Evolved Levels of Placental Invasion in Human and Bovine Endometrial Stroma
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ABSTRACT:
ORGANISM(S): Bos taurus Homo sapiens
PROVIDER: GSE136299 | GEO | 2019/10/24
REPOSITORIES: GEO
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Project description:The hemochorial placentation site is characterized by a dynamic interplay between trophoblast cells and maternal cells. These cells cooperate to establish an interface required for nutrient delivery to promote fetal growth. In the human, trophoblast cells penetrate deep into the uterus. This is not a consistent feature of hemochorial placentation and has hindered the establishment of suitable animal models. The rat represents an intriguing model for investigating hemochorial placentation with deep trophoblast cell invasion. In this study, we used single cell RNA sequencing to characterize the transcriptome of the invasive trophoblast cell lineage, as well as other cell populations within the rat uterine-placental interface during early (gestation day, gd, 15.5) and late (gd 19.5) stages of intrauterine trophoblast cell invasion. We identified a robust set of transcripts that define invasive trophoblast cells, as well as transcripts that distinguished endothelial, smooth muscle, natural killer, and macrophage cells. Invasive trophoblast, immune, and endothelial cell populations exhibited distinct spatial relationships within the uterine-placental interface. Furthermore, the maturation stage of invasive trophoblast cell development could be determined by assessing gestation-stage dependent changes in transcript expression. Finally, and most importantly, expression of a prominent subset of rat invasive trophoblast cell transcripts is conserved in the invasive extravillous trophoblast cell lineage of the human placenta. These findings provide foundational data to identify and interrogate key conserved regulatory mechanisms essential for development and function of an important compartment within the hemochorial placentation site that is essential for a healthy pregnancy.
2022-09-20 | GSE206086 | GEO
Project description:The secretome of cancer and stromal cells generates a microenvironment which contributes to tumour cell invasion and angiogenesis. Here, we compare the secretome of human mammary normal fibroblasts and cancer-associated fibroblasts (CAF). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminse-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase which reduces TGM2 and regulate TGM2 binding to its cofactors. Finally, CLIC3 is secreted also by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers, and its levels correlate with poor clinical outcome. This work reveals an unprecedented invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion.
2016-12-13 | PXD002444 | Pride
Project description:Establishment of the hemochorial placentation site requires the exodus of trophoblast cells from the placenta and their transformative actions on the uterine vasculature, which is a critical but poorly understood developmental process. CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) is a member of the CITED protein family of co-regulators and has been shown to possess roles in embryogenesis, including placenta development. We examined the involvement of CITED2 in the rat, which exhibits deep hemochorial placentation, a feature it shares with the human. CITED2 is distinctively expressed in the junctional zone compartment of the rat placentation site and in intrauterine invasive trophoblast cells. Homozygous disruption of the rat Cited2 locus resulted in placental and fetal growth restriction and abnormalities in heart and lung development, which are also characteristic of the CITED deficient mouse model. However, other features of the mouse Cited2 null phenotype, including exencephaly, adrenal gland agenesis, and prenatal lethality were not associated with CITED2 deficiency in the rat. Trophoblast-specific lentiviral CITED2 knockdown in the rat yielded a growth arrested placental phenotype. Smaller Cited2 null placentas were associated with a growth restricted junctional zone and coincided with a delay in intrauterine trophoblast cell invasion. Invasive trophoblast cells arise from the junctional zone. Transcriptomes of the junctional zone, the invasive trophoblast cell lineage, and differentiating trophoblast stem cells were affected by CITED2 disruption, as were placental adaptations to hypoxia and exposure to viral mimetics. Evidence for the conservation of CITED2 expression in human placental tissue and conserved actions in invasive/extravillous trophoblast cell development were demonstrated. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation.
2023-05-18 | GSE203192 | GEO
Project description:Establishment of the hemochorial placentation site requires the exodus of trophoblast cells from the placenta and their transformative actions on the uterine vasculature, which is a critical but poorly understood developmental process. CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) is a member of the CITED protein family of co-regulators and has been shown to possess roles in embryogenesis, including placenta development. We examined the involvement of CITED2 in the rat, which exhibits deep hemochorial placentation, a feature it shares with the human. CITED2 is distinctively expressed in the junctional zone compartment of the rat placentation site and in intrauterine invasive trophoblast cells. Homozygous disruption of the rat Cited2 locus resulted in placental and fetal growth restriction and abnormalities in heart and lung development, which are also characteristic of the CITED deficient mouse model. However, other features of the mouse Cited2 null phenotype, including exencephaly, adrenal gland agenesis, and prenatal lethality were not associated with CITED2 deficiency in the rat. Trophoblast-specific lentiviral CITED2 knockdown in the rat yielded a growth arrested placental phenotype. Smaller Cited2 null placentas were associated with a growth restricted junctional zone and coincided with a delay in intrauterine trophoblast cell invasion. Invasive trophoblast cells arise from the junctional zone. Transcriptomes of the junctional zone, the invasive trophoblast cell lineage, and differentiating trophoblast stem cells were affected by CITED2 disruption, as were placental adaptations to hypoxia and exposure to viral mimetics. Evidence for the conservation of CITED2 expression in human placental tissue and conserved actions in invasive/extravillous trophoblast cell development were demonstrated. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation.
