Trophoblast Syncytialization Research Articles

Alteration of Trophoblast Syncytialization by Plasmodium falciparum-Infected Erythrocytes.

Malaria during pregnancy has been associated with significant risks to both the mother and the fetus, leading to complications such as anemia, low birth weight, and increased infant mortality. The trophoblast cells, a key component of the placenta, are crucial for nutrient and oxygen exchange between mother and fetus. The differentiation of cytotrophoblasts (CTBs) into syncytiotrophoblasts (STBs) is critical for proper pregnancy development. These cells form the bi-stratified epithelium surrounding the placental villi. While previous studies have described an inflammatory activation of STB cells exposed to Plasmodium falciparum-infected erythrocytes (P. falciparum-IE) or components such as hemozoin (HZ), little is known about the direct effect this parasite may have on the epithelial turnover and function of trophoblast cells. This study aims to contribute to understanding mechanisms leading to placental damage during placental malaria using a BeWo cell line as a differentiation model. It was found that P. falciparum-IE interferes with the fusion of BeWo cells, affecting the differentiation process of trophoblast. A reduction in syncytialization could be associated with the adverse effects of infection in fetal health, altering the remodeling of the trophoblast epithelial barrier and reducing their capacity to exchange substances. However, further studies are necessary to assess alterations in the functionality of this epithelium.

Elevated levels of KLF12 impair trophoblast syncytialization via GCM1 downregulation

Objective: Placental dysfunction is a major contributor to miscarriages in humans. We observed elevated expression of Kruppel-like factor 12 (KLF12) in placental villi of women who experienced miscarriage compared to that in women with healthy pregnancies. This study aimed to elucidate the role of KLF12 in maintaining a successful pregnancy. Methods: To investigate the role of KLF12 in placentation, we employed a model of forskolin-induced syncytialization in BeWo cells. Results: Our findings revealed that KLF12 expression is downregulated during normal syncytialization. Conversely, we observed that abnormally high KLF12 levels directly suppressed glial cells missing-1 (GCM1) expression. This suppression of GCM1 expression subsequently impaired BeWo cell syncytialization. Furthermore, we observed placental deformities in KLF12-overexpressing mouse fetuses. Conclusion: This study demonstrated that elevated levels of KLF12 disrupt trophoblast syncytialization by downregulating GCM1 expression. These findings suggest that KLF12 may be a novel candidate gene contributing to unexplained miscarriages.

TFEB safeguards trophoblast syncytialization in humans and mice

Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent study demonstrated that the placenta adapts to nutrient insufficiency through mechanistic target of rapamycin (mTOR) inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype mediating 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. TFEB deficiency significantly impaired STB differentiation in human trophoblasts and placenta organoids. Consistently, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Mechanistically, TFEB conferred direct transcriptional activation of the fusogen ERVFRD-1 in human trophoblasts and thereby promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. Moreover, we demonstrated that TFEB directed the trophoblast syncytialization response driven by mTOR complex 1 (mTORC1) signaling. TFEB expression positively correlated with the reinforced trophoblast syncytialization in human fetal growth-restricted 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.

Comprehensive analytics for virus-cell and cell-cell multinucleation system

Cell-fusion mediated generation of multinucleated syncytia represent critical feature during viral infection and in development. Efficiency of syncytia formation is usually illustrated as fusion efficiency under given condition by quantifying total number of nuclei in syncytia normalized to total number of nuclei (both within syncytia and unfused cell nuclei) in unit field of view. However heterogeneity in multinucleated syncytia sizes poses challenge in quantification of cell-fusion multinucleation under diverse conditions. Taking in-vitro SARS-CoV-2 spike-protein variants mediated virus-cell fusion model and placenta trophoblast syncytialization as cell-cell fusion model; herein we emphasize wide application of simple unbiased detailed measure of virus-cell and cell-cell multinucleation using experiential cumulative distribution function (CDF) and fusion number events (FNE) approaches illustrating comprehensive metrics for syncytia interpretation.

