable progress in identifying some of the proteins involved in these and other cell-fusion processes. However, even for the best-characterized cell fusions, we still do not know the mechanisms that regulate the timing of cell-fusion events. Are they fully controlled by the expression of fusogenic proteins or do they also depend on some triggering signal that activates these proteins? The latter scenario would be analogous to the mechanisms that control the timing of exocytosis initiated by Ca influx and virus-cell fusion initiated by low pH- or receptor interaction. Diverse cell fusions are accompanied by the nonapoptotic exposure of phosphatidylserine at the surface of fusing cells. Here we review data on the dependence of membrane remodeling in cell fusion on phosphatidylserine and phosphatidylserine-recognizing proteins and discuss the hypothesis that cell surface phosphatidylserine serves as a conserved "fuse me" signal regulating the time and place of cell-fusion processes.
Topics: Cell Fusion; Exocytosis; Humans; Phosphatidylserines; Signal Transduction; Virus Internalization
PubMed: 33581114
DOI: 10.1016/j.jbc.2021.100411 -
Journal of Toxicologic Pathology Oct 2023A fused triplet placenta was observed in a Wistar Hannover rat on gestation day 15. Each placenta (referred to as PL-A, PL-B, and PL-C) of this fused placenta was...
A fused triplet placenta was observed in a Wistar Hannover rat on gestation day 15. Each placenta (referred to as PL-A, PL-B, and PL-C) of this fused placenta was attached to one fetus each, but their fetal weights were lower than that of the fetus attached to the only normal placenta (referred to as PL-N) in this dam. Histopathologically, thinning of the trophoblastic septa and dilatation of the maternal sinusoid in the labyrinth zone were observed in PL-B and PL-C, but not in PL-A or PL-N. The points of placental fusion were at the junctional zone derived from each side of the placenta without connective tissues, and the septum was composed of trophoblastic giant cells. Although PL-A had a solitary metrial gland, PL-B and PL-C shared one metrial gland with one spiral artery terminus branching towards each labyrinth zone.
PubMed: 37868115
DOI: 10.1293/tox.2023-0026 -
The International Journal of... 2010While the aortic region, the para-aortic splanchnopleura/aorta-gonads-mesonephros (P-Sp/AGM) is currently considered as the source of definitive hematopoietic stem cells... (Review)
Review
While the aortic region, the para-aortic splanchnopleura/aorta-gonads-mesonephros (P-Sp/AGM) is currently considered as the source of definitive hematopoietic stem cells during development, the mouse placenta has been found to generate large numbers of these cells and to remain functional in this respect for a longer period than the P-Sp/AGM. The fetal component, which derives from the fused allantois and chorion, is responsible for this activity. We and others have shown that the pre-fusion allantois (before the stage of 6 pairs of somites) is able to yield clonogenic progenitors, provided that it is pre-cultured in toto before it is dissociated into single cells and seeded in semi-solid medium. Thus placental hematopoiesis can be concluded to derive from intrinsic precursors. It is similar in this regard to the yolk sac which both produces hematopoietic progenitors and supports their multiplication and differentiation. Hematopoietic activity, detected by in vitro colony assays, has also been recently uncovered in the human placenta. According to the data available, this newly identified source probably provides a large number of HSC during development and must play a foremost role in founding the definitive hematopoietic system.
Topics: Allantois; Animals; Chick Embryo; Female; Hematopoiesis; Hematopoietic Stem Cells; Hematopoietic System; Mice; Placenta; Pregnancy
PubMed: 20563985
DOI: 10.1387/ijdb.093047fd -
Cell Death Discovery Oct 2023As an essential component of the maternal-fetal interface, the placental syncytiotrophoblast layer contributes to a successful pregnancy by secreting hormones necessary... (Review)
Review
As an essential component of the maternal-fetal interface, the placental syncytiotrophoblast layer contributes to a successful pregnancy by secreting hormones necessary for pregnancy, transporting nutrients, mediating gas exchange, balancing immune tolerance, and resisting pathogen infection. Notably, the deficiency in mononuclear trophoblast cells fusing into multinucleated syncytiotrophoblast has been linked to adverse pregnancy outcomes, such as preeclampsia, fetal growth restriction, preterm birth, and stillbirth. Despite the availability of many models for the study of trophoblast fusion, there exists a notable disparity from the ideal model, limiting the deeper exploration into the placental development. Here, we reviewed the existing models employed for the investigation of human trophoblast fusion from several aspects, including the development history, latest progress, advantages, disadvantages, scope of application, and challenges. The literature searched covers the monolayer cell lines, primary human trophoblast, placental explants, human trophoblast stem cells, human pluripotent stem cells, three-dimensional cell spheres, organoids, and placenta-on-a-chip from 1938 to 2023. These diverse models have significantly enhanced our comprehension of placental development regulation and the underlying mechanisms of placental-related disorders. Through this review, our objective is to provide readers with a thorough understanding of the existing trophoblast fusion models, making it easier to select most suitable models to address specific experimental requirements or scientific inquiries. Establishment and application of the existing human placental trophoblast fusion models.
PubMed: 37816723
DOI: 10.1038/s41420-023-01670-0