ABSTRACT
BACKGROUND: Recurrent spontaneous abortion (RSA) is a serious and common complication of pregnancy caused by multiple factors. The etiology remains incompletely understood, but immunologic factors play important roles. Here, we aimed to evaluate whether circulating immune cells causally impacted RSA. METHODS: In this study, we conducted a comprehensive two-sample Mendelian randomization (MR) study to determine the causal association between the 731 immunophenotypes of human peripheral blood lymphocytes and the number of spontaneous abortions as well as recurrent miscarriage. Sensitivity analyses were performed to assess and minimize heterogeneity and horizontal pleiotropy. Reverse MR analysis was used to assess reverse causality. RESULTS: After Bonferroni-correction, eight immunophenotypes were significantly associated with the number of spontaneous abortions: FSC-A on CD4+ T cell (beta = -0.051, 95% CI = [-0.085, -0.017], P-value = 0.004), CD8 on HLA DR+ CD8+ T cell (beta = -0.040, 95% CI = [-0.067, -0.014], P-value = 0.003), HLA DR on CD33dim HLA DR+ CD11b- (beta = -0.021, 95% CI = [-0.036, -0.005], P-value = 0.010), HLA DR+ T cell Absolute Count (beta = 0.022, 95% CI = [0.006, 0.037], P-value = 0.008), HLA DR+ T cell % lymphocyte (beta = 0.026, 95% CI = [0.010, 0.041], P-value = 0.001), HLA DR+ T cell % T cell (beta = 0.023, 95% CI = [0.007, 0.039], P-value = 0.004), HLA DR+ CD4+ T cell % lymphocyte (beta = 0.034, 95% CI = [0.007, 0.060], P-value = 0.012), and HLA DR on B cell (beta = 0.012, 95% CI = [0.003, 0.021], P-value = 0.010). In addition, we identified two immunophenotypes associated with recurrent miscarriage: HLA DR on B cell (OR = 0.854, 95% CI = [0.757, 0.964], P-value = 0.011), and CD19 on naive-mature B cell (OR = 4.595, 95% CI = [1.674, 12.617], P-value = 0.003). There was no evidence of heterogeneity, horizontal pleiotropy and reverse causality. CONCLUSIONS: Our study demonstrated a tight link between adaptive immune cells and RSA through genetic means, thus providing potential therapeutic targets or novel diagnostic biomarkers.
Subject(s)
Abortion, Habitual , Immunophenotyping , Mendelian Randomization Analysis , Humans , Female , Abortion, Habitual/immunology , Abortion, Habitual/blood , Abortion, Habitual/genetics , Pregnancy , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunologyABSTRACT
Trophoblast stem cells (TSCs) can be chemically converted from embryonic stem cells (ESCs) in vitro. Although several transcription factors (TFs) have been recognized as essential for TSC formation, it remains unclear how differentiation cues link elimination of stemness with the establishment of TSC identity. Here, we show that PRDM14, a critical pluripotent circuitry component, is reduced during the formation of TSCs. The reduction is further shown to be due to the activation of Wnt/ß-catenin signaling. The extinction of PRDM14 results in the erasure of H3K27me3 marks and chromatin opening in the gene loci of TSC TFs, including GATA3 and TFAP2C, which enables their expression and thus the initiation of the TSC formation process. Accordingly, PRDM14 reduction is proposed here as a critical event that couples elimination of stemness with the initiation of TSC formation. The present study provides novel insights into how induction signals initiate TSC formation.
