Insulin Receptor Substrate 2 regulates placental syncytiotrophoblast differentiation at the maternal-fetal interface
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE310183 | GEO | 2026/09/03
REPOSITORIES: GEO
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Project description:<p>Background: Placental metabolic abnormalities are linked to pregnancy complications such as preeclampsia, gestational diabetes mellitus and fetal growth restriction. However, little is known about how the metabolic processes regulate placental development and trophoblast differentiation. The adipokine chemerin has elevated serum levels in pregnant women and regulates placental lipid metabolism, potentially playing a role in both placental development and trophoblast differentiation.</p><p>Results: In this study, we observed the increased chemerin expression on the serum and placenta from the pregnant mice. Chemerin is highly expressed in the extraembryonic primary parietal trophoblast giant cells and the ectoplacental cone (EPC) trophoblast cells. Excessive chemerin treatment in mice results in the increased placental lipid accumulation, promotes the expansion of glycogen trophoblast cell (GlyT) and syncytiotrophoblast, and restricts the growth of spongiotrophoblast (SpT) and sinusoidal trophoblast giant cell (S-TGC). Chemerin deficiency led to increased expression of placental fatty acid oxidation enzymes and disrupted the proliferation of SpT and S-TGC in the labyrinth. Furthermore, we utilized the fatty acid oxidation inhibitor etomoxir, demonstrated that blocking fatty acid oxidation hinders the proliferation of SpT and S-TGC in the labyrinth.</p><p>Conclusions: Our study demonstrated that chemerin-related lipid metabolism is crucial for EPC trophoblast differentiation during placental development, providing evidence that chemerin determines the growth of SpT and S-TGC through fatty acid oxidation. These findings also imply a possible pathological mechanism for pregnancy complications associated with chemerin.</p>
2025-06-13 | MTBLS12552 | MetaboLights
Project description:The glycosylphosphatidylinositol (GPI) biosynthetic pathway in the endoplasmic reticulum (ER) is crucial for generating GPI-anchored proteins (GPI-APs), which are translocated to the cell surface and play a vital role in cell signaling and adhesion. This study focuses on two integral components of the GPI pathway, the PIGL and PIGF proteins, and their significance in trophoblast biology. We show that GPI pathway mutations impact on placental development impairing the development of the syncytiotrophoblast (SynT), and especially the SynT-II layer, which is essential for the establishment of the definitive nutrient exchange area within the placental labyrinth. CRISPR/Cas9 knockout of Pigl and Pigf in mouse trophoblast stem cells (mTSC) confirms the role of these GPI enzymes in syncytiotrophoblast differentiation. Mechanistically, impaired GPI-AP generation induces an excessive unfolded protein response (UPR) in the ER in mTSCs growing in stem cell conditions, akin to what is observed in human preeclampsia. Remarkably, the transcriptomic profile of Pigl- and Pigf-deficient cells separates human patient placental samples into preeclampsia and control groups suggesting an involvement of Pigl and Pigf in establishing a preeclamptic gene signature. Upon differentiation, the impairment of the GPI pathway hinders the induction of WNT signaling for early SynT-II development. Our study unveils the pivotal role of GPI biosynthesis in early placentation and uncovers a new preeclampsia gene expression profile associated with mutations in the GPI biosynthesis pathway, providing novel molecular insights into placental development with implications for enhanced patient stratification and timely interventions.
2024-05-19 | GSE266153 | GEO
Project description:The placenta establishes the interface between maternal and fetal tissues during pregnancy, enabling the selective exchange of nutrients and gases between maternal and fetal circulations. In humans and mice, this exchange surface is lined by a multinucleated epithelial layer called the syncytiotrophoblast (SynT). SynT formation from trophoblast precursors requires epithelial plasticity to permit cell differentiation, fusion, and morphogenesis, while preserving epithelial integrity to maintain the maternal-fetal exchange barrier. However, the mechanisms that safeguard epithelial features during SynT development remain unclear. OVO-like 2 (OVOL2), a transcriptional repressor of mesenchymal programs and key regulator of epithelial identity, is highly expressed in the mouse placenta and essential for its development. We hypothesized that OVOL2 promotes SynT lineage formation by restricting mesenchymal transformation during trophoblast differentiation. To test this, placental development was examined following Ovol2+/- matings, and wild-type and Ovol2-deficient trophoblast stem cells were analyzed under stem conditions or differentiated with CHIR99021 to enrich for SynT lineages. SynT lineage development was disrupted in both Ovol2-deficient placentas and differentiating trophoblast stem cells. Chromatin profiling identified OVOL2 binding near genes associated with epithelial-to-mesenchymal transition, including Id1, Zeb1, and Vim, which were upregulated in Ovol2-deficient trophoblasts. Consistent with these observations, Ovol2-deficient cells showed elevated levels of mesenchymal markers such as ZEB1 and Vimentin and reduced levels of epithelial markers including E-cadherin. These findings identify OVOL2 as a critical regulator of SynT lineage formation and epithelial identity in the mouse placenta.