Endogenous retrovirus HERVH-derived lncRNA UCA1 controls human trophoblast development

Endogenous retroviruses (ERVs) are frequently reactivated in mammalian placenta. It has been proposed that ERVs contribute to shaping the gene regulatory network of mammalian trophoblasts, dominantly acting as species- and placental-specific enhancers. However, whether and how ERVs control human trophoblast development through alternative pathways remains poorly understood. Besides the well-recognized function of human endogenous retrovirus-H (HERVH) in maintaining pluripotency of early human epiblast, here we present a unique role of HERVH on trophoblast lineage development. We found that the LTR7C/HERVH subfamily exhibits an accessible chromatin state in the human trophoblast lineage. Particularly, the LTR7C/HERVH-derived Urothelial Cancer Associated 1 (UCA1), a primate-specific long non-coding RNA (lncRNA), is transcribed in human trophoblasts and promotes the proliferation of human trophoblast stem cells (hTSCs), whereas its ectopic expression compromises human trophoblast syncytialization coinciding with increased interferon signaling pathway. Importantly, UCA1 upregulation is detectable in placental samples from early-onset preeclampsia (EO-PE) patients and the transcriptome of EO-PE placenta exhibits considerable similarities to that of the syncytiotrophoblasts differentiated from UCA1-overexpressing hTSCs, supporting up-regulated UCA1 as a potential biomarker of this disease. Altogether, our data shed light on the versatile regulatory role of HERVH in early human development and provide a unique mechanism whereby ERVs exert a function in human placentation and placental syndromes.

Gestational exposure to PM2.5 disrupts fetal development by suppressing placental trophoblast syncytialization via progranulin/mTOR signaling

Recent epidemiological and animal studies have indicated that ambient fine particulate matter (PM2.5) exposure during pregnancy is closely associated with intrauterine growth restriction (IUGR). However, the underlying mechanisms remain to be revealed. In this study, we found that gestational exposure to PM2.5 significantly decreased fetal weight and crown-rump length in mice, accompanied by insufficient placental trophoblast syncytialization and increased expression of progranulin (PGRN) in mice placenta. Administering PGRN neutralizing antibody to pregnant mice alleviated growth restriction and insufficient placental trophoblast syncytialization caused by PM2.5, accompanied with suppressed activation of the mTOR signaling pathway. Furthermore, in vitro experiments using human placental BeWo cells showed that 10 μg·mL−1 PM2.5 activated PGRN/mTOR signaling and suppressed forskolin-induced cell fusion, which was blocked by knockdown of PGRN. Taken together, our results demonstrated that PM2.5 exposure during pregnancy inhibited placental trophoblast syncytialization by activating PGRN/mTOR signaling, leading to abnormal placental development and IUGR. This study reveals a novel mechanism underlying the developmental toxicity of PM2.5 exposure during pregnancy.

PIBF1 regulates trophoblast syncytialization and promotes cardiovascular development

Proper placental development in early pregnancy ensures a positive outcome later on. The developmental relationship between the placenta and embryonic organs, such as the heart, is crucial for a normal pregnancy. However, the mechanism through which the placenta influences the development of embryonic organs remains unclear. Trophoblasts fuse to form multinucleated syncytiotrophoblasts (SynT), which primarily make up the placental materno-fetal interface. We discovered that endogenous progesterone immunomodulatory binding factor 1 (PIBF1) is vital for trophoblast differentiation and fusion into SynT in humans and mice. PIBF1 facilitates communication between SynT and adjacent vascular cells, promoting vascular network development in the primary placenta. This process affected the early development of the embryonic cardiovascular system in mice. Moreover, in vitro experiments showed that PIBF1 promotes the development of cardiovascular characteristics in heart organoids. Our findings show how SynTs organize the barrier and imply their possible roles in supporting embryogenesis, including cardiovascular development. SynT-derived factors and SynT within the placenta may play critical roles in ensuring proper organogenesis of other organs in the embryo.

Epigenetic drug screening for trophoblast syncytialization reveals a novel role for MLL1 in regulating fetoplacental growth.

