• Humans
• Graft Rejection/immunology
• Graft Rejection/prevention & control
• Stem Cells/immunology
• Stem Cells/cytology
• Stem Cells/metabolism
• Apoptosis
• Genetic Engineering
• Stem Cell Transplantation

• 2019YFA0801700 National Key Research and Development Program of China
• National Key Research and Development Program of China

• Apoptosis
• Exosomes
• Gemcitabine
• Mesenchymal stem cells
• Pancreatic cancer

• biomarkers
• exosomes
• hypertension
• placenta
• preeclampsia
• spiral artery
• trophoblast

• Humans
• Pregnancy
• Pre-Eclampsia/metabolism
• Exosomes/metabolism
• Female
• Placenta/metabolism
• Placenta/immunology
• Biomarkers/metabolism
• Animals
• Cell Communication

• REV/1612/12-2023 Indian Council of Medical Research

• chimeric transcripts
• dsRNA
• innate immunity
• retrotransposon-derived gene
• retrotransposons

• Humans
• Retroelements/genetics
• Pathogen-Associated Molecular Pattern Molecules
• RNA, Messenger
• Genome, Human
• Immunity, Innate/genetics

• Percoll gradient
• Placenta
• Transfection
• Villous cytotrophoblastic cells
• siRNA

• Pregnancy
• Humans
• Female
• Placenta
• Trophoblasts
• Epithelial Cells
• Transfection
• Cell Differentiation

• Gestational trophoblastic disease
• HERVs
• Preeclampsia
• Suppressyn
• Syncytin-1
• Syncytin-2

• Pregnancy
• Female
• Humans
• Placenta
• Gene Products, env/genetics
• Pregnancy Proteins/genetics
• Endogenous Retroviruses
• Pre-Eclampsia

• VEGA 1/0559/22 Agentúra Ministerstva Školstva, Vedy, Výskumu a Športu SR (SK)
• Comenius University in Bratislava

• bioinformatics
• biomarker
• endogenous retrovirus
• immunotherapy
• kidney renal clear cell carcinoma

• Humans
• Endogenous Retroviruses
• Immunotherapy
• Biomarkers
• Carcinoma
• Kidney
• Tumor Microenvironment

• CNS targeting
• Exosomes
• extracellular vesicles
• in vivo biodistribution
• targeted delivery

• drug delivery system
• electroporation
• exosome
• extracellular vesicle
• gene therapy
• liposome
• microvesicle
• trophoblast

• Pregnancy
• Female
• Humans
• Placenta
• Extracellular Vesicles
• DNA
• Drug Delivery Systems
• Plasmids/genetics

• K99 EB033857 NIBIB NIH HHS

Extracellular vesicles (EVs) are nanosized vesicles that act as snapshots of cellular components and mediate cellular communications, but they may contain cargo contents with undesired effects. We developed a model to improve the effects of endometrium-derived EVs (Endo-EVs) on the porcine embryo attachment in feeder-free culture conditions. Endo-EVs cargo contents were analyzed using conventional and real-time PCR for micro-RNAs, messenger RNAs, and proteomics. Porcine embryos were generated by parthenogenetic electric activation in feeder-free culture conditions supplemented with or without Endo-EVs. The cellular uptake of Endo-EVs was confirmed using the lipophilic dye PKH26. Endo-EVs cargo contained miR-100, miR-132, and miR-155, together with the mRNAs of porcine endogenous retrovirus (PERV) and β-catenin. Targeting PERV with CRISPR/Cas9 resulted in reduced expression of PERV mRNA transcripts and increased miR-155 in the Endo-EVs, and supplementing these in embryos reduced embryo attachment. Supplementing the medium containing Endo-EVs with miR-155 inhibitor significantly improved the embryo attachment with a few outgrowths, while supplementing with Rho-kinase inhibitor (RI, Y-27632) dramatically improved both embryo attachment and outgrowths. Moreover, the expression of miR-100, miR-132, and the mRNA transcripts of BCL2, zinc finger E-box-binding homeobox 1, β-catenin, interferon-γ, protein tyrosine phosphatase non-receptor type 1, PERV, and cyclin-dependent kinase 2 were all increased in embryos supplemented with Endo-EVs + RI compared to those in the control group. Endo-EVs + RI reduced apoptosis and increased the expression of OCT4 and CDX2 and the cell number of embryonic outgrowths. We examined the individual and combined effects of RI compared to those of the miR-155 mimic and found that RI can alleviate the negative effects of the miR-155 mimic on embryo attachment and outgrowths. EVs can improve embryo attachment and the unwanted effects of the de trop cargo contents (miR-155) can be alleviated through anti-apoptotic molecules such as the ROCK inhibitor.

