Trophoblast syncytialization maintains the placenta-heart axis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE229265 | GEO | 2024/01/06
REPOSITORIES: GEO
Similar Datasets
Project description:Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent research demonstrates that the placenta adapts to nutrient insufficiency through mTOR inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype directing extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. Endogenous TFEB deficiency significantly impaired STB differentiation in trophoblast cells and placenta organoids. Mechanistically, TFEB conferred direct transcriptional regulation of the fusogen ERVFRD-1 in human trophoblasts and thereby profoundly promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. In line with the in vitro findings, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Moreover, TFEB directs the trophoblast syncytialization response driven by mTORC1 signaling. Importantly, TFEB expression positively correlates with the reinforced trophoblast syncytialization in human fetal growth restriction (FGR) placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.
2024-06-16 | GSE252253 | GEO
Project description:Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent research demonstrates that the placenta adapts to nutrient insufficiency through mTOR inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype directing extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. Endogenous TFEB deficiency significantly impaired STB differentiation in trophoblast cells and placenta organoids. Mechanistically, TFEB conferred direct transcriptional regulation of the fusogen ERVFRD-1 in human trophoblasts and thereby profoundly promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. In line with the in vitro findings, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Moreover, TFEB directs the trophoblast syncytialization response driven by mTORC1 signaling. Importantly, TFEB expression positively correlates with the reinforced trophoblast syncytialization in human fetal growth restriction (FGR) placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.
2024-06-16 | GSE252252 | GEO
Project description:Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent research demonstrates that the placenta adapts to nutrient insufficiency through mTOR inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype directing extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. Endogenous TFEB deficiency significantly impaired STB differentiation in trophoblast cells and placenta organoids. Mechanistically, TFEB conferred direct transcriptional regulation of the fusogen ERVFRD-1 in human trophoblasts and thereby profoundly promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. In line with the in vitro findings, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Moreover, TFEB directs the trophoblast syncytialization response driven by mTORC1 signaling. Importantly, TFEB expression positively correlates with the reinforced trophoblast syncytialization in human fetal growth restriction (FGR) placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.
2024-06-16 | GSE252251 | GEO
Project description:The mammalian genome contains two ERK/MAP kinase kinase genes, Map2k1 and Map2k2, encoding dual-specificity kinases responsible for ERK/MAP kinase activation. Loss of Map2k1 function in mouse causes embryonic lethality due to placental defects, while Map2k2 mutant mice survive with a normal lifespan. The Map2k1 mutation interferes with the growth of the labyrinthine region of the placenta and its vascularization. Map2k1+/-Map2k2+/- embryos also die during gestation of underdevelopment of the labyrinth. In Map2k1+/-Map2k2+/- mutants, the vascularization of the labyrinth is reduced and defects in SynT-II formation lead to the accumulation of multinucleated trophoblasts giant cells (MTG). Deletion of both Map2k1 alleles in allantoïs-derived tissues in Map2k1+/ Map2k2+/- placenta (Map2k1flox/-Map2k2+/-Tg+/Sox2Cre) increases the penetrance and the expressivity of the MTG placental phenotype. Microarray analysis with RNA extracted from placentas of E12.5 wt, Map2k1+/-Map2k2+/- and Map2k1flox/-Map2k2+/-Tg+/Sox2Cre embryos was performed to evaluate the molecular impact of the loss of Map2k alleles on placenta development. Total RNA was isolated from placentas of E12.5 Map2k1+/+Map2k2+/+(control), from E12.5 Map2k1+/-Map2k2+/- embryos (experimental) and from E12.5 and Map2k1flox/-Map2k2+/-Tg+/Sox2Cre embryos (experimental). Four specimens were analyzed per genotype.