Abnormal placental development is a significant factor contributing to perinatal morbidity and mortality, affecting approximately 5-7% of pregnant women. Trophoblast syncytialization plays a pivotal role in the establishment and maturation of the placenta, and its dysregulation is closely associated with several pregnancy-related disorders, including preeclampsia and intrauterine growth restriction. However, the underlying mechanisms and genetic determinants of syncytialization are largely unknown. We conducted a systematic drug screen using an epigenetic compound library to systematically investigate the epigenetic mechanism essential for syncytialization, and identified mixed lineage leukemia 1 (MLL1), a histone 3 lysine 4 methyltransferase, as a crucial regulator of trophoblast syncytialization. BeWo cells were utilized to investigate the role of MLL1 during trophoblast syncytialization. RNA sequencing and CUT&Tag were further performed to search for potential target genes and the molecular pathways involved. Human placenta tissue was used to investigate the role of MLL1 in TEA domain transcription factor 4 (TEAD4) expression and the upstream signaling during syncytialization. A mouse model was used to examine whether inhibition of MLL1-mediated H3K4me3 regulated placental TEAD4 expression and fetoplacental growth. Genetic knockdown of MLL1 or pharmacological inhibition of the MLL1 methyltransferase complex (by MI-3454) markedly enhanced syncytialization, while overexpression of MLL1 inhibited forskolin (FSK)-induced syncytiotrophoblast formation. In human placental villous tissue, MLL1 was predominantly localized in the nuclei of cytotrophoblasts. Moreover, a notable upregulation in MLL1 expression was observed in the villus tissue of patients with preeclampsia compared with that in the control group. Based on RNA sequencing and CUT&Tag analyses, depletion of MLL1 inhibited the Hippo signaling pathway by suppressing TEAD4 expression by modulating H3K4me3 levels on the TEAD4 promoter region. TEAD4 overexpression significantly reversed the FSK-induced or MLL1 silencing-mediated trophoblast syncytialization. Additionally, decreased hypoxia-inducible factor 1A (HIF1A) enrichment at the MLL1 promoter was observed during syncytialization. Under hypoxic conditions, HIF1A could bind to and upregulate MLL1, leading to the activation of the MLL1/TEAD4 axis. In vivo studies demonstrated that the administration of MI-3454 significantly enhanced fetal vessel development and increased the thickness of the syncytial layer, thereby supporting fetoplacental growth. These results revealed a novel epigenetic mechanism underlying the progression of syncytialization with MLL1, and suggest potential avenues for identifying new therapeutic targets for pregnancy-related disorders.

Engineering placental trophoblast fusion: A potential role for biomechanics in syncytialization

The process by which placental trophoblasts fuse to form the syncytiotrophoblast around the chorionic villi is not fully understood. Mechanical features of the in vivo and in vitro culture environments have recently emerged as having the potential to influence fusion efficiency, and considering these mechanical cues may ultimately allow predictive control of trophoblast syncytialization. Here, we review recent studies that suggest that biomechanical factors such as shear stress, tissue stiffness, and dimensionally-related stresses affect villous trophoblast fusion efficiency. We then discuss how these stimuli might arise in vivo and how they can be incorporated in cultures to study and enhance villous trophoblast fusion. We believe that this mechanical paradigm will provide novel insight into manipulating the syncytialization process to better engineer improved models, understand disease progression, and ultimately develop novel therapeutic strategies.