Subject(s)
Cell Differentiation , DNA-Binding Proteins , Transcription Factors , Trophoblasts , Wnt Signaling Pathway , Trophoblasts/metabolism , Trophoblasts/cytology , Animals , Mice , Transcription Factors/metabolism , Transcription Factors/genetics , Cell Differentiation/genetics , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , GATA3 Transcription Factor/metabolism , GATA3 Transcription Factor/genetics , Transcription Factor AP-2/metabolism , Transcription Factor AP-2/genetics , Stem Cells/metabolism , Stem Cells/cytology , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Histones/metabolism , Histones/geneticsABSTRACT
BACKGROUND: Preeclampsia is a serious disease of pregnancy that lacks early diagnosis methods or effective treatment, except delivery. Dysregulated uterine immune cells and spiral arteries are implicated in preeclampsia, but the mechanistic link remains unclear. METHODS: Single-cell RNA sequencing and spatial transcriptomics were used to identify immune cell subsets associated with preeclampsia. Cell-based studies and animal models including conditional knockout mice and a new preeclampsia mouse model induced by recombinant mouse galectin-9 were applied to validate the pathogenic role of a CD11chigh subpopulation of decidual macrophages (dMφ) and to determine its underlying regulatory mechanisms in preeclampsia. A retrospective preeclampsia cohort study was performed to determine the value of circulating galectin-9 in predicting preeclampsia. RESULTS: We discovered a distinct CD11chigh dMφ subset that inhibits spiral artery remodeling in preeclampsia. The proinflammatory CD11chigh dMφ exhibits perivascular enrichment in the decidua from patients with preeclampsia. We also showed that trophoblast-derived galectin-9 activates CD11chigh dMφ by means of CD44 binding to suppress spiral artery remodeling. In 3 independent preeclampsia mouse models, placental and plasma galectin-9 levels were elevated. Galectin-9 administration in mice induces preeclampsia-like phenotypes with increased CD11chigh dMφ and defective spiral arteries, whereas galectin-9 blockade or macrophage-specific CD44 deletion prevents such phenotypes. In pregnant women, increased circulating galectin-9 levels in the first trimester and at 16 to 20 gestational weeks can predict subsequent preeclampsia onset. CONCLUSIONS: These findings highlight a key role of a distinct perivascular inflammatory CD11chigh dMφ subpopulation in the pathogenesis of preeclampsia. CD11chigh dMφ activated by increased galectin-9 from trophoblasts suppresses uterine spiral artery remodeling, contributing to preeclampsia. Increased circulating galectin-9 may be a biomarker for preeclampsia prediction and intervention.
Subject(s)
Decidua , Galectins , Macrophages , Pre-Eclampsia , Vascular Remodeling , Pre-Eclampsia/metabolism , Pre-Eclampsia/immunology , Pregnancy , Female , Animals , Galectins/metabolism , Macrophages/metabolism , Macrophages/immunology , Macrophages/pathology , Mice , Humans , Decidua/metabolism , Decidua/pathology , Mice, Knockout , Uterus/metabolism , Uterus/blood supply , Disease Models, Animal , Hyaluronan Receptors/metabolism , Hyaluronan Receptors/genetics , Retrospective Studies , Mice, Inbred C57BL , CD11 AntigensABSTRACT
In brief: Corticotropin-releasing hormone binding protein (CRHBP) is fundamental to the stress response and plays an important role in parturition during pregnancy. This study shows that abnormal CRHBP expression could be an early warning sign of recurrent pregnancy loss and that CRHBP knockdown could suppress HTR8/SVneo cell invasion by the PKC signaling pathway via interacting with CRH receptor 2. Abstract: Trophoblast invasion is critical for placentation and pregnancy success. Trophoblast dysfunction results in many pregnancy complications, including recurrent pregnancy loss (RPL). Corticotropin-releasing hormone binding protein (CRHBP) is fundamental to the stress response and plays an important role in parturition during pregnancy via binding with CRH. To further characterize its function in early pregnancy, we explored the expression of CRHBP in villi during early pregnancy. Compared with normal pregnant women, we demonstrated that the expression of CRHBP decreased in the trophoblasts and villi in RPL patients and that knockdown of CRHBP expression could suppress HTR8/SVneo cell invasion significantly. Our further exploration indicated that the capacity of CRHBP for regulating trophoblast invasion was associated with the PKC signaling pathway via interacting with CRH receptor 2. These findings might provide a new fundamental mechanism for successful pregnancy and a new diagnostic and therapeutic target for RPL.
Subject(s)
Abortion, Habitual , Receptors, Corticotropin-Releasing Hormone , Pregnancy , Humans , Female , Receptors, Corticotropin-Releasing Hormone/genetics , Receptors, Corticotropin-Releasing Hormone/metabolism , Down-Regulation , Corticotropin-Releasing Hormone/genetics , Corticotropin-Releasing Hormone/metabolism , Cell Line , Trophoblasts/metabolism , Abortion, Habitual/metabolism , Cell MovementABSTRACT
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.