2014-08-01 | E-GEOD-51644 | biostudies-arrayexpress
Project description:The mammalian genome contains two ERK/MAP kinase kinase genes, Map2k1 and Map2k2, encoding dual-specificity kinases responsible for ERK/MAP kinase activation. Loss of Map2k1 function in mouse causes embryonic lethality due to placental defects, while Map2k2 mutant mice survive with a normal lifespan. The Map2k1 mutation interferes with the growth of the labyrinthine region of the placenta and its vascularization. Map2k1+/-Map2k2+/- embryos also die during gestation of underdevelopment of the labyrinth. In Map2k1+/-Map2k2+/- mutants, the vascularization of the labyrinth is reduced and defects in SynT-II formation lead to the accumulation of multinucleated trophoblasts giant cells (MTG). Deletion of both Map2k1 alleles in allantoïs-derived tissues in Map2k1+/ Map2k2+/- placenta (Map2k1flox/-Map2k2+/-Tg+/Sox2Cre) increases the penetrance and the expressivity of the MTG placental phenotype. Microarray analysis with RNA extracted from placentas of E12.5 wt, Map2k1+/-Map2k2+/- and Map2k1flox/-Map2k2+/-Tg+/Sox2Cre embryos was performed to evaluate the molecular impact of the loss of Map2k alleles on placenta development.
2014-08-01 | GSE51644 | GEO
Project description:Cellular senescence is a permanent state of cell cycle arrest that protects the organism from tumorigenesis and regulates tissue integrity upon damage. Recently, several studies have shown that senescence plays a role in embryonic and placental development. Molecular markers of senescence are expressed in human syncytiotrophoblast, but the molecular mechanisms that govern senescence in these cells are not yet understood. To unravel the molecular mechanisms that mediate the impact of senescence on the placenta, we studied human syncytiotrophoblast in culture. We isolated cytotrophoblast cells from human term placentas. In culture, cytotrophoblast cells spontaneously differentiate into syncytium, creating the large multinucleated syncytiotrophoblast structure that can be monitored and studied for its molecular and cellular characteristics (Kliman et al., 1986; Li and Schust, 2015). We performed mRNA profiling on two human term placenta trophoblast cultures, at 1.5, 2, 3 and 5 days after seeding.
2018-10-01 | GSE118351 | GEO
Project description:The placenta establishes a maternal–fetal exchange interface which ensures transportation of nutrients and gases between the mother and the fetus. A critically conserved step in the establishment of this exchange surface in mammals is the fusion of trophoblast cells into a multinucleated syncytiotrophoblasts (SynT). In mice, SynTs develop via differentiation of the labyrinth trophoblast progenitors (LaTP) of the developing placenta, and in humans, SynTs develop via differentiation of villous cytotrophoblast (CTB) progenitors. Despite being an indispensable step for mammalian development in utero, conserved molecular mechanisms that ensure SynT development are poorly understood. Herein, we show that GATA2 and GATA3 (GATA factors) plays an essential role in labyrinth trophoblast progenitors (LaTPs) thereby committing these cells towards the SynT differentiation program. Mature syncytial layer specific immunostaining with established markers, and ultrastructure analysis of the labyrinth revealed that the loss of GATA factors was impairing the formation of mature SynT cells. We therefore focused our attention on the status of the labyrinth progenitor trophoblast cells in the GATA DKO vs the control placentae. To do that we performed single cell RNA Sequencing (scRNA-Seq) with E9.5 control and Gcm1Cre GATA KO placentae.