Quercetin stimulates trophoblast fusion via the mitochondrial function

The fusion of mononuclear trophoblasts into multinucleate syncytiotrophoblasts is the critical event in the process of syncytialization, and its dysregulation can lead to pregnancy complications, notably hypertensive disorders of pregnancy (HDP). Oxidative stress may disrupt trophoblast syncytialization in HDP. Specifically, placentas with HDP exhibit impaired mitochondria, giving rise to the generation of reactive oxygen species (ROS) and subsequent oxidative stress. Quercetin, a bioflavonoid known for its antioxidant and anti-aging properties, has the potential to mitigate oxidative stress during trophoblast syncytialization. However, the precise mechanism underlying the action of quercetin in these processes remains to be elucidated. To explore the impact of quercetin on syncytialization, mitochondrial function, and ROS generation, cyclic AMP-stimulated BeWo cells were treated with quercetin. The expression of markers associated with cell fusion, mitochondrial function, and oxidative stress was determined using qPCR and western blotting. Additionally, morphological syncytialization and mitophagy (mitochondrial degradation) were assessed by immunofluorescence analysis. Our results revealed that quercetin increased the expression of syncytialization markers and promoted cell fusion. Furthermore, this compound also upregulated markers associated with mitophagy and mitochondrial fusion, which are corroborated by visual evidence of mitophagy through the fluorescence microscope. Cell fusion naturally stimulated ROS generation, which was attenuated by quercetin. Quercetin downregulated the expression of NRF2 and HO-1 during syncytialization, while increasing the expression of sirtuin1/3/6, which are known to play essential roles in antioxidant responses. In conclusion, quercetin effectively regulates mitochondrial function through its antioxidant properties and the suppression of ROS generation, ultimately promoting trophoblast fusion, suggesting that the flavonoid has the potential to ameliorate pregnancy-related disorder stemming from placental dysplasia.

The Role of DNMT1 and C/EBPα in the Regulation of CYP11A1 Expression During Syncytialization of Human Placental Trophoblasts.

Progesterone synthesized in the placenta is essential for pregnancy maintenance. CYP11A1 is a key enzyme in progesterone synthesis, and its expression increases greatly during trophoblast syncytialization. However, the underlying mechanism remains elusive. Here, we demonstrated that passive demethylation of CYP11A1 promoter accounted for the upregulation of CYP11A1 expression during syncytialization with the participation of the transcription factor C/EBPα. We found that the methylation rate of a CpG locus in the CYP11A1 promoter was significantly reduced along with decreased DNA methyltransferase 1 (DNMT1) expression and its enrichment at the CYP11A1 promoter during syncytialization. DNMT1 overexpression not only increased the methylation of this CpG locus in the CYP11A1 promoter, but also decreased CYP11A1 expression and progesterone production. In silico analysis disclosed multiple C/EBPα binding sites in both CYP11A1 and DNMT1 promoters. C/EBPα expression and its enrichments at both the DNMT1 and CYP11A1 promoters were significantly increased during syncytialization. Knocking-down C/EBPα expression increased DNMT1 while it decreased CYP11A1 expression during syncytialization. Conclusively, C/EBPα plays a dual role in the regulation of CYP11A1 during syncytialization. C/EBPα not only drives CYP11A1 expression directly, but also indirectly through downregulation of DNMT1, which leads to decreased methylation in the CpG locus of the CYP11A1 promoter, resulting in increased progesterone production during syncytialization.

Quantification of Trophoblast Syncytialization by Fluorescent Membrane Labeling.

Trophoblast fusion or syncytialization is a fundamental yet poorly understood process during placental development. Primary cultured cytotrophoblasts and human choriocarcinoma cell lines are commonly used to study trophoblast fusion mechanisms in vitro. Quantification of trophoblast fusion index is a key for the in vitro studies. In this chapter, we describe a new method to quantify fusion index, which is based on fluorescent labeling of the plasma membrane using Di-8-ANEPPS, a membrane potential dye. This method directly works on live cells, thereby is simple, economic, and reliable.

Trophoblast Syncytialization: A Metabolic Crossroads.

During placentation, villous cytotrophoblast (CTB) stem cells proliferate and fuse, giving rise to the multinucleated syncytiotrophoblast (STB), which represents the terminally differentiated villous layer as well as the maternal-fetal interface. The syncytiotrophoblast is at the forefront of nutrient, gas, and waste exchange while also harboring essential endocrine functions to support pregnancy and fetal development. Considering that mitochondrial dynamics and respiration have been implicated in stem cell fate decisions of several cell types and that the placenta is a mitochondria-rich organ, we will highlight the role of mitochondria in facilitating trophoblast differentiation and maintaining trophoblast function. We discuss both the process of syncytialization and the distinct metabolic characteristics associated with CTB and STB sub-lineages prior to and during syncytialization. As mitochondrial respiration is tightly coupled to redox homeostasis, we emphasize the adaptations of mitochondrial respiration to the hypoxic placental environment. Furthermore, we highlight the critical role of mitochondria in conferring the steroidogenic potential of the STB following differentiation. Ultimately, mitochondrial function and morphological changes centrally regulate respiration and influence trophoblast fate decisions through the production of reactive oxygen species (ROS), whose levels modulate the transcriptional activation or suppression of pluripotency or commitment genes.