• CRISPR/Cas9
• ROCK inhibitor
• embryo
• extracellular vesicles
• miR-155

• Amides
• Animals
• Cyclin-Dependent Kinase 2/metabolism
• Endometrium/metabolism
• Extracellular Vesicles/metabolism
• Female
• Interferon-gamma/metabolism
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Protein Tyrosine Phosphatases/metabolism
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Pyridines
• RNA, Messenger/metabolism
• Swine
• Zinc Finger E-box-Binding Homeobox 1/metabolism
• beta Catenin/metabolism
• rho-Associated Kinases/metabolism

Human endogenous retroviruses (HERVs) are relics of ancestral infections and represent 8% of the human genome. They are no longer infectious, but their activation has been associated with several disorders, including neuropsychiatric conditions. Enhanced expression of HERV-K and HERV-H envelope genes has been found in the blood of autism spectrum disorder (ASD) patients, but no information is available on syncytin 1 (SYN1), SYN2, and multiple sclerosis-associated retrovirus (MSRV), which are thought to be implicated in brain development and immune responses. HERV activation is regulated by TRIM28 and SETDB1, which are part of the epigenetic mechanisms that organize the chromatin architecture in response to external stimuli and are involved in neural cell differentiation and brain inflammation. We assessed, through a PCR realtime Taqman amplification assay, the transcription levels of pol genes of HERV-H, -K, and -W families, of env genes of SYN1, SYN2, and MSRV, as well as of TRIM28 and SETDB1 in the blood of 33 ASD children (28 males, median 3.8 years, 25–75% interquartile range 3.0–6.0 y) and healthy controls (HC). Significantly higher expressions of TRIM28 and SETDB1, as well as of all the HERV genes tested, except for HERV-W-pol, were found in ASD, as compared with HC. Positive correlations were observed between the mRNA levels of TRIM28 or SETDB1 and every HERV gene in ASD patients, but not in HC. Overexpression of TRIM28/SETDB1 and several HERVs in children with ASD and the positive correlations between their transcriptional levels suggest that these may be main players in pathogenetic mechanisms leading to ASD.

• SETDB1
• TRIM28
• autism spectrum disorder
• children
• human endogenous retroviruses

• HERV-W
• Immune response
• Inflammation
• Nonfusogenic activity
• Preeclampsia
• Syncytin-1

• Animals
• Female
• Gene Products, env/genetics
• Gene Products, env/metabolism
• Humans
• Inflammation/pathology
• Mice
• Placenta/metabolism
• Pre-Eclampsia/genetics
• Pregnancy
• Pregnancy Proteins
• Trophoblasts

• The Leading Talents in Medical and Health Profession Program and the Fenghuanchao Program of the Wuxi Taihu Talent Plan
• The Jiangsu Shuangchuang Talent Program
• The Postdoctoral Training Program of Nanjing Medical University

• adverse pregnancy outcome
• cancer
• exosomes
• immune exhaustion
• immune-therapy
• pla-xosomes
• pregnancy

• breastfeeding
• human breast milk
• immunity
• microbiota
• mother and infant health

• Breast Feeding
• Child
• Female
• Humans
• Immune System
• Immunity, Active
• Infant
• Infant, Newborn
• Milk, Human
• Mothers

• zferv
• Endogenous retrovirus
• LTR
• Reporter line
• Retroelement
• Zebrafish

• Animals
• Animals, Genetically Modified
• Endogenous Retroviruses/genetics
• Mammals
• Neurons
• Retroviridae Infections/genetics
• Zebrafish/genetics

• Wellcome Trust
• G0700091 Medical Research Council
• NC/M001490/1 National Centre for the Replacement, Refinement and Reduction of Animals in Research
• Association Européenne contre les Leucodystrophies
• Sir Jules Thorn Charitable Trust
• Agence Nationale de la Recherche
• The University of Sheffield Bateson Centre