2026-08-31 | GSE324788 | GEO
Project description:The placenta establishes the interface between maternal and fetal tissues during pregnancy, enabling the selective exchange of nutrients and gases between maternal and fetal circulations. In humans and mice, this exchange surface is lined by a multinucleated epithelial layer called the syncytiotrophoblast (SynT). SynT formation from trophoblast precursors requires epithelial plasticity to permit cell differentiation, fusion, and morphogenesis, while preserving epithelial integrity to maintain the maternal-fetal exchange barrier. However, the mechanisms that safeguard epithelial features during SynT development remain unclear. OVO-like 2 (OVOL2), a transcriptional repressor of mesenchymal programs and key regulator of epithelial identity, is highly expressed in the mouse placenta and essential for its development. We hypothesized that OVOL2 promotes SynT lineage formation by restricting mesenchymal transformation during trophoblast differentiation. To test this, placental development was examined following Ovol2+/- matings, and wild-type and Ovol2-deficient trophoblast stem cells were analyzed under stem conditions or differentiated with CHIR99021 to enrich for SynT lineages. SynT lineage development was disrupted in both Ovol2-deficient placentas and differentiating trophoblast stem cells. Chromatin profiling identified OVOL2 binding near genes associated with epithelial-to-mesenchymal transition, including Id1, Zeb1, and Vim, which were upregulated in Ovol2-deficient trophoblasts. Consistent with these observations, Ovol2-deficient cells showed elevated levels of mesenchymal markers such as ZEB1 and Vimentin and reduced levels of epithelial markers including E-cadherin. These findings identify OVOL2 as a critical regulator of SynT lineage formation and epithelial identity in the mouse placenta.
2026-08-31 | GSE324789 | 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 developmental connection between the placenta and certain embryonic organs, such as the heart, is associated with normal pregnancy and complications, but how the placenta governs embryonic cardiogenesis is poorly understood. Trophoblasts fuse into a multinucleated syncytiotrophoblast (SynT) layer, primarily consisting of a placental materno-fetal interface. We identify that endogenous progesterone immunomodulatory binding factor 1 (PIBF1) is essential for trophoblast differentiation and fusion into SynT in human trophoblasts and mouse placentas. Moreover, SynT-derived PIBF1 enables the communication between SynT and adjacent vascular cells to develop the vascular network in the primary placenta and further impacts the early development of the embryonic cardiovascular system in an endocrine manner. Thus, SynT-derived factors and SynT itself in the placenta may play crucial roles in the proper organogenesis of other organs in the embryo.
2024-01-06 | GSE229265 | GEO
Project description:This study investigates the role of the calcium-permeable ion channel TRPV2 in placental development, with a focus on trophoblast differentiation and syncytiotrophoblast lineage specification. Using a conditional knockout mouse model, we demonstrate that loss of Trpv2 leads to placental abnormalities characterized by impaired labyrinth organization and reduced vascularization. In situ hybridization reveal that Trpv2 is expressed in specific trophoblast subpopulations, including syncytiotrophoblast lineage cells. To assess transcriptional consequences of Trpv2 loss at the tissue level, bulk RNA sequencing was performed on isolated placental labyrinth tissue from control and knockout embryos at mid- and late gestation stages. To complement the in vivo analysis, we generated Trpv2 knockout mouse trophoblast stem cells (mTSCs) using CRISPR/Cas9 and performed bulk RNA sequencing under stem and differentiation conditions. These experiments were designed to identify cell-autonomous transcriptional changes and to assess the role of TRPV2 in regulating trophoblast differentiation programs.
2026-08-13 | GSE334003 | 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
Project description:Background Placental metabolic abnormalities are linked to pregnancy complications such as preeclampsia, gestational diabetes mellitus, and fetal growth restriction. However, little is known about how the metabolic processes regulate placental development and trophoblast differentiation. The adipokine chemerin has elevated serum levels in pregnant women and regulates placental lipid metabolism, potentially playing a role in both placental development and trophoblast differentiation. Results In this study, we observed the increased chemerin expression on the serum and placenta from the pregnant mice. Chemerin is highly expressed in the extraembryonic primary parietal trophoblast giant cells and the ectoplacental cone (EPC) trophoblast cells. Excessive chemerin treatment in mice results in the increased placental lipid accumulation, promotes the expansion of glycogen trophoblast cell (GlyT) and syncytiotrophoblast, and restricts the growth of spongiotrophoblast (SpT) and sinusoidal trophoblast giant cell (S-TGC). Chemerin deficiency led to increased expression of placental fatty acid oxidation enzymes and disrupted the proliferation of SpT and S-TGC in the labyrinth. Furthermore, we utilized the fatty acid oxidation inhibitor etomoxir, demonstrated that blocking fatty acid oxidation hinders the proliferation of SpT and S-TGC in the labyrinth. Conclusions Our study demonstrated that chemerin-related lipid metabolism is crucial for EPC trophoblast differentiation during placental development, providing evidence that chemerin determines the growth of SpT and S-TGC through fatty acid oxidation. These findings also imply a possible pathological mechanism for pregnancy complications associated with chemerin.
2025-06-05 | GSE298315 | GEO
Project description:While placental functioning arbitrates fetal outcome, the molecular players that underpin normal placental development remain poorly understood. Here, we provide evidence that the Transient Receptor Potential Vanilloid 2 (TRPV2) channel plays an important role in normal placental development, determining fetal size and survival. Its absence severely affects placental morphology, causing fetal growth restriction and embryonic lethality, which was found to be allocated to a non-redundant role in the trophoblast, but not in the embryo. CRISPR/Cas9-mediated Trpv2 deletion in mouse trophoblast stem cells demonstrated that Trpv2 contributes to the differentiation towards Syncytiotrophoblast layer II (SynTII) cells, which was confirmed by the growth restriction phenotype in SynTII-specific Trpv2 knockout animals. Finally, TRPV2 was functionally expressed in human trophoblast cells and enriched in trophoblast populations undergoing syncytial differentiation. Together, our findings identify an important role for TRPV2 during placental development and consequently fetal outcomes.
2026-08-28 | GSE344692 | GEO