DNMT1-mediated DNA methylation contributes to CYP11A1 expression in progesterone synthesis in placental trophoblast syncytialization

DNMT1-mediated DNA methylation contributes to CYP11A1 expression in progesterone synthesis in placental trophoblast syncytialization

Effects of valproic acid on syncytialization in human placental trophoblast cell lines

The placenta is a critical organ for fetal development and a healthy pregnancy, and has multifaceted functions (e.g., substance exchange and hormone secretion). Syncytialization of trophoblasts is important for maintaining placental functions. Epilepsy is one of the most common neurological conditions worldwide. Therefore, this study aimed to reveal the influence of antiepileptic drugs, including valproic acid (VPA), carbamazepine, lamotrigine, gabapentin, levetiracetam, topiramate, lacosamide, and clobazam, at clinically relevant concentrations on syncytialization using in vitro models of trophoblasts. To induce differentiation into syncytiotrophoblast-like cells, BeWo cells were treated with forskolin. Exposure to VPA was found to dose-dependently influence syncytialization-associated genes (ERVW-1, ERVFRD-1, GJA1, CGB, CSH, SLC1A5, and ABCC4) in differentiated BeWo cells. Herein, the biomarkers between differentiated BeWo cells and the human trophoblast stem model (TSCT) were compared. In particular, MFSD2A levels were low in BeWo cells but abundant in TSCT cells. VPA exposure affected the expression of ERVW-1, ERVFRD-1, GJA1, CSH, MFSD2A, and ABCC4 in differentiated cells (ST-TSCT). Furthermore, VPA exposure attenuated BeWo and TSCT cell fusion. Finally, the relationships between neonatal/placental parameters and the expression of syncytialization markers in human term placentas were analyzed. MFSD2A expression was positively correlated with neonatal body weight, head circumference, chest circumference, and placental weight. Our findings have important implications for better understanding the mechanisms of toxicity of antiepileptic drugs and predicting the risks to placental and fetal development.

Self-assembled human placental model from trophoblast stem cells in a dynamic organ-on-a-chip system.

The placental barrier plays a key role in protecting the developing fetus from xenobiotics and exchanging substances between the fetus and mother. However, the trophoblast cell lines and animal models are often inadequate to recapitulate the key architecture and functional characteristics of human placental barrier. Here, we described a biomimetic placental barrier model from human trophoblast stem cells (hTSCs) in a perfused organ chip system. The placental barrier was constructed by co-culture of hTSCs and endothelial cells on the opposite sides of a collagen-coated membrane on chip. hTSCs can differentiate into cytotrophoblasts (CT) and syncytiotrophoblast (ST), which self-assembled into bilayered trophoblastic epithelium with placental microvilli-like structure under dynamic cultures. The formed placental barrier displayed dense microvilli, higher level secretion of human chorionic gonadotropin (hCG), enhanced glucose transport activity. Moreover, RNA-seq analysis revealed upregulated ST expression and activation of trophoblast differentiation-related signalling pathways. These results indicated the key role of fluid flow in promoting trophoblast syncytialization and placental early development. After exposure to mono-2-ethylhexyl phthalate, one of the endocrine disrupting chemicals, the model showed inhibited hCG production and disturbed ST formation in trophoblastic epithelium, suggesting impaired placental structure and function elicited by environmental toxicants. Collectively, the hTSCs-derived placental model can recapitulate placenta physiology and pathological response to external stimuli in a biomimetic manner, which is useful for the study of placental biology and associated diseases.

Endogenous retrovirus-derived enhancers confer the transcriptional regulation of human trophoblast syncytialization.

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.

Regulators involved in trophoblast syncytialization in the placenta of intrauterine growth restriction.