• HERVs
• cellular senescence
• fusion
• syncytia
• virus

• COVID-19
• Cellular Senescence/physiology
• Humans
• Membrane Fusion
• Neurodegenerative Diseases
• SARS-CoV-2
• Viruses

• 001 World Health Organization

Cell fusion is involved in many physiological and pathological processes, including gamete binding, and cancer development. The basic processes of cell fusion include membrane fusion, cytoplasmic mixing, and nuclear fusion. Cell fusion is regulated by different proteins and signaling pathways. Syncytin-1, syncytin-2, glial cell missing 1, galectin-1 and other proteins (annexins, myomaker, myomerger etc.) involved in cell fusion via the cyclic adenosine-dependent protein kinase A, mitogen-activated protein kinase, wingless/integrase-1, and c-Jun N-terminal kinase signaling pathways. In the progression of malignant tumors, cell fusion is essential during the organ-specific metastasis, epithelial-mesenchymal transformation, the formation of cancer stem cells (CSCs), cancer angiogenesis and cancer immunity. In addition, diploid cells can be induced to form polyploid giant cancer cells (PGCCs) via cell fusion under many kinds of stimuli, including cobalt chloride, chemotherapy, radiotherapy, and traditional Chinese medicine. PGCCs have CSC-like properties, and the daughter cells derived from PGCCs have a mesenchymal phenotype and exhibit strong migration, invasion, and proliferation abilities. Therefore, exploring the molecular mechanisms of cell fusion can enable us better understand the development of malignant tumors. In this review, the basic process of cell fusion and its significance in cancer is discussed.

• cancer stem cells
• cell fusion
• glial cell missing 1
• polyploid giant cancer cells
• syncytin

• Epstein-Barr virus
• human endogenous retrovirus-W
• human herpesvirus-6
• inflammatory cascade
• molecular mimicry
• multiple sclerosis

• cancer
• computational modeling
• human retroviral
• proinflammatory response
• systems biology

• Autoimmune Diseases/etiology
• Autoimmune Diseases/immunology
• Autoimmune Diseases/virology
• Biological Evolution
• DNA Transposable Elements/genetics
• Endogenous Retroviruses/genetics
• Endogenous Retroviruses/immunology
• Endogenous Retroviruses/pathogenicity
• Genome, Human
• Humans
• Immunity, Innate
• Inflammation/etiology
• Inflammation/immunology
• Inflammation/virology
• Machine Learning
• Microbiota/immunology
• Models, Biological
• Neoplasms/etiology
• Neoplasms/immunology
• Neoplasms/virology
• Neurodegenerative Diseases/etiology
• Neurodegenerative Diseases/immunology
• Neurodegenerative Diseases/virology
• Systems Biology

• Agency for Science, Technology and Research

The advancement of precision medicine critically depends on the robustness and specificity of the carriers used for the targeted delivery of effector molecules in the human body. Numerous nanocarriers have been explored in vivo, to ensure the precise delivery of molecular cargos via tissue-specific targeting, including the endocrine part of the pancreas, thyroid, and adrenal glands. However, even after reaching the target organ, the cargo-carrying vehicle needs to enter the cell and then escape lysosomal destruction. Most artificial nanocarriers suffer from intrinsic limitations that prevent them from completing the specific delivery of the cargo. In this respect, extracellular vesicles (EVs) seem to be the natural tool for payload delivery due to their versatility and low toxicity. However, EV-mediated delivery is not selective and is usually short-ranged. By inserting the viral membrane fusion proteins into exosomes, it is possible to increase the efficiency of membrane recognition and also ease the process of membrane fusion. This review describes the molecular details of the viral-assisted interaction between the target cell and EVs. We also discuss the question of the usability of viral fusion proteins in developing extracellular vesicle-based nanocarriers with a higher efficacy of payload delivery. Finally, this review specifically highlights the role of Gag and RNA binding proteins in RNA sorting into EVs.

