Decidual γδT cells of early human pregnancy produce angiogenic and immunomodulatory proteins while also possessing cytotoxic potential.

During pregnancy, the maternal immune system must allow and support the growth of the developing placenta while maintaining the integrity of the mother's body. The trophoblast's unique HLA signature is a key factor in this physiological process. This study focuses on decidual γδT cell populations and examines their expression of receptors that bind to non-classical HLA molecules, HLA-E and HLA-G. We demonstrate that decidual γδT cell subsets, including Vδ1, Vδ2, and double-negative (DN) Vδ1-/Vδ2- cells express HLA-specific regulatory receptors, such as NKG2C, NKG2A, ILT2, and KIR2DL4, each with varying dominance. Furthermore, decidual γδT cells produce cytokines (G-CSF, FGF2) and cytotoxic mediators (Granulysin, IFN-γ), suggesting functions in placental growth and pathogen defense. However, these processes seem to be controlled by factors other than trophoblast-derived non-classical HLA molecules. These findings indicate that decidual γδT cells have the potential to actively contribute to the maintenance of healthy human pregnancy.

Uterine macrophages and NK cells exhibit population and gene-level changes after implantation but maintain pro-invasive properties.

Introduction: Prior to pregnancy, hormonal changes lead to cellular adaptations in the endometrium allowing for embryo implantation. Critical for successful pregnancy establishment, innate immune cells constitute a significant proportion of uterine cells prior to arrival of the embryo and throughout the first trimester in humans and animal models. Abnormal uterine immune cell function during implantation is believed to play a role in multiple adverse pregnancy outcomes. Current work in humans has focused on uterine immune cells present after pregnancy establishment, and limited in vitro models exist to explore unique functions of these cells. Methods: With single-cell RNA-sequencing (scRNAseq), we comprehensively compared the human uterine immune landscape of the endometrium during the window of implantation and the decidua during the first trimester of pregnancy. Results: We uncovered global and cell-type-specific gene signatures for each timepoint. Immune cells in the endometrium prior to implantation expressed genes associated with immune metabolism, division, and activation. In contrast, we observed widespread interferon signaling during the first trimester of pregnancy. We also provide evidence of specific inflammatory pathways enriched in pre- and post-implantation macrophages and natural killer (NK) cells in the uterine lining. Using our novel implantation-on-a-chip (IOC) to model human implantation ex vivo, we demonstrate for the first time that uterine macrophages strongly promote invasion of extravillous trophoblasts (EVTs), a process essential for pregnancy establishment. Pre- and post-implantation uterine macrophages promoted EVT invasion to a similar degree as pre- and post-implantation NK cells on the IOC. Conclusions: This work provides a foundation for further investigation of the individual roles of uterine immune cell subtypes present prior to embryo implantation and during early pregnancy, which will be critical for our understanding of pregnancy complications associated with abnormal trophoblast invasion and placentation.

NK cell receptor profiling of endometrial and decidual NK cells reveals pregnancy-induced adaptations.

Natural killer (NK) cells, with a unique NK cell receptor phenotype, are abundantly present in the non-pregnant (endometrium) and pregnant (decidua) humanuterine mucosa. It is hypothesized that NK cells in the endometrium are precursors for decidual NK cells present during pregnancy. Microenvironmental changes can alter the phenotype of NK cells, but it is unclear whether decidual NK cell precursors in the endometrium alter their NK cell receptor repertoire under the influence of pregnancy. To examine whether decidual NK cell precursors reveal phenotypic modifications upon pregnancy, we immunophenotyped the NK cell receptor repertoire of both endometrial and early-pregnancy decidual NK cells using flow cytometry. We showed that NK cells in pre-pregnancy endometrium have a different phenotypic composition compared to NK cells in early-pregnancy decidua. The frequency of killer-immunoglobulin-like receptor (KIR expressing NK cells, especially KIR2DS1, KIR2DL2L3S2, and KIR2DL2S2 was significantly lower in decidua, while the frequency of NK cells expressing activating receptors NKG2D, NKp30, NKp46, and CD244 was significantly higher compared to endometrium. Furthermore, co-expression patterns showed a lower frequency of NK cells co-expressing KIR3DL1S1 and KIR2DL2L3S2 in decidua. Our results provide new insights into the adaptations in NK cell receptor repertoire composition that NK cells in the uterine mucosa undergo upon pregnancy.