Subject(s)
Pre-Eclampsia , Pregnancy , Female , Mice , Humans , Animals , Pre-Eclampsia/therapy , Pre-Eclampsia/metabolism , Trophoblasts/metabolism , Adrenomedullin/metabolism , Placenta/metabolism , Cell DifferentiationABSTRACT
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes progressive joint destruction, leading to impaired life quality, disability, and even premature mortality. However, current medications suffer from limited clinical outcomes and severe side effects due to low bioavailability and non-specific distribution after administration. Herein, a targeting nanosystem (HAP-Lipo@Leo) was constructed for efficient RA treatment, which can precisely deliver a natural anti-arthritic drug leonurine (Leo) to the inflamed joint by HAP-1 peptide-mediated recognition of activated fibroblast-like synoviocytes (FLS). More specifically, HAP-Lipo@Leo was prepared by a combination of thin film hydration and high-pressure microfluidization and surface-decorated with HAP-1 peptide and PEG before encapsulating Leo by the ammonium sulfate gradient method. The as-obtained HAP-Lipo@Leo can be selectively internalized by activated FLS and impairs the lamellipodia formation and overexpression of inflammatory cytokines, both of which play detrimental roles in joint damage. Furthermore, HAP-Lipo@Leo demonstrated arthritic joint-specific distribution, significant inhibition of synovial inflammation, and reversal of cartilage and bone destruction in adjuvant-induced arthritis rats as evidenced by comprehensive investigations including ELISA tests, histopathology examinations, and micro-CT analysis. In addition, HAP-Lipo@Leo exhibited good biocompatibility and safety both in vitro and in vivo. Taken together, HAP-Lipo@Leo holds great potential for clinical RA management by integrating activated FLS targeting, long circulation, multifaceted therapeutic effects, and excellent biocompatibility.
ABSTRACT
The success of pregnancy mainly depends on immune tolerance of the mother for the semi-allogeneic fetus. The placenta carrying paternal antigens develops in the maternal uterus without suffering immune attack, making the underlying mechanism of maternal tolerance an enduring mystery. As we all know, human leukocyte antigen (HLA) plays an important role in antigen processing and presentation, thus inducing specific immune responses. Therefore, it is reasonable to speculate that the absence of classical HLA class-Iï¼HLA-I) and HLA class-II (HLA-II) molecules in trophoblasts may account for the maternal-fetal tolerance. Here, we review the HLA-involved interactions between trophoblast cells and decidual immune cells, which contribute to the immunotolerance in the development of normal pregnancy. We also compare the similarity between the maternal-fetal interface and tumor-immune microenvironment because the important role of HLA molecules in tumor immune invasion can provide some references to studies of maternal-fetal immune tolerance. Besides, the abnormal HLA expression is likely to be associated with unexplained miscarriage, making HLA molecules potential therapeutic targets. The advances reported by these studies may exert profound influences on other research areas, including tumor immunity, organ transplantation and autoimmune disease in the future.
Subject(s)
Neoplasms , Trophoblasts , Pregnancy , Female , Humans , Trophoblasts/metabolism , Histocompatibility Antigens Class I , HLA Antigens , Immune Tolerance , Histocompatibility Antigens Class II/metabolism , Antigen Presentation , Maternal-Fetal Exchange , Tumor MicroenvironmentABSTRACT
OBJECTIVE AND DESIGN: To investigate the balancing mechanisms between decidualization-associated inflammation and pregnancy-related immunotolerance. MATERIAL OR SUBJECTS: Decidual samples from women with normal pregnancy (n = 58) or unexplained spontaneous miscarriage (n = 13), peripheral blood from normal pregnancy and endometria from non-pregnancy (n = 10) were collected. Primary endometrial stromal cells (ESCs), decidual stromal cells (DSCs), decidual immune cells (DICs) and peripheral blood mononuclear cells (PBMCs) were isolated. TREATMENT: The plasmid carrying neuropilin-1 (NRP1) gene was transfected into ESC for overexpression. To induce decidualization in vitro, ESCs were treated with a combination of 10 nM estradiol, 100 nM progesterone and 0.5 mM cAMP. Anti-Sema3a and anti-NRP1 neutralizing antibodies were applied to block the ligand-receptor interactions. METHODS: RNA-seq analysis was performed to identify differentially expressed genes in DSCs and DICs, and NRP1 expression was verified by Western blotting and flow cytometry. The secretion of inflammatory mediators was measured using a multifactor cytometric bead array. The effects of Sema3a-NRP1 pathway on DICs were determined by flow cytometry. Statistical differences between groups were compared using the T test and one way or two-way ANOVA. RESULTS: Combined with five RNA-seq datasets, NRP1 was the only immune checkpoint changing oppositely between DSCs and DICs. The decreased expression of NRP1 in DSCs allowed intrinsic inflammatory responses required for decidualization, while its increased expression in DICs enhanced tolerant phenotypes beneficial to pregnancy maintenance. DSC-secreted Sema3a promoted immunosuppression in DICs via NRP1 binding. In women with miscarriage, NRP1 was abnormally elevated in DSCs but diminished in decidual macrophages and NK cells. CONCLUSION: NRP1 is a multifunctional controller that balances the inflammatory states of DSCs and DICs in gravid uterus. Abnormal expression of NRP1 is implicated in miscarriage.