• RNA sorting
• extracellular vesicles
• fusion protein
• target delivery

Exosomes are cell-secreted nanoparticles (generally with a size of 30–150 nm) bearing numerous biological molecules including nucleic acids, proteins and lipids, which are thought to play important roles in intercellular communication. As carriers, exosomes hold promise as advanced platforms for targeted drug/gene delivery, owing to their unique properties, such as innate stability, low immunogenicity and excellent tissue/cell penetration capacity. However, their practical applications can be limited due to insufficient targeting ability or low efficacy in some cases. In order to overcome these existing challenges, various approaches have been applied to engineer cell-derived exosomes for a higher selectivity and effectiveness. This review presents the state-of-the-art designs and applications of advanced exosome-based systems for targeted cargo delivery. By discussing experts’ opinions, we hope this review will inspire the researchers in this field to develop more practical exosomal delivery systems for clinical applications.

• drug delivery
• exosome engineering
• exosomes
• extracellular vesicles
• gene delivery
• targeted delivery

Ovarian cancer and pregnancy are two states in which the host immune system is exposed to novel antigens. Indeed, both the tumor and placenta must invade tissues, remodel vasculature to establish a robust blood supply, and evade detection by the immune system. Interestingly, tumor and placenta tissue use similar mechanisms to induce these necessary changes. One mediator is emerging as a key player in invasion, vascular remodeling, and immune evasion: extracellular vesicles (EVs). Many studies have identified EVs as a key mediator of cell-to-cell communication. Specifically, the cargo carried by EVs, which includes proteins, nucleic acids, and lipids, can interact with cells to induce changes in the target cell ranging from gene expression to migration and metabolism. EVs can promote cell division and tissue invasion, immunosuppression, and angiogenesis which are essential for both cancer and pregnancy. In this review, we examine the role of EVs in ovarian cancer metastasis, chemoresistance, and immune modulation. We then focus on the role of EVs in pregnancy with special attention on the vascular remodeling and regulation of the maternal immune system. Lastly, we discuss the clinical utility of EVs as markers and therapeutics for ovarian cancer and pre-eclampsia.

• angiogenesis
• exosome
• extracellular vesicle
• immune modulation
• invasion
• ovarian cancer
• placenta
• preeclampsia
• pregnancy
• syncytial knot

• Autoimmune diseases
• Celiac disease
• Children
• Human endogenous retroviruses

• COVID-19
• SARS-CoV-2
• SETDB1
• TRIM28
• children
• human endogenous retroviruses
• interferon

• COVID-19/epidemiology
• COVID-19/metabolism
• COVID-19/pathology
• COVID-19/virology
• Case-Control Studies
• Child
• Endogenous Retroviruses/genetics
• Endogenous Retroviruses/metabolism
• Female
• Histone-Lysine N-Methyltransferase/genetics
• Histone-Lysine N-Methyltransferase/metabolism
• Humans
• Interferon Type I/genetics
• Interferon Type I/metabolism
• Interferon-gamma/genetics
• Interferon-gamma/metabolism
• Interferons/genetics
• Interferons/metabolism
• Italy/epidemiology
• Male
• SARS-CoV-2/isolation & purification
• Severity of Illness Index
• Tripartite Motif-Containing Protein 28/genetics
• Tripartite Motif-Containing Protein 28/metabolism
• Interferon Lambda

Pregnancy maintenance depends on the formation of normal placentas accompanied by trophoblast invasion and vascular remodeling. Various types of cells, such as trophoblasts, endothelial cells, immune cells, mesenchymal stem cells (MSCs), and adipocytes, mediate cell-to-cell interactions through soluble factors to maintain normal placental development. Extracellular vesicles (EVs) are diverse nanosized to microsized membrane-bound particles released from various cells. EVs contain tens to thousands of different RNA, proteins, small molecules, DNA fragments, and bioactive lipids. EV-derived microRNAs (miRNAs) and proteins regulate inflammation and trophoblast invasion in the placental microenvironment. Maternal-fetal communication through EV can regulate the key signaling pathways involved in pregnancy maintenance, from implantation to immune regulation. Therefore, EVs and the encapsulating factors play important roles in pregnancy, some of which might be potential biomarkers.

In this review, we have summarized published studies about the EVs in the placentation and pregnancy-related diseases. By summarizing the role of EVs and their delivering active molecules in pregnancy-related diseases, it provides novel insight into the diagnosis and treatment of diseases.