Corrigendum: Deciphering decidual leukocyte traffic with serial intravascular staining.

[This corrects the article DOI: 10.3389/fimmu.2023.1332943.].

Estrogen and Progesterone Receptors Are Dysregulated at the BPH/5 Mouse Preeclamptic-Like Maternal-Fetal Interface.

The etiopathogenesis of preeclampsia, a leading hypertensive disorder of pregnancy, has been proposed to involve an abnormal circulating sex hormone profile and misexpression of placental estrogen and progesterone receptors (ER and PR, respectively). However, existing research is vastly confined to third trimester preeclamptic placentas. Consequently, the placental-uterine molecular crosstalk and the dynamic ER and PR expression pattern in the peri-conception period remain overlooked. Herein, our goal was to use the BPH/5 mouse to elucidate pre-pregnancy and early gestation Er and Pr dynamics in a preeclamptic-like uterus. BPH/5 females display low circulating estrogen concentration during proestrus, followed by early gestation hypoestrogenemia, hyperprogesteronemia, and a spontaneous preeclamptic-like phenotype. Preceding pregnancy, the gene encoding Er alpha (Erα, Esr1) is upregulated in the diestrual BPH/5 uterus. At the peak of decidualization, Esr1, Er beta (Erß, Esr2), and Pr isoform B (Pr-B) were upregulated in the BPH/5 maternal-fetal interface. At the protein level, BPH/5 females display higher percentage of decidual cells with nuclear Erα expression, as well as Pr downregulation in the decidua, luminal and glandular epithelium. In conclusion, we provide evidence of disrupted sex hormone signaling in the peri-conception period of preeclamptic-like pregnancies, potentially shedding some light onto the intricate role of sex hormone signaling at unexplored timepoints of human preeclampsia.

Decidual leukocytes respond to African lineage Zika virus infection with mild anti-inflammatory changes during acute infection in rhesus macaques.

Zika virus (ZIKV) can be vertically transmitted during pregnancy resulting in a range of adverse pregnancy outcomes. The decidua is commonly found to be infected by ZIKV, yet the acute immune response to infection remains understudied in vivo. We hypothesized that in vivo African-lineage ZIKV infection induces a pro-inflammatory response in the decidua. To test this hypothesis, we evaluated the decidua in pregnant rhesus macaques within the first two weeks following infection with an African-lineage ZIKV and compared our findings to gestationally aged-matched controls. Decidual leukocytes were phenotypically evaluated using spectral flow cytometry, and cytokines and chemokines were measured in tissue homogenates from the decidua, placenta, and fetal membranes. The results of this study did not support our hypothesis. Although ZIKV RNA was detected in the decidual tissue samples from all ZIKV infected dams, phenotypic changes in decidual leukocytes and differences in cytokine profiles suggest that the decidua undergoes mild anti-inflammatory changes in response to that infection. Our findings emphasize the immunological state of the gravid uterus as a relatively immune privileged site that prioritizes tolerance of the fetus over mounting a pro-inflammatory response to clear infection.

Current understanding of the pathogenesis of placenta accreta spectrum disorder with focus on mitochondrial function.

AIM: The refinement of assisted reproductive technology, including the development of cryopreservation techniques (vitrification) and ovarian stimulation protocols, makes frozen embryo transfer (FET) an alternative to fresh ET and has contributed to the success of assisted reproductive technology. Compared with fresh ET cycles, FET cycles were associated with better in vitro fertilization outcomes; however, the occurrence of pregnancy-induced hypertension, preeclampsia, and placenta accreta spectrum (PAS) was higher in FET cycles. PAS has been increasing steadily in incidence as a life-threatening condition along with cesarean rates worldwide. In this review, we summarize the current understanding of the pathogenesis of PAS and discuss future research directions. METHODS: A literature search was performed in the PubMed and Google Scholar databases. RESULTS: Risk factors associated with PAS incidence include a primary defect of the decidua basalis or scar dehiscence, aberrant vascular remodeling, and abnormally invasive trophoblasts, or a combination thereof. Freezing, thawing, and hormone replacement manipulations have been shown to affect multiple cellular pathways, including cell proliferation, invasion, epithelial-to-mesenchymal transition (EMT), and mitochondrial function. Molecules involved in abnormal migration and EMT of extravillous trophoblast cells are beginning to be identified in PAS placentas. Many of these molecules were also found to be involved in mitochondrial biogenesis and dynamics. CONCLUSION: The etiology of PAS may be a multifactorial genesis with intrinsic predisposition (e.g., placental abnormalities) and certain environmental factors (e.g., defective decidua) as triggers for its development. A distinctive feature of this review is its focus on the potential factors linking mitochondrial function to PAS development.