Subject(s)
Abortion, Spontaneous , Decidua , Humans , Pregnancy , Female , Decidua/metabolism , Neuropilin-1/genetics , Neuropilin-1/metabolism , Leukocytes, Mononuclear/metabolism , Cells, Cultured , Stromal Cells/metabolismABSTRACT
Ischemic stroke (IS) constitutes the leading cause of global morbidity and mortality. Neuroprotectants are essential to ameliorate the clinical prognosis, but their therapeutic outcomes are tremendously compromised by insufficient delivery to the ischemic lesion and intricate pathogenesis associated with neuronal damage, oxidative stress, inflammation responses, blood-brain barrier (BBB) dysfunction, etc. Herein, a biomimetic nanosystem (Leo@NM-Lipo) composed of neutrophil membrane-fused nanoliposomal leonurine (Leo) is constructed, which can not only efficiently penetrate and repair the disrupted BBB but also robustly remodel the harsh cerebral microenvironment to reverse ischemia-reperfusion (I/R) injury. More specifically, the neutrophil membrane inherits the BBB penetrating, infarct core targeting, inflammation neutralization, and immune evasion properties of neutrophils, while Leo, a naturally occurring neuroprotectant, exerts pleiotropic effects to attenuate brain damage. Remarkably, comprehensive investigations disclose the critical factors influencing the targetability and therapeutic performances of biomimetic nanosystems. Leo@NM-Lipo with a low membrane protein-to-lipid ratio of 1:10 efficiently targets the ischemic lesion and rescues the injured brain by alleviating neuronal apoptosis, oxidative stress, neuroinflammation, and restoring BBB integrity in transient middle cerebral artery occlusion (tMCAO) rats. Taken together, our study provides a neutrophil-mimetic nanoplatform for targeted IS therapy and sheds light on the rational design of biomimetic nanosystems favoring wide medical applications.
ABSTRACT
cAMP signaling is widely known to be indispensable for decidualization, but the details are not fully understood. Here, we show that cAMP signaling promotes AKT deactivation in endometrial stromal cells, which favors their decidualization. The deactivation of AKT is found to be a consequence of the reduced expression of several inhibitors of PP2A, the major phosphatase of AKT, with CIP2A being the most prominent. CIP2A reduction is obligatory for decidualization, as persistent CIP2A expression impairs chromatin remodeling and the expression of several decidualization markers (IGFBP1, PRL, MAOA, and IL-15). Furthermore, analyses of the responsiveness of the CIP2A promoter to cAMP signaling suggest the ETS family to be a bridge between cAMP signaling and CIP2A reduction. Our results provide novel insights into the role of cAMP signaling in decidualization and might benefit the development of novel therapies for decidualization deficiency, AKT-driven tumors, and the reverse, insulin resistance.
Subject(s)
Decidua , Endometrium , Female , Humans , Decidua/metabolism , Endometrium/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Stromal Cells/metabolismABSTRACT
Hyperlipidemia is a lipid metabolism disorder that requires long-term and daily medication. Leonurine (Leo), an active alkaloid derived from Herba leonuri, can effectively ameliorate lipid profiles in mammals and serve as a candidate antihyperlipidemic agent for clinical applications. In this paper, poly(lactic-co-glycolic acid) (PLGA) microsphere (MP)-based drug delivery platforms were for the first time employed for hyperlipidemia management by encapsulating leonurine nanocrystals (Leo-nano) by a modified solid-in-oil-in-water (S/O/W) double emulsion-solvent emulsion technique. The optimal formulation (Leo-nano@MP) was characterized by a high drug loading and encapsulation efficiency of 19.90 ± 0.82% and 79.62 ± 3.57%, respectively, which followed first-order drug release kinetics over 20 days in vitro. Interestingly, Leo-nano@MP exhibited a unique morphology with a condensed surface yet a porous internal structure, which potentially contributed to the enhanced drug loading and release properties. Furthermore, subcutaneous injection of Leo-nano@MP every two weeks significantly ameliorated the lipid profiles and alleviated liver and kidney injury in HFD-fed rats in comparison with daily administration of free Leo. Besides, no abnormalities in the heart, lung, spleen, and skin tissues at injection sites were observed. In summary, Leo-nano@MP with enhanced therapeutic efficacy, reduced administration frequency, and good biosafety constitutes a promising sustained-release platform for hyperlipidemia management.