Placental dysfunction refers to the insufficiency of placental perfusion and chronic hypoxia during early pregnancy, which impairs placental function and causes inadequate supply of oxygen and nutrients to the fetus, affecting fetal development and health. Fetal intrauterine growth restriction, one of the most common outcomes of pregnancy-induced hypertensions, can be caused by placental dysfunction, resulting from deficient trophoblast syncytialization, inadequate trophoblast invasion and impaired vascular remodeling. During placental development, cytotrophoblasts fuse to form a multinucleated syncytia barrier, which supplies oxygen and nutrients to meet the metabolic demands for fetal growth. A reduction in the cell fusion index and the number of nuclei in the syncytiotrophoblast are found in the placentas of pregnancies complicated by IUGR, suggesting that the occurrence of IUGR may be related to inadequate trophoblast syncytialization. During the multiple processes of trophoblasts syncytialization, specific proteins and several signaling pathways are involved in coordinating these events and regulating placental function. In addition, epigenetic modifications, cell metabolism, senescence, and autophagy are also involved. Study findings have indicated several abnormally expressed syncytialization-related proteins and signaling pathways in the placentas of pregnancies complicated by IUGR, suggesting that these elements may play a crucial role in the occurrence of IUGR. In this review, we discuss the regulators of trophoblast syncytialization and their abnormal expression in the placentas of pregnancies complicated by IUGR.

Silver nanoparticles suppress forskolin-induced syncytialization in BeWo cells

Opportunities for the exposure of pregnant women to engineered nanoparticles have been increasing with the expanding use of these materials. Therefore, there are concerns that nanoparticles could have adverse effects on the establishment and maintenance of pregnancy. The effects of nanoparticles on the mother and fetus have been evaluated from this perspective, but there is still little knowledge about the effects on placentation and function acquisition, which are essential for the successful establishment and maintenance of pregnancy. Formation of the syncytiotrophoblast is indispensable for the acquisition of placental function, and impairment of syncytialization inevitably affects pregnancy outcomes. Here, we assessed the effect of nanoparticles on placental formation by using forskolin-treated BeWo cells, a typical in vitro model of trophoblast syncytialization. Immunofluorescence staining analysis revealed that silver nanoparticles with a diameter of 10 nm (nAg10) (at 0.156 µg/mL) significantly decreased the proportion of syncytialized BeWo cells, but gold nanoparticles with a diameter of 10 nm did not. Consistently, only nAg10 (at 0.156 µg/mL) significantly suppressed forskolin-induced elevation of CGB and SDC1 mRNA expression levels and human chorionic gonadotropin β production in a dose-dependent manner; these molecules are all markers of syncytialization. Besides, nAg10 significantly decreased the expression of ERVFRD-1, which encodes proteins associated with cell fusion. Moreover, nAg10 tended to suppress the expression of sFlt-1 e15a, a placental angiogenesis marker. Collectively, our data suggest that nAg10 could suppress formation of the syncytiotrophoblast and that induce placental dysfunction and the following poor pregnancy outcomes.

S100P promotes trophoblast syncytialization during early placenta development by regulating YAP1.

Recurrent pregnancy loss (RPL) is a severe complication of pregnancy that is caused by genetic abnormalities, immune dysfunction, aberrant cell biology, and tissue structure destruction. Among which, placental dysfunction is crucial in the pathogenetic progression of RPL. Although some regulatory factors associated with RPL have been reported, the placental changes correlated with RPL still need to be elucidated. Here, we found that a portion of RPL patients presented with low serum and placental S100P expression. Using a human trophoblast stem cell model, we demonstrated that S100P was exclusively expressed in syncytiotrophoblast (ST)-like syncytia (ST(2D)-TSCT) and that loss of S100P expression in ST(2D)-TSCT cells impaired β-hCG secretion, leading to syncytialization failure during early placental development. Moreover, we found that S100P is involved in regulating trophoblast syncytialization by downregulating the protein level of Yes-associated protein 1 (YAP1), which plays a pivotal role in maintaining trophoblast stemness. Together, our findings suggest that S100P plays an essential role in regulating trophoblast syncytialization during early placental development in humans via YAP1. Additionally, lower serum S100P levels may predict poor pregnancy outcomes and represent a potentially useful marker for evaluating placental biological function during early pregnancy.