Isolation of Primary Human Decidual Cells from the Fetal Membranes of Term Placentae.

The maternal decidua is a transient and dynamic tissue that functions as an immunoprivileged matrix related to nutritional and endocrine processes. The function of decidual cells is key to the success of embryo implantation and the maintenance of pregnancy with a positive maternal-fetal outcome. Therefore, establishing a method to optimize the isolation of primary decidual cells is essential. Our protocol described here provides a good yield of decidual cells in an optimized time.

Placenta Accreta Spectrum: Evaluation of classic and non-classic presentations, pathologic grading, and uterine scar dehiscence features in a modern institutional series.

INTRODUCTION: The aim of this study is to document the distribution of classic versus non-classic presentation of Placenta Accreta Spectrum (PAS) disorders as well as grading categories by the Society for Pediatric Pathology (SPP) and FIGO systems in an institutional cohort of gravid hysterectomies. We also document the prevalence of uterine scar as a histologic correlate for uterine scar dehiscence, a phenomenon raised by some as central to PAS pathogenesis. METHODS: PAS cases were assigned grade and designated as classic (anterior lower uterine segment implantation, prior C-section) or non-classic (implantation away from anterior lower uterine segment and/or no prior C-section). Features of dehiscence (uterine window, histologic evidence of scar) were recorded. RESULTS: Sixty-two patients were included: 76 % had prior C-section; 55 % had other forms of uterine instrumentation. Classic PAS was recorded in 52 % patients; notably, 48 % had non-classic presentation; of these, all but one had prior instrumentation (curettage, myomectomy, laparoscopy). Uterine window was described in 53 % classic and 23 % non-classic PAS. Scar was demonstrated in 31 % classic and 23 % non-classic PAS; trichrome/reticulin stains were confirmatory. 32 % cases were SPP grade 1, 18 % grade 2, 18 % grade 3a and 32 % grade 3d. Grade 3 was significantly more common in classic (72 %) than non-classic (27 %) PAS. DISCUSSION: While most PAS patients have classic presentation, a large subset does not; in addition, scar tissue is not identified histologically in most PAS hysterectomies; in these settings, PAS cannot be fully attributed to scar dehiscence. Uterine instrumentation often precedes non-classic PAS reinforcing the concept of decidual disruption as central to PAS pathogenesis. PAS grading as defined correlates with presentation (classic vs non-classic).

Placenta accreta spectrum disorder at single-cell resolution: a loss of boundary limits in the decidua and endothelium.