Exosomes are a subset of extracellular vesicles with an average diameter of ~100nm. Exosomes are released by all cells through an endosome-dependent pathway and carry nucleic acids, proteins, lipids, cytokines and metabolites, mirroring the state of the originating cells. The function of exosomes has been implicated in various reproduction processes, such as embryo development, implantation, decidualization and placentation. Placenta-derived exosomes (pEXO) can be detected in the maternal blood as early as 6 weeks after conception and their levels increase with gestational age. Importantly, alternations in the molecular signatures of pEXO are observed in pregnancy-related complications. Thus, these differentially expressed molecules could be the potential biomarkers for diagnosis of the pregnancy-associated diseases. Recent studies have demonstrated that pEXO play a key role in the establishment of maternal immune tolerance, which is critical for a successful pregnancy. To gain a better understanding of the underlying mechanism, we highlighted the advanced studies of pEXO on immune cells in pregnancy.

• exosomes
• gestational diabetes mellitus
• maternal immune tolerance
• placenta
• preeclampsia
• preterm

The anti-vaccination movement claims an alleged danger of the COVID-19 vaccine based on the presupposed similarity between syncytin, which plays a role in human placentation and the SARS-CoV-2 spike protein. We argue that because of very low sequence similarity between human syncytin-1 and the SARS-CoV-2 S protein, it is unlikely that any S protein-specific SARS-CoV-2 vaccine would generate an immune response which would affect fertility and pregnancy. However, further evaluation of potential impacts of COVID-19 vaccines on fertility, placentation, pregnancy and general health of mother and newborn is required.

Human placenta formation relies on the interaction between fused trophoblast cells of the embryo with uterine endometrium. The fusion between trophoblast cells, first into cytotrophoblast and then into syncytiotrophoblast, is facilitated by the fusogenic protein syncytin. Syncytin derives from an envelope glycoprotein (ENV) of retroviral origin. In exogenous retroviruses, the envelope glycoproteins coded by env genes allow fusion of the viral envelope with the host cell membrane and entry of the virus into a host cell. During mammalian evolution, the env genes have been repeatedly, and independently, captured by various mammalian species to facilitate the formation of the placenta. Such a shift in the function of a gene, or a trait, for a different purpose during evolution is called an exaptation (co-option). We discuss the structure and origin of the placenta, the fusogenic and non-fusogenic functions of syncytin, and the mechanism of cell fusion. We also comment on an alleged danger of the COVID-19 vaccine based on the presupposed similarity between syncytin and the SARS-CoV-2 spike protein.

• COVID-19 vaccine
• SARS-CoV-2
• placenta
• retrovirus
• spike protein
• syncytin

Multinucleate syncytialized trophoblast is found in three forms in the human placenta. In the earliest stages of pregnancy, it is seen at the invasive leading edge of the implanting embryo and has been called primitive trophoblast. In later pregnancy, it is represented by the immense, multinucleated layer covering the surface of placental villi and by the trophoblast giant cells found deep within the uterine decidua and myometrium. These syncytia interact with local and/or systemic maternal immune effector cells in a fine balance that allows for invasion and persistence of allogeneic cells in a mother who must retain immunocompetence for 40 weeks of pregnancy. Maternal immune interactions with syncytialized trophoblast require tightly regulated mechanisms that may differ depending on the location of fetal cells and their invasiveness, the nature of the surrounding immune effector cells and the gestational age of the pregnancy. Some specifically reflect the unique mechanisms involved in trophoblast cell–cell fusion (aka syncytialization). Here we will review and summarize several of the mechanisms that support healthy maternal–fetal immune interactions specifically at syncytiotrophoblast interfaces.