Subject(s)
Hyperlipidemias , Nanoparticles , Rats , Animals , Emulsions/chemistry , Microspheres , Hyperlipidemias/drug therapy , Nanoparticles/chemistry , Lipids , Particle Size , Delayed-Action Preparations/chemistry , MammalsABSTRACT
Iron is necessary for various critical biological processes, but iron overload is also dangerous since labile iron is redox-active and toxic. We found that low serum iron and decidual local iron deposition existed simultaneously in recurrent pregnancy loss (RPL) patients. Mice fed with a low-iron diet (LID) also showed iron deposition in the decidua and adverse pregnancy outcomes. Decreased ferroportin (cellular iron exporter) expression that inhibited the iron export from decidual stromal cells (DSCs) might be the reason for local iron deposition in DSCs from low-serum-iron RPL patients and LID-fed mice. Iron supplementation reduced iron deposition in the decidua of spontaneous abortion models and improved pregnancy outcomes. Local iron overload caused ferroptosis of DSCs by downregulating glutathione (GSH) and glutathione peroxidase 4 levels. Both GSH and cystine (for the synthesis of GSH) supplementation reduced iron-induced lipid reactive oxygen species (ROS) and cell death in DSCs. Ferroptosis inhibitor, cysteine, and GSH supplementation all effectively attenuated DSC ferroptosis and reversed embryo loss in the spontaneous abortion model and LPS-induced abortion model, making ferroptosis mitigation a potential therapeutic target for RPL patients. Further study that improves our understanding of low-serum-iron-induced DSC ferroptosis is needed to inform further clinical evaluations of the safety and efficacy of iron supplementation in women during pregnancy.
Subject(s)
Abortion, Habitual , Ferroptosis , Iron Overload , Pregnancy , Humans , Female , Animals , Mice , Iron/metabolism , Ferroptosis/physiology , Abortion, Habitual/metabolism , Stromal Cells/metabolism , Iron Overload/metabolismABSTRACT
A defining feature of successful vaccination is the ability to induce long-lived antigen-specific memory cells. T follicular helper (Tfh) cells specialize in providing help to B cells in mounting protective humoral immunity in infection and after vaccination. Memory Tfh cells that retain the CXCR5 expression can confer protection through enhancing humoral response upon antigen re-exposure but how they are maintained is poorly understood. CXCR5+ memory Tfh cells in human blood are divided into Tfh1, Tfh2, and Tfh17 cells by the expression of chemokine receptors CXCR3 and CCR6 associated with Th1 and Th17, respectively. Here, we developed a new method to induce Tfh1, Tfh2, and Tfh17-like (iTfh1, iTfh2, and iTfh17) mouse cells in vitro. Although all three iTfh subsets efficiently support antibody responses in recipient mice with immediate immunization, iTfh17 cells are superior to iTfh1 and iTfh2 cells in supporting antibody response to a later immunization after extended resting in vivo to mimic memory maintenance. Notably, the counterpart human Tfh17 cells are selectively enriched in CCR7+ central memory Tfh cells with survival and proliferative advantages. Furthermore, the analysis of multiple human cohorts that received different vaccines for HBV, influenza virus, tetanus toxin or measles revealed that vaccine-specific Tfh17 cells outcompete Tfh1 or Tfh2 cells for the persistence in memory phase. Therefore, the complementary mouse and human results showing the advantage of Tfh17 cells in maintenance and memory function supports the notion that Tfh17-induced immunization might be preferable in vaccine development to confer long-term protection.