BACKGROUND: Placenta accreta spectrum disorders are associated with severe maternal morbidity and mortality. Placenta accreta spectrum disorders involve excessive adherence of the placenta preventing separation at birth. Traditionally, this condition has been attributed to excessive trophoblast invasion; however, an alternative view is a fundamental defect in decidual biology. OBJECTIVE: This study aimed to gain insights into the understanding of placenta accreta spectrum disorder by using single-cell and spatially resolved transcriptomics to characterize cellular heterogeneity at the maternal-fetal interface in placenta accreta spectrum disorders. STUDY DESIGN: To assess cellular heterogeneity and the function of cell types, single-cell RNA sequencing and spatially resolved transcriptomics were used. A total of 12 placentas were included, 6 placentas with placenta accreta spectrum disorder and 6 controls. For each placenta with placenta accreta spectrum disorder, multiple biopsies were taken at the following sites: placenta accreta spectrum adherent and nonadherent sites in the same placenta. Of note, 2 platforms were used to generate libraries: the 10× Chromium and NanoString GeoMX Digital Spatial Profiler for single-cell and spatially resolved transcriptomes, respectively. Differential gene expression analysis was performed using a suite of bioinformatic tools (Seurat and GeoMxTools R packages). Correction for multiple testing was performed using Clipper. In situ hybridization was performed with RNAscope, and immunohistochemistry was used to assess protein expression. RESULTS: In creating a placenta accreta cell atlas, there were dramatic difference in the transcriptional profile by site of biopsy between placenta accreta spectrum and controls. Most of the differences were noted at the site of adherence; however, differences existed within the placenta between the adherent and nonadherent site of the same placenta in placenta accreta. Among all cell types, the endothelial-stromal populations exhibited the greatest difference in gene expression, driven by changes in collagen genes, namely collagen type III alpha 1 chain (COL3A1), growth factors, epidermal growth factor-like protein 6 (EGFL6), and hepatocyte growth factor (HGF), and angiogenesis-related genes, namely delta-like noncanonical Notch ligand 1 (DLK1) and platelet endothelial cell adhesion molecule-1 (PECAM1). Intraplacental tropism (adherent versus non-adherent sites in the same placenta) was driven by differences in endothelial-stromal cells with notable differences in bone morphogenic protein 5 (BMP5) and osteopontin (SPP1) in the adherent vs nonadherent site of placenta accreta spectrum. CONCLUSION: Placenta accreta spectrum disorders were characterized at single-cell resolution to gain insight into the pathophysiology of the disease. An atlas of the placenta at single cell resolution in accreta allows for understanding in the biology of the intimate maternal and fetal interaction. The contributions of stromal and endothelial cells were demonstrated through alterations in the extracellular matrix, growth factors, and angiogenesis. Transcriptional and protein changes in the stroma of placenta accreta spectrum shift the etiologic explanation away from "invasive trophoblast" to "loss of boundary limits" in the decidua. Gene targets identified in this study may be used to refine diagnostic assays in early pregnancy, track disease progression over time, and inform therapeutic discoveries.

An investigation of the distributions of ferroptosis and necroptosis mediators in the maternal-fetal interface at different days of rat pregnancy.

Ferroptosis and necroptosis are recognized as playing major roles in the regulation of various physiological processes. However, the physiological role of the cell death mediated by these two pathways in the developmental process has not yet been clearly established. This study investigated ferroptosis and necroptosis signalling pathways in maternal-fetal tissue in the different gestational days (GD) of rat pregnancy using immunohistochemical and western blot methods in order to fill this gap. Twenty-four female Wistar albino rats were mated and divided into three groups. Maternal-fetal tissue samples were collected on GD 5, 12 and 19 of pregnancy. Expression and total protein levels of the markers glutathione peroxidase-4, soluble transporter family 7 member 11, transferrin receptor, receptor-interacting serine/threonine-protein kinase 1, receptor-interacting serine/threonine-protein kinase 3 and mixed lineage kinase domain-like protein were investigated on both the maternal and fetal surfaces of the placenta using immunohistochemical and western blot methods. The results showed varying levels of protein expression of both ferroptosis and necroptosis mediators in the GD 5, 12 and 19 of pregnancy. Immunohistochemical analyses revealed that these mediators were located on both the maternal (decidua and metrial gland) and fetal surfaces (labyrinth zone, yolk sac and basal zone) and that their expression levels changed in the different GD. The findings revealed the existence of important ferroptosis and necroptosis pathway mediators in rat maternal-fetal tissue. These results may provide a molecular framework for a better understanding of the communication between the placenta, decidua and fetus during the developmental process.

Verification of the efficacy of deciduae for determining the genetic type of mouse embryos.

Mouse embryos in the early-implantation stage require manipulation under a microscope. While the extraction of DNA, RNA and proteins from a single sample allows for both determination of genetic type and analysis of gene expression, whole mount analysis is not possible. In this study, we explored the applicability of PCR using extraembryonic tissues, especially the decidual side tissue after isolating the embryos from implantation sites to establish a method for determining the genetic type of embryos. The implantation site was resected at each day from the date of vaginal plug confirmation, separated into embryos and deciduae. Genomic DNA were isolated separately from the embryos and the deciduae. PCR was performed using these genomic DNA, and the band patterns were compared after electrophoresis. As a result, we demonstrated that detecting embryo-derived cells in the decidua allows determination of the sex and presence of transgenes without harming the mouse embryos themselves, from 8.5 days of age. This method enables the determination of the genetic type of mouse embryos without damaging. This technique would expand the adaptations for analysis of mouse implanted embryos.