2024-01-26 | GSE214389 | GEO
Project description:The human placenta is covered by a single multinucleated fetal cell, the syncytiotrophoblast, which is bathed in maternal blood. During all pregnancies, membrane enclosed extracellular vesicles derived from the syncytiotrophoblast are extruded into the maternal blood.The large size of these extracellular vesicles (diameter larger than 10 µm) is referred to as trophoblast debris in this study. We have shown in the past that trophoblast debris from first trimester can contribute to maternal cardiovascular physiological adaptations. This study aimed to characterise the transcriptional changes that occur in human vascular endothelial cells following exposure to preeclmaptic and normotensive trophoblast debris. Primeview human gene expression arrays were used to probe transcriptomic changes in human microvascular endothelial cells after exposure to preeclmaptic or normotensive trophoblast debris for 21 hours
2019-08-22 | GSE86032 | GEO
Project description:The human placenta is covered by a single multinucleated fetal cell, the syncytiotrophoblast, which is bathed in maternal blood. During all pregnancies, membrane enclosed extracellular vesicles derived from the syncytiotrophoblast are extruded into the maternal blood.The large size of these extracellular vesicles (diameter larger than 10µm) is referred to as trophoblastic debris in this study. We have shown in the past that endothleial cells are involved in clearence of this trophoblastic debris and induction of immune tolerence by trophoblastic debris.This study aimed to characterise the transcriptional changes that occur in human vascular endothelial cells following exposure to trophoblastic debris from normal first trimester placentae. Microarrays were used to probe transcriptomic changes 2 and 21 hours after exposure of endothelial cells (Human microvascular endothelial cell line,HMEC-1) to trophoblastic debris from normal first trimester placentae
2016-08-21 | GSE69996 | GEO
Project description:In most mammalian species, a critical step of placental development is the fusion of trophoblast cell into a multinucleated syncytiotrophoblast layer, which separates the fetal and maternal blood circulations. Advancement in understanding this process came from the identification of two pairs of envelope genes of retroviral origin, independently acquired by the human (syncytin-1 and M-^V2) and mouse (syncytin-A and M-^VB) genomes, specifically expressed in the placenta and with in vitro cell-cell fusion activity. We previously showed that syncytin-A is involved in the formation of one of the two syncytiotrophoblast layer of the mouse placenta -ST-I , facing the maternal lacuna- with syncytin-A null embryos dying at mid-gestation, and their placenta disclosing impaired formation of the ST-I layer. Here by generating syncytin-B KO mice, we demonstrated that syncytin-B null placenta have defects in formation of the syncytiotrophoblast layer-II facing the fetal blood vessels, with refined electron microscopy analyses showing evidence of unfused apposed cells. Lack of trophoblast fusion is associated with signs of trophoblast degeneration and with formation of huge maternal blood lacuna, ultimately disrupting the architecture of the labyrinth layer. These alterations did not result in complete abortion of syncytin-B null embryos, at variance with the syncytin-A KO phenotype, but in a reduced proportion of homozygous syncytin-B knockout individuals at birth, with evidence of late-onset embryonic growth retardation. Double knockout mice experiments demonstrate a premature death of syncytin-A null embryos if syncytin-B is deleted, thus strongly suggesting cooperative involvement of both syncytiotrophoblast layer-I and layer-II for the structural and functional integrity of the maternofetal interface and exchanges. Finally, a microarray analysis of wild-type and syncytin-B null placenta transcripts disclosed alterations in gene expression level for only a very limited number of genes, with the largest change (a 7-fold induction in the syncytin-B null placenta) observed for the connexin-30 gene. Immunohistochemistry further localized the connexin-30 protein in the labyrinth zone of mutant placenta, at the level of the fetomaternal interface. It is proposed that this might correspond to a compensatory process whereby disruption of syncytialization in syncytin-B knockout placenta is counteracted by an enhanced, gap junction mediated, cell-cell communication. These data demonstrate that syncytin-B is required for ST-II syncytial differentiation and the functional integrity of the labyrinth. Altogether, these findings definitively demonstrate that the two endogenous retroviral syncytin-A and -B Env genes contribute independently to the formation of the two syncytiotrophoblast layers during placenta formation, and provide additional insights into the subtle mechanisms of syncytiotrophoblast differentiation in the mouse. Experimental design: Placenta RNA of embryos homozygous for the syncytin-B deletion (SynB-/-) were compared to placental RNA of wild-type embryos (SynB+/+) of the same litter. Two stages of gestation, day 12 and d14, were analyzed. At day 12, 3 litters were obtained; for two of them, the RNAs were analyzed individually, and for the third one, placenta RNAs of the wild-type genotype were pooled. At day 14, one litter was obtained; RNA samples with the same genotype were pooled
2011-10-19 | E-TABM-1188 | biostudies-arrayexpress