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Nature Genetics Feb 2024The human placenta has a vital role in ensuring a successful pregnancy. Despite the growing body of knowledge about its cellular compositions and functions, there has...
The human placenta has a vital role in ensuring a successful pregnancy. Despite the growing body of knowledge about its cellular compositions and functions, there has been limited research on the heterogeneity of the billions of nuclei within the syncytiotrophoblast (STB), a multinucleated entity primarily responsible for placental function. Here we conducted integrated single-nucleus RNA sequencing and single-nucleus ATAC sequencing analyses of human placentas from early and late pregnancy. Our findings demonstrate the dynamic heterogeneity and developmental trajectories of STB nuclei and their correspondence with human trophoblast stem cell (hTSC)-derived STB. Furthermore, we identified transcription factors associated with diverse STB nuclear lineages through their gene regulatory networks and experimentally confirmed their function in hTSC and trophoblast organoid-derived STBs. Together, our data provide insights into the heterogeneity of human STB and represent a valuable resource for interpreting associated pregnancy complications.
Topics: Pregnancy; Humans; Female; Placenta; Multiomics; Trophoblasts; Cell Nucleus; Transcription Factors; Cell Differentiation
PubMed: 38267607
DOI: 10.1038/s41588-023-01647-w -
Science Advances Feb 2024The initiation of human pregnancy is marked by the implantation of an embryo into the uterine environment; however, the underlying mechanisms remain largely elusive. To...
The initiation of human pregnancy is marked by the implantation of an embryo into the uterine environment; however, the underlying mechanisms remain largely elusive. To address this knowledge gap, we developed hormone-responsive endometrial organoids (EMO), termed apical-out (AO)-EMO, which emulate the in vivo architecture of endometrial tissue. The AO-EMO comprise an exposed apical epithelium surface, dense stromal cells, and a self-formed endothelial network. When cocultured with human embryonic stem cell-derived blastoids, the three-dimensional feto-maternal assembloid system recapitulates critical implantation stages, including apposition, adhesion, and invasion. Endometrial epithelial cells were subsequently disrupted by syncytial cells, which invade and fuse with endometrial stromal cells. We validated this fusion of syncytiotrophoblasts and stromal cells using human blastocysts. Our model provides a foundation for investigating embryo implantation and feto-maternal interactions, offering valuable insights for advancing reproductive medicine.
Topics: Pregnancy; Female; Humans; Embryo Implantation; Endometrium; Blastocyst; Embryo, Mammalian; Trophoblasts
PubMed: 38394208
DOI: 10.1126/sciadv.adi4819 -
Science Advances Nov 2023Early-onset preeclampsia (EOPE) is a severe pregnancy complication associated with defective trophoblast differentiation and functions at implantation, but manifestation...
Early-onset preeclampsia (EOPE) is a severe pregnancy complication associated with defective trophoblast differentiation and functions at implantation, but manifestation of its phenotypes is in late pregnancy. There is no reliable method for early prediction and treatment of EOPE. Adrenomedullin (ADM) is an abundant placental peptide in early pregnancy. Integrated single-cell sequencing and spatial transcriptomics confirm a high ADM expression in the human villous cytotrophoblast and syncytiotrophoblast. The levels of ADM in chorionic villi and serum were lower in first-trimester pregnant women who later developed EOPE than those with normotensive pregnancy. ADM stimulates differentiation of trophoblast stem cells and trophoblast organoids in vitro. In pregnant mice, placenta-specific ADM suppression led to EOPE-like phenotypes. The EOPE-like phenotypes in a mouse PE model were reduced by a placenta-specific nanoparticle-based forced expression of ADM. Our study reveals the roles of trophoblastic ADM in placental development, EOPE pathogenesis, and its potential clinical uses.