Spatial Localization of Eubacterial 16S rRNA in Early Pregnancy Placenta and Decidua.

Bacteria derived from the maternal circulation have been suggested to seed the human placenta during pregnancy leading to development of an intrinsic placental microbiome; however, other data indicates these bacteria are artifactual contaminants. Limited research on the localization of bacteria in human placental tissue is available, which may help differentiate resident placental bacteria from contaminants. This study spatially localizes bacteria in situ in normal late first to early second trimester human placenta by 16S rRNA chromogenic in situ hybridization and demonstrates patterns consistent with both contaminants and intraparenchymal signals. These results suggest that placental microbiome studies may benefit from spatial strategies that can exclude surface contamination.

Recent Advances in Folates and Autoantibodies against Folate Receptors in Early Pregnancy and Miscarriage.

Though firstly identified in cerebral folate deficiency, autoantibodies against folate receptors (FRAbs) have been implicated in pregnancy complications such as miscarriage; however, the underlying mechanism needs to be further elaborated. FRAbs can be produced via sensitization mediated by folate-binding protein as well as gene mutation, aberrant modulation, or degradation of folate receptors (FRs). FRAbs may interfere with folate internalization and metabolism through blocking or binding with FRs. Interestingly, different types of FRs are expressed on trophoblast cells, decidual epithelium or stroma, and macrophages at the maternal-fetal interface, implying FRAbs may be involved in the critical events necessary for a successful pregnancy. Thus, we propose that FRAbs may disturb pregnancy establishment and maintenance by modulating trophoblastic biofunctions, placental development, decidualization, and decidua homeostasis as well as the functions of FOLR2+ macrophages. In light of these findings, FRAbs may be a critical factor in pathological pregnancy, and deserve careful consideration in therapies involving folic acid supplementation for pregnancy complications.

Turpentine Ointment for the Treatment of Folliculitis: An Open, Prospective, Randomized, Placebo- and Comparator-Controlled Multicenter Trial.

INTRODUCTION: Folliculitis is a painful infection and inflammation of the hair follicles, mostly caused by bacterial, fungal, or, more rarely, viral infections. Turpentine derivatives have been used traditionally to treat various skin infections and could thus also be effective in treating folliculitis. We carried out an open, prospective, randomized, placebo- and comparator-controlled multicenter trial to evaluate the efficacy and safety of an ointment containing pine turpentine oil, larch turpentine, and eucalyptus oil in the treatment of acute folliculitis. METHODS: Seventy outpatients with acute folliculitis were treated with the turpentine ointment, a comparator (povidone iodine solution), or a placebo (Vaseline) for 7 days. Photographs of the affected skin areas were taken by the physicians at four visits and by the patients on a daily basis. Photographs were evaluated by blinded observers. Primary efficacy endpoint was the change in total hair follicle lesion counts. Secondary endpoints included the evolution of the lesion counts in the course of the study, responder rate (improvement of follicle lesions by at least one count), and the patient's global assessment. Safety endpoints were the tolerability of the treatments and adverse event recording. RESULTS: A decrease of follicle lesions counts was detected for both active treatments but not for placebo, but the differences among groups were not statistically significant. As for the secondary endpoints, the ointment showed statistically significant superiority over placebo for the evolution of the lesions during the course of the study (p = 0.017), the responder rate (p = 0.032), and the subjective efficacy assessment by patients (p = 0.029). All treatments were equally well tolerated, with a similar number of treatment-emergent adverse events. CONCLUSION: The turpentine ointment is an effective and safe option for the treatment of folliculitis.

Immune Responses Potentially Involved in the Gestational Complications of Brucella Infection.

Infection by Brucella species in pregnant animals and humans is associated with an increased risk of abortion, preterm birth, and transmission of the infection to the offspring. The pathogen has a marked tropism for the placenta and the pregnant uterus and has the ability to invade and replicate within cells of the maternal-fetal unit, including trophoblasts and decidual cells. Placentitis is a common finding in infected pregnant animals. Several proinflammatory factors have been found to be increased in both the placenta of Brucella-infected animals and in trophoblasts or decidual cells infected in vitro. As normal pregnancies require an anti-inflammatory placental environment during most of the gestational period, Brucella-induced placentitis is thought to be associated with the obstetric complications of brucellosis. A few studies suggest that the blockade of proinflammatory factors may prevent abortion in these cases.