2023-05-18 | GSE202338 | GEO
Project description:Establishment of the hemochorial placentation site requires the exodus of trophoblast cells from the placenta and their transformative actions on the uterine vasculature, which is a critical but poorly understood developmental process. CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) is a member of the CITED protein family of co-regulators and has been shown to possess roles in embryogenesis, including placenta development. We examined the involvement of CITED2 in the rat, which exhibits deep hemochorial placentation, a feature it shares with the human. CITED2 is distinctively expressed in the junctional zone compartment of the rat placentation site and in intrauterine invasive trophoblast cells. Homozygous disruption of the rat Cited2 locus resulted in placental and fetal growth restriction and abnormalities in heart and lung development, which are also characteristic of the CITED deficient mouse model. However, other features of the mouse Cited2 null phenotype, including exencephaly, adrenal gland agenesis, and prenatal lethality were not associated with CITED2 deficiency in the rat. Trophoblast-specific lentiviral CITED2 knockdown in the rat yielded a growth arrested placental phenotype. Smaller Cited2 null placentas were associated with a growth restricted junctional zone and coincided with a delay in intrauterine trophoblast cell invasion. Invasive trophoblast cells arise from the junctional zone. Transcriptomes of the junctional zone, the invasive trophoblast cell lineage, and differentiating trophoblast stem cells were affected by CITED2 disruption, as were placental adaptations to hypoxia and exposure to viral mimetics. Evidence for the conservation of CITED2 expression in human placental tissue and conserved actions in invasive/extravillous trophoblast cell development were demonstrated. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation.
2023-05-18 | GSE202337 | GEO
Project description:Establishment of the hemochorial placentation site requires the exodus of trophoblast cells from the placenta and their transformative actions on the uterine vasculature, which is a critical but poorly understood developmental process. CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl terminal domain 2 (CITED2) is a member of the CITED protein family of co-regulators and has been shown to possess roles in embryogenesis, including placenta development. We examined the involvement of CITED2 in the rat, which exhibits deep hemochorial placentation, a feature it shares with the human. CITED2 is distinctively expressed in the junctional zone compartment of the rat placentation site and in intrauterine invasive trophoblast cells. Homozygous disruption of the rat Cited2 locus resulted in placental and fetal growth restriction and abnormalities in heart and lung development, which are also characteristic of the CITED deficient mouse model. However, other features of the mouse Cited2 null phenotype, including exencephaly, adrenal gland agenesis, and prenatal lethality were not associated with CITED2 deficiency in the rat. Trophoblast-specific lentiviral CITED2 knockdown in the rat yielded a growth arrested placental phenotype. Smaller Cited2 null placentas were associated with a growth restricted junctional zone and coincided with a delay in intrauterine trophoblast cell invasion. Invasive trophoblast cells arise from the junctional zone. Transcriptomes of the junctional zone, the invasive trophoblast cell lineage, and differentiating trophoblast stem cells were affected by CITED2 disruption, as were placental adaptations to hypoxia and exposure to viral mimetics. Evidence for the conservation of CITED2 expression in human placental tissue and conserved actions in invasive/extravillous trophoblast cell development were demonstrated. We conclude that CITED2 is a conserved regulator of deep hemochorial placentation.
2023-05-18 | GSE202336 | GEO
Project description:Evolved Levels of Placental Invasion in Human and Bovine Endometrial Stroma
| PRJNA562073 | ENA
Project description:Invasive trophoblast cells are critical to spiral artery remodeling in hemochorial placentation. Insufficient trophoblast invasion and vascular remodeling can lead to pregnancy disorders including preeclampsia, preterm birth, and intrauterine growth restriction. Previous studies in the mouse identified achaete-scute homolog 2 (ASCL2) as essential to extraembryonic development. We hypothesized that ASCL2 is a critical and conserved regulator of invasive trophoblast 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 report, we investigated invasive/extravillous trophoblast (EVT) cell differentiation using human trophoblast stem (TS) cells and a loss-of-function mutant Ascl2 rat model. ASCL2 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 upregulation of ASCL2 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 downregulation of EVT cell-associated transcripts and upregulation 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 species-specific modulator of the syncytiotrophoblast lineage.
2021-03-01 | GSE154350 | GEO
Project description:The tumor microenvironment modifies the malignancy of tumors. In solid tumors this environment is populated by many macrophages (tumor-associated macrophages; TAMs) that in genetic studies that depleted these cells from mouse models of breast cancer were shown to promote tumor progression to malignancy and increase metastatic potential. Mechanistic studies showed that these effects are through the stimulation of tumor cell migration, invasion, intravasation as well as an enhancement of angiogenesis. Using an in vivo invasion assay it was demonstrated that invasive carcinoma cells are a unique sub-population of tumor cells whose invasion and chemotaxis is dependent upon the co-migration of TAMs with obligate reciprocal signaling through an EGF/CSF-1 paracrine loop. In this study these invasion-promoting macrophages were isolated and subjected to analysis of their transcriptome in comparison to TAMs isolated indiscriminately to function using established macrophage markers by flow cytometry. Five biological replicates for each population (Invasive and General TAM) were used.
2010-05-16 | E-GEOD-18295 | biostudies-arrayexpress
Project description:After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or pre-eclampsia (PE). Placental growth factor (PlGF) can increase cell stiffness contributing to pathological angiogenesis but the biomechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine vasculature by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signalling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signalling. Taken together, perturbed PlGF-NFAT5-SGK1 mechano-signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs -endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.
2024-10-17 | PXD051697 | Pride