Topics: Pregnancy; Female; Mice; Humans; Animals; Pre-Eclampsia; Trophoblasts; Adrenomedullin; Placenta; Cell Differentiation
PubMed: 37922358
DOI: 10.1126/sciadv.adi4777 -
Frontiers in Immunology 2023A successful human pregnancy requires the maternal immune system to recognize and tolerate the semi-allogeneic fetus, allowing for appropriate trophoblasts invasion and... (Review)
Review
A successful human pregnancy requires the maternal immune system to recognize and tolerate the semi-allogeneic fetus, allowing for appropriate trophoblasts invasion and protecting the fetus from invading pathogens. Therefore, maternal immunity is critical for the establishment and maintenance of pregnancy, especially at the maternal-fetal interface. Anatomically, the maternal-fetal interface has both maternally- and fetally- derived cells, including fetal originated trophoblasts and maternal derived immune cells and stromal cells. Besides, a commensal microbiota in the uterus was supposed to aid the unique immunity in pregnancy. The appropriate crosstalk between fetal derived and maternal originated cells and uterine microbiota are critical for normal pregnancy. Dysfunctional maternal-fetal interactions might be associated with the development of pregnancy complications. This review elaborates the latest knowledge on the interactions between trophoblasts and decidual immune cells, highlighting their critical roles in maternal-fetal tolerance and pregnancy development. We also characterize the role of commensal bacteria in promoting pregnancy progression. Furthermore, this review may provide new thought on future basic research and the development of clinical applications for pregnancy complications.
Topics: Pregnancy; Female; Humans; Decidua; Fetus; Uterus; Trophoblasts; Pregnancy Complications
PubMed: 37350956
DOI: 10.3389/fimmu.2023.1198430 -
Frontiers in Endocrinology 2023The human endometrium is only receptive to an implanting blastocyst in the mid-secretory phase of each menstrual cycle. Such time-dependent alterations in function... (Review)
Review
The human endometrium is only receptive to an implanting blastocyst in the mid-secretory phase of each menstrual cycle. Such time-dependent alterations in function require intricate interplay of various factors, largely coordinated by estrogen and progesterone. Abnormal endometrial receptivity is thought to contribute to two-thirds of the implantation failure in humans and therefore significantly hindering IVF success. Despite the incontrovertible importance of endometrial receptivity in implantation, the precise mechanisms involved in the regulation of endometrial receptivity remain poorly defined. This is mainly due to a lack of proper models that recapitulate the environment of the receptive human endometrium. Organoids were recently established from human endometrium with promising features to better mimic the receptive phase. Endometrial organoids show long-term expandability and the capability to preserve the structural and functional characteristics of the endometrial tissue of origin. This three-dimensional model maintains a good responsiveness to steroid hormones and replicates key morphological features of the receptive endometrium , including pinopodes and pseudostratified epithelium. Here, we review the current findings of endometrial organoid studies that have been focused on investigating endometrial receptivity and place an emphasis on methods to further refine and improve this model.
Topics: Female; Humans; Endometrium; Menstrual Cycle; Blastocyst; Embryo Implantation; Organoids
PubMed: 37693361
DOI: 10.3389/fendo.2023.1158515 -
Nucleic Acids Research Jun 2023Endogenous retroviruses (ERVs) have been proposed as a driving force for the evolution of the mammalian placenta, however, the contribution of ERVs to placental...
Endogenous retroviruses (ERVs) have been proposed as a driving force for the evolution of the mammalian placenta, however, the contribution of ERVs to placental development and the underlying regulatory mechanism remain largely elusive. A key process of placental development is the formation of multinucleated syncytiotrophoblasts (STBs) in direct contact with maternal blood, through which constitutes the maternal-fetal interface critical for nutrient allocation, hormone production and immunological modulation during pregnancy. We delineate that ERVs profoundly rewire the transcriptional program of trophoblast syncytialization. Here, we first determined the dynamic landscape of bivalent ERV-derived enhancers with dual occupancy of H3K27ac and H3K9me3 in human trophoblast stem cells (hTSCs). We further demonstrated that enhancers overlapping several ERV families tend to exhibit increased H3K27ac and reduced H3K9me3 occupancy in STBs relative to hTSCs. Particularly, bivalent enhancers derived from the Simiiformes-specific MER50 transposons were linked to a cluster of genes important for STB formation. Importantly, deletions of MER50 elements adjacent to several STB genes, including MFSD2A and TNFAIP2, significantly attenuated their expression concomitant to compromised syncytium formation. Together, we propose that ERV-derived enhancers, MER50 specifically, fine-tune the transcriptional networks accounting for human trophoblast syncytialization, which sheds light on a novel ERV-mediated regulatory mechanism underlying placental development.
