Comparative analysis of the syncytiotrophoblast in placenta tissue and trophoblast organoids using snRNA sequencing
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ABSTRACT:
PROVIDER: PRJNA1218790 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32893500.fastq.gz | Fastqsanger.gz | |||
| SRR32893501.fastq.gz | Fastqsanger.gz | |||
| SRR32893502.fastq.gz | Fastqsanger.gz | |||
| SRR32893503.fastq.gz | Fastqsanger.gz | |||
| SRR32893504.fastq.gz | Fastqsanger.gz |
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Project description:The outer surface of chorionic villi in the human placenta consists of a single multinucleated cell called the syncytiotrophoblast (STB). The unique cellular ultrastructure of the STB presents challenges in deciphering its gene expression signature at the single-cell level, as the STB contains billions of nuclei in a single cell. There are many gaps in understanding the molecular mechanisms and developmental trajectories involved in STB formation and differentiation. To identify the underlying control of the STB, we performed comparative single nucleus (SN) and single cell (SC) RNA sequencing on placental tissue and tissue-derived trophoblast organoids (TOs). We found that SN was essential to capture the STB population from both tissue and TOs. Differential gene expression and pseudotime analysis of TO-derived STB identified three distinct nuclear subtypes reminiscent of those recently identified in vivo. These included a juvenile nuclear population that exhibited both CTB and STB marker expression, a population enriched in genes involved in oxygen sensing, and finally a subtype enriched in transport and GTPase signaling molecules. Notably, suspension culture conditions of TOs that restore the native orientation of the STB (STBout) showed elevated expression of canonical STB markers and pregnancy hormones, along with a greater proportion of the STB nucleus subtype specializing in transport and GTPase signaling, compared to those cultivated with an inverted STB polarity (STBin). Gene regulatory analysis identified novel markers of STB differentiation conserved in tissue and TOs, including the chromatin remodeler RYBP, that exhibited STB-specific RNA and protein expression. CRISPR/Cas9 knock out of RYBP in STBin TOs did not affect cell-cell fusion, but bulk sequencing demonstrates the downregulation of the pregnancy hormone CSH1 and upregulation of many genes that define the oxygen sensing STB nuclear subtype. Finally, we compared STB gene expression signatures amongst first trimester tissue, full-term tissue, and TOs, identifying many commonalities but also notable variability across each sample type. This indicates that STB gene expression is responsive to its environmental context. Our findings emphasize the utility of TOs to accurately model STB differentiation and the distinct nuclear subtypes observed in vivo, offering a versatile platform for unraveling the molecular mechanisms governing STB functions in placental biology and disease. The processed datasets can be visualized online at https://gladfelterlab.shinyapps.io/PlacentaRNAsequencing/.
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Project description:TFEB, a bHLH-leucine zipper transcription factor belonging to the MiT/TFE family, globally modulates cell metabolism by regulating autophagy and lysosomal functions. Remarkably, loss of TFEB in mice causes embryonic lethality due to severe defects in placentation associated with aberrant vascularization and resulting hypoxia. However, the molecular mechanism underlying this phenotype has remained elusive. By integrating multi-omics approaches with functional assays, we have uncovered an unprecedented function for TFEB in promoting the formation of a functional syncytiotrophoblast in the placenta. Our findings demonstrate that syncytiotrophoblast formation is marked by TFEB nuclear translocation and binding to the promoters of crucial placental genes, including genes encoding fusogenic proteins (Syncytin-1 and Syncythin-2) and enzymes involved in steroidogenic pathways, such as CYP19A1, the rate-limiting enzyme for the synthesis of 17β-Estradiol (E2). Conversely, TFEB depletion impairs both syncytial fusion and endocrine properties of syncytiotrophoblast, as demonstrated by a significant decrease in the secretion of placental hormones and E2 production. Notably, restoration of TFEB expression resets syncytiotrophoblast identity. Our findings identify that TFEB controls placental development and function by orchestrating both the transcriptional program underlying trophoblast fusion and the acquisition of endocrine function, which are crucial for the bioenergetic requirements of embryonic development.
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Project description:TFEB, a bHLH-leucine zipper transcription factor belonging to the MiT/TFE family, is a renowned global modulator of cell metabolism by regulating autophagy and lysosomal functions. Remarkably, loss of TFEB in mice causes embryonic lethality due to severe defects in placentation associated with aberrant vascularization and resulting hypoxia. However, the molecular mechanism underlying the described phenotype has yet to be elucidated. By integrating multi-omics approaches with functional assays, we uncover an unprecedented function for TFEB in promoting the formation of a functional syncytiotrophoblast in the placenta. Here, we showed that syncytiotrophoblast formation is marked by TFEB nuclear translocation and its association with the promoters of crucial placental genes, including fusogenic proteins (Syncytin-1 and Syncythin-2) and enzymes involved in the steroidogenic pathway, such as CYP19A1, the rate-limiting enzyme for the synthesis of 17β-Estradiol (E2). Conversely, the depletion of TFEB negatively impacts both the syncytial fusion and the endocrine properties of the syncytiotrophoblast, as demonstrated by a significant decrease in the secretion of placenta hormones and E2 production. Notably, the restoration of TFEB expression resets the syncytiotrophoblast identity. Finally, we identified reduced expression levels of TFEB and its target CYP19A1 in the placenta of pre-eclampsia women, suggesting that dysregulation of the TFEB-CYP19A1 axis might underlie the impairment of placental steroidogenesis described in pre-eclampsia. Our findings elect TFEB as a central controller of the metabolic properties of the placenta by orchestrating both the transcriptional program underlying trophoblast fusion and the acquisition of endocrine function, which are crucial for the bioenergetic requirements of embryonic development.
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2018-11-28 | E-MTAB-7204 | biostudies-arrayexpress
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.
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Project description:Trophoblast organoids derived from placental villi provide a 3D model system of human placental development, but access to first-trimester tissues is limited. Here we report that trophoblast stem cells isolated from naïve human pluripotent stem cells (hPSCs) can efficiently self-organize into 3D stem cell-derived trophoblast organoids (SC-TOs) with a villous architecture similar to primary trophoblast organoids. Single cell transcriptome analysis reveals the presence of distinct cytotrophoblast and syncytiotrophoblast clusters and a small cluster of extravillous trophoblasts, which closely correspond to trophoblast identities in the post-implantation embryo. These organoid cultures display clonal X chromosome inactivation patterns previously described in the human placenta. We further demonstrate that SC-TOs exhibit selective vulnerability to emerging pathogens (SARS-CoV-2 and Zika virus), which correlates with expression levels of their respective entry factors. The generation of trophoblast organoids from naïve hPSCs provides an accessible 3D model system of the developing placenta and its susceptibility to emerging pathogens.
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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.
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