Subject(s)
Immunologic Memory , T Follicular Helper Cells , Humans , Animals , Mice , Th17 Cells/metabolism , B-Lymphocytes , T-Lymphocytes, Helper-InducerABSTRACT
T-cell immunoglobulin mucin-3 (Tim-3) is an important checkpoint that induces maternal-fetal tolerance in pregnancy. Macrophages (Mφs) play essential roles in maintaining maternal-fetal tolerance, remodeling spiral arteries, and regulating trophoblast biological behaviors. In the present study, the formation of the labyrinth zone showed striking defects in pregnant mice treated with Tim-3 neutralizing antibodies. The adoptive transfer of Tim-3+Mφs, rather than Tim-3-Mφs, reversed the murine placental dysplasia resulting from Mφ depletion. With the higher production of angiogenic growth factors (AGFs, including PDGF-AA, TGF-α, and VEGF), Tim-3+dMφs were more beneficial in promoting the invasion and tube formation ability of trophoblasts. The blockade of AGFs in Tim-3+Mφs led to the narrowing of the labyrinthine layer of the placenta, compromising maternal-fetal tolerance, and increasing the risk of fetal loss. Meanwhile, the AGFs-treated Tim-3-Mφs could resolve the placental dysplasia and fetal loss resulting from Mφ depletion. These findings emphasized the vital roles of Tim-3 in coordinating Mφs-extravillous trophoblasts interaction via AGFs to promote pregnancy maintenance and in extending the role of checkpoint signaling in placental development. The results obtained in our study also firmly demonstrated that careful consideration of reproductive safety should be taken when selecting immune checkpoint and AGF blockade therapies in real-world clinical care.
Subject(s)
Cell Communication , Macrophages , Placenta , Pregnancy Maintenance , Trophoblasts , Animals , Female , Mice , Pregnancy , Decidua/metabolism , Hepatitis A Virus Cellular Receptor 2/genetics , Hepatitis A Virus Cellular Receptor 2/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Macrophages/metabolism , Placenta/metabolism , Pregnancy Maintenance/genetics , Pregnancy Maintenance/physiology , Trophoblasts/metabolism , Cell Communication/genetics , Cell Communication/physiologyABSTRACT
Circular RNAs (circRNAs), produced by precursor mRNAs, are a type of covalently closed circular molecule without 5' caps and 3' polyadenylated tails. Recently, advances in high-throughput sequencing, transcriptomics and bioinformatics, have revealed that circRNAs with specific traits in tissue or cells play emerging roles in both physiological and panthological contexts instead of as simple by-products of transcription. However, bringing circRNAs to the forefront of clinical practice is still a long way off. In this review, we highlight the progress in the formation and function of circRNAs, and how circRNAs work in female reproductive-related diseases, such as recurrent spontaneous abortion, preeclampsia, and endometriosis. We also discussed the clinical potential of circRNAs as biomarkers, and therapeutic agents in female reproductive diseases as well as research controversies, technical issues, and biological knowledge gaps that need to be addressed. This review may instruct future basic research and clinical applications on circRNAs, especially in female reproduction.
Subject(s)
RNA, Circular , RNA , Pregnancy , Female , Humans , RNA, Messenger , Gene Expression Profiling , BiomarkersABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new type of coronavirus that has caused fatal infectious diseases and global spread. This novel coronavirus attacks target cells through the interaction of spike protein and angiotensin-converting enzyme II (ACE2), leading to different clinical symptoms. However, for a successful pregnancy, a well-established in-uterine environment includes a specific immune environment, and multi-interactions between specific cell types are prerequisites. The immune-related changes in patients infected with novel coronavirus could interfere with the immune microenvironment in the uterus, leading to fetal loss. We first reviewed the intrauterine environment in the normal development process and the possible pregnancy outcome in the infection state. Then, we summarized the immune response induced by SARS-CoV-2 in patients and analyzed the changes in ACE2 expression in the female reproductive system. Finally, the present observational evidence of infection in pregnant women was also reviewed.
Subject(s)
COVID-19 , Humans , Female , Pregnancy , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2 , Peptidyl-Dipeptidase A/metabolism , Pregnancy OutcomeABSTRACT
As the soil of life, the composition and shaping process of the immune microenvironment of the uterus is worth exploring. Macrophages, indispensable constituents of the innate immune system, are essential mediators of inflammation and tissue remodeling as well. Recent insights into the heterogeneity of macrophage subpopulations have renewed interest in their functional diversity in both physiological and pathological settings. Macrophages display remarkable plasticity and switch from one phenotype to another. Intrinsic plasticity enables tissue macrophages to perform a variety of functions in response to changing tissue contexts, such as cancer and pregnancy. The remarkable diversity and plasticity make macrophages particularly intriguing cells given their dichotomous role in either attacking or protecting tumors and semi-allogeneic fetuses, which of both are characterized functionally by immunomodulation and neovascularization. Here, we reviewed and compared novel perspectives on macrophage biology of these two settings, including origin, phenotype, differentiation, and essential roles in corresponding microenvironments, as informed by recent studies on the heterogeneity of macrophage identity and function, as well as their mechanisms that might offer opportunities for new therapeutic strategies on malignancy and pregnancy complications.