Topics: Animals; Female; Humans; Pregnancy; Endogenous Retroviruses; Gene Expression Regulation; Mammals; Placenta; Trophoblasts; Enhancer Elements, Genetic
PubMed: 36864754
DOI: 10.1093/nar/gkad109 -
Nature Communications Sep 2023Zika virus (ZIKV) infection during pregnancy threatens pregnancy and fetal health. However, the infectivity and pathological effects of ZIKV on placental trophoblast...
Zika virus (ZIKV) infection during pregnancy threatens pregnancy and fetal health. However, the infectivity and pathological effects of ZIKV on placental trophoblast progenitor cells in early human embryos remain largely unknown. Here, using human trophoblast stem cells (hTSCs), we demonstrated that hTSCs were permissive to ZIKV infection, and resistance to ZIKV increased with hTSC differentiation. Combining gene knockout and transcriptome analysis, we demonstrated that the intrinsic expression of AXL and TIM-1, and the absence of potent interferon (IFN)-stimulated genes (ISGs) and IFNs contributed to the high sensitivity of hTSCs to ZIKV. Furthermore, using our newly developed hTSC-derived trophoblast organoid (hTSC-organoid), we demonstrated that ZIKV infection disrupted the structure of mature hTSC-organoids and inhibited syncytialization. Single-cell RNA sequencing (scRNA-seq) further demonstrated that ZIKV infection of hTSC-organoids disrupted the stemness of hTSCs and the proliferation of cytotrophoblast cells (CTBs) and probably led to a preeclampsia (PE) phenotype. Overall, our results clearly demonstrate that hTSCs represent the major target cells of ZIKV, and a reduced syncytialization may result from ZIKV infection of early developing placenta. These findings deepen our understanding of the characteristics and consequences of ZIKV infection of hTSCs in early human embryos.
Topics: Pregnancy; Humans; Female; Trophoblasts; Placenta; Zika Virus; Zika Virus Infection; Organoids
PubMed: 37684223
DOI: 10.1038/s41467-023-41158-0 -
EBioMedicine Jul 2023Preeclampsia (PE) is a common hypertensive pregnancy disorder associated with shallow trophoblast invasion. Although bone morphogenetic protein 2 (BMP2) has been shown...
BACKGROUND
Preeclampsia (PE) is a common hypertensive pregnancy disorder associated with shallow trophoblast invasion. Although bone morphogenetic protein 2 (BMP2) has been shown to promote trophoblast invasion in vitro, its cellular origin and molecular regulation in placenta, as well as its potential role in PE, has yet to be established. Additionally, whether BMP2 and/or its downstream molecules could serve as potential diagnostic or therapeutic targets for PE has not been explored.
METHODS
Placentas and sera from PE and healthy pregnant women were subjected to multi-omics analyses, immunoblots, qPCR, and ELISA assays. Immortalized trophoblast cells, primary cultures of human trophoblasts, and first-trimester villous explants were used for in vitro experiments. Adenovirus expressing sFlt-1 (Ad Flt1)-induced PE rat model was used for in vivo studies.
FINDINGS
We find globally decreased H3K27me3 modifications and increased BMP2 signalling in preeclamptic placentas, which is negatively correlated with clinical manifestations. BMP2 is derived from Hofbauer cells and epigenetically regulated by H3K27me3 modification. BMP2 promotes trophoblast invasion and vascular mimicry by upregulating BMP6 via BMPR1A-SMAD2/3-SMAD4 signalling. BMP2 supplementation alleviates high blood pressure and fetal growth restriction phenotypes in Ad Flt1-induced rat PE model.
INTERPRETATION
Our findings demonstrate that epigenetically regulated Hofbauer cell-derived BMP2 signalling enhancement in late gestation could serve as a compensatory response for shallow trophoblast invasion in PE, suggesting opportunities for diagnostic marker and therapeutic target applications in PE clinical management.
FUNDING
National Key Research and Development Program of China (2022YFC2702400), National Natural Science Foundation of China (82101784, 82171648, 31988101), and Natural Science Foundation of Shandong Province (ZR2020QH051, ZR2020MH039).
Topics: Pregnancy; Humans; Female; Rats; Animals; Trophoblasts; Histones; Pre-Eclampsia; Bone Morphogenetic Protein 2; Placenta; Cell Movement
PubMed: 37331163
DOI: 10.1016/j.ebiom.2023.104664