• extracellular vesicles (EV)
• human endogenous retroviruses (HERVs)
• immune checkpoint molecules
• syncytiotrophoblast (STB)
• toll-like receptors (TLRs)

• Animals
• Chorionic Villi/immunology
• Extracellular Vesicles/immunology
• Female
• Humans
• Immunity
• Placenta/immunology
• Placentation
• Pregnancy
• Toll-Like Receptors/immunology
• Trophoblasts/immunology

• P30 GM118228 NIGMS NIH HHS
• R21 AI145071 NIAID NIH HHS

• Placenta
• extracellular vesicles
• microRNA
• trophoblast
• viruses

• Extracellular Vesicles/immunology
• Female
• Humans
• Nanostructures
• Organ Specificity
• Placenta/immunology
• Pregnancy/immunology
• Retroviridae/physiology
• Retroviridae Infections/immunology
• Trophoblasts/immunology
• Virulence
• Virus Replication

• R01 HD086325 NICHD NIH HHS
• R37 HD086916 NICHD NIH HHS

• CD4/CD8 ratio
• HIV-1
• biomarkers
• extracellular vesicles
• immune activation
• inflammation
• miR-155
• miR-223
• miR-92
• microRNA

• biomarker
• diagnosis
• embryo
• exosomes
• extracellular vesicles
• miRNA
• microvesicles
• protein
• reproduction
• therapy

• Humans
• Extracellular Vesicles/metabolism
• Extracellular Vesicles/physiology
• Female
• Pregnancy
• Fertilization/physiology
• Animals
• Reproduction/physiology
• Cell Communication
• Embryo, Mammalian/metabolism

• Cytotrophoblast
• Decidua
• Extracellular vesicle
• Human
• Placenta
• TNFα

Cancer is a major challenge in our societies, according to the World Health Organization (WHO) about 1/6 deaths were cancer related in 2018 and it is considered the second leading cause of death globally. Immunotherapies have changed the paradigm of oncologic treatment for several cancers where the field had fallen short in providing competent therapies. Despite the improvement, broadly acting and highly effective therapies capable of eliminating or preventing human cancers with insufficient mutated antigens are still missing. Adenoviral vector-based vaccines are a successful tool in the treatment of various diseases including cancer; however, their success has been limited. In this review we discuss the potential of adenovirus as therapeutic tools and the current developments to use them against cancer. More specifically, we examine how to use them to target endogenous retroviruses (ERVs). ERVs, comprising 8% of the human genome, have been detected in several cancers, while they remain silent in healthy tissues. Their low immunogenicity together with their immunosuppressive capacity aid cancer to escape immunosurveillance. In that regard, virus-like-vaccine (VLV) technology, combining adenoviral vectors and virus-like-particles (VLPs), can be ideal to target ERVs and elicit B-cell responses, as well as CD8⁺ and CD4⁺ T-cells responses.

• adenoviral vector
• adenovirus
• cancer
• endogenous retrovirus
• envelope
• immunology
• immunotherapy
• virus-like-particles
• virus-like-vaccines

• Adenoviridae/immunology
• Adenovirus Vaccines/immunology
• Animals
• Endogenous Retroviruses/immunology
• Genetic Vectors/immunology
• Humans
• Immunity/immunology
• Immunotherapy/methods
• Neoplasms/immunology
• Neoplasms/virology
• Viral Vaccines/immunology

• embryo implantation
• exosomes
• extracellular vesicles
• placenta
• pregnancy

• Exosomes/physiology
• Female
• Fetus/cytology
• Humans
• Maternal-Fetal Exchange
• Placenta/cytology
• Pregnancy

• 2016/21/B/NZ7/02747 Narodowe Centrum Nauki

Extracellular vesicles (EVs) are nanosized, membranous vesicles released by almost all types of cells. Extracellular vesicles can be classified into distinct subtypes according to their sizes, origins and functions. Extracellular vesicles play important roles in intercellular communication through the transfer of a wide spectrum of bioactive molecules, contributing to the regulation of diverse physiological and pathological processes. Recently, it has been established that EVs mediate foetal‐maternal communication across gestation. Abnormal changes in EVs have been reported to be critically involved in pregnancy‐related diseases. Moreover, EVs have shown great potential to serve as biomarkers for the diagnosis of pregnancy‐related diseases. In this review, we discussed about the roles of EVs in normal pregnancy and how changes in EVs led to complicated pregnancy with an emphasis on their values in predicting and monitoring of pregnancy‐related diseases.

• biomarkers
• complications
• exosomes
• extracellular vesicles
• pregnancy

• ERVFRD-1
• syncytialization
• villous cytotrophoblasts
• β-galactoside-binding lectin