Subject(s)
Neoplasms , Female , Pregnancy , Humans , Neovascularization, Pathologic/pathology , Macrophages , Histiocytes , Tumor MicroenvironmentABSTRACT
Recurrent pregnancy loss (RPL) puzzles 1-3% of women of childbearing age worldwide. Immunological factors account for more than 60% of cases of unexplained RPL (URPL); however, the underlying mechanism remains unclear. Here, using single-cell sequencing data and functional experiments with clinical samples, we identified a distinct population of CCR1+ decidual macrophages (dMφ) that were preferentially enriched in the decidua from normal early pregnancies but were substantially decreased in patients with URPL. Specific gene signatures endowed CCR1+ dMφ with immunosuppressive and migration-regulatory properties, which were attenuated in URPL. Additionally, CCR1+ dMφ promoted epithelial-to-mesenchymal transition (EMT) to promote trophoblast migration and invasion by activating the ERK1/2 signaling pathway. Decidual stromal cell (DSC)-derived CCL8 was the key regulator of CCR1+ dMφ as CCL8 recruited peripheral CCR1+ monocytes, induced a CCR1+ dMφ-like phenotype, and reinforced the CCR1+ dMφ-exerted modulation of trophoblasts. In patients with URPL, CCL8 expression in DSCs was decreased and trophoblast EMT was defective. Our findings revealed that CCR1+ dMφ play an important role in immune tolerance and trophoblast functions at the maternal-fetal interface. Additionally, decreased quantity and dysregulated function of CCR1+ dMφ result in URPL. In conclusion, we provide insights into the crosstalk between CCR1+ dMφ, trophoblasts, and DSCs at the maternal-fetal interface and macrophage-targeted interventions of URPL.
Subject(s)
Abortion, Habitual , Decidua , Pregnancy , Humans , Female , Trophoblasts/metabolism , Abortion, Habitual/metabolism , Macrophages , Risk Factors , Receptors, CCR1/genetics , Receptors, CCR1/metabolismABSTRACT
BACKGROUND: Sleep disturbance can cause adverse pregnancy outcomes by changing circadian gene expression. The potential mechanisms remain unclear. Decidualization is critical for the establishment and maintenance of normal pregnancy, which can be regulated by circadian genes. Whether Rev-erbα, a critical circadian gene, affects early pregnancy outcome by regulating decidualization needs to be explored. METHODS: QPCR, western blot and artificial decidualization mouse model were used to confirm the effect of sleep disturbance on Rev-erbα expression and decidualization. The regulatory mechanism of Rev-erbα on decidualization was assessed using QPCR, western blot, RNA-Seq, and Chip-PCR. Finally, sleep disturbance mouse model was used to investigate the effect of therapeutic methods targeting Rev-erbα and interleukin 6 (IL-6) on improving adverse pregnancy outcomes induced by sleep disturbance. RESULTS: Dysregulation of circadian rhythm due to sleep disturbance displayed abnormal expression profile of circadian genes in uterine including decreased level of Rev-erbα, accompanied by defective decidualization. Rev-erbα could regulate decidualization by directly repressing IL-6, which reduced the expression of CCAAT/enhancer-binding protein ß (C/EBPß) and its target insulin-like growth factor binding protein 1 (IGFBP1), the marker of decidualization, by inhibiting progesterone receptors (PR) expression. Moreover, deficient decidualization, higher abortion rate and lower implantation number were exhibited in the mouse models with sleep disturbance compared with those in normal mouse. Pharmacological activation of Rev-erbα or neutralization of IL-6 alleviated the adverse effect of sleep disturbance on pregnancy outcomes. CONCLUSIONS: Taken together, Rev-erbα regulated decidualization via IL-6-PR-C/EBPß axis and might be a connector between sleep and pregnancy outcome. Therapies targeting Rev-erbα and IL-6 might help improving adverse pregnancy outcomes induced by sleep disturbance.