Identification of m6A Modification Regulated by Dysregulated circRNAs in Decidua of Recurrent Pregnancy Loss.

N6-methyladenosine (m6A) modification is a prevalent modification of messenger ribonucleic acid (mRNA) in eukaryote cells and is closely associated with recurrent pregnancy loss (RPL). Circular RNAs (circRNAs) play critical roles in embryo implantation, trophoblast invasion and immune balance, which are important events during pregnancy. However, how m6A modification is regulated by circRNAs and the potential regulatory mechanism of circRNAs on RPL occurrence remain largely unclassified. We displayed the expression profiles of circRNAs and mRNAs in the decidua of normal pregnancies and RPL patients based on circRNA sequencing and the Gene Expression Omnibus database. A total of 936 differentially expressed circRNAs were identified, including 509 upregulated and 427 downregulated circRNAs. Differentially expressed circRNAs were enriched in immune, metabolism, signaling and other related pathways via the analysis of Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The competitive endogenous RNA (ceRNA) network was predicted to supply the possible role of circRNAs in RPL occurrence, and we further analyzed the profiles of nine m6A regulators (seven readers, one writer and one eraser) managed by circRNAs in this network. We also showed the expression profiles of circRNAs in the serum, trying to seek a potential biomarker to help in the diagnosis of RPL. These data imply that circRNAs are involved in pathogenesis of RPL by changing immune activities, metabolism and m6A modification in the ceRNA network. Our study might provide assistance in exploring the pathogenesis and diagnosis of RPL.

High Expression and Significance of Siglec10/CD24 in Unexplained Missed Abortion.

OBJECTIVE: To investigate the expression of Siglec10 and CD24 in normal early pregnancy and missed abortion, and their significance in the maternal-fetal interface. METHODS: For our research, we employed Q-PCR and WB techniques to evaluate the traits and expression of Siglec10 and CD24 in the nonpregnant endometrium, as well as in the villus and decidua of women in their 6-10 weeks of normal early pregnancy and those who experienced missed abortion. Additionally, we utilized ELISA to determine the levels of Siglec10 and CD24 in the peripheral blood of pregnancy, missed abortion, and non-pregnant individuals. T-test and ANOVA were used to compare groups. RESULTS: 1. Villous tissues in early pregnancy showed high expression of Siglec10 and CD24, with a significant increase in expression in the missed abortion group (P < 0.01).2. Nonpregnant endometrial tissue showed low expression of Siglec10 and CD24, while early pregnancy decidua showed high expression, with even higher expression in missed abortion (all P < 0.05).3. Serum levels of Siglec10 and CD24 in normal early pregnancy were significantly higher than non-pregnancy (P < 0.01). However, the missed abortion group showed significantly higher levels than normal pregnancy (P < 0.01).4. CD24 expression in serum of missed abortion increases with Siglec10 expression, indicating a significant positive correlation (r = 0.500, P < 0.01). CONCLUSION: Siglec10 and CD24 expression in villus, decidua, and peripheral blood are up-regulated in unexplained missed abortions than those of women with normal pregnancies. This suggests that the levels of serum Siglec10 and CD24 can be used as an effective predictor of missed abortion.

EGF-Enhanced GnRH-II Regulation in Decidual Stromal Cell Motility through Twist and N-Cadherin Signaling.

Crucial roles in embryo implantation and placentation in humans include the invasion of the maternal decidua by extravillous trophoblasts and the motile behavior of decidual endometrial stromal cells. The effects of the epidermal growth factor (EGF) and GnRH-II in the endometrium take part in early pregnancy. In the present study, we demonstrated the coaction of EGF- and GnRH-II-promoted motility of human decidual endometrial stromal cells, indicating the possible roles of EGF and GnRH-II in embryo implantation and early pregnancy. After obtaining informed consent, we obtained human decidual endometrial stromal cells from decidual tissues from normal pregnancies at 6 to 12 weeks of gestation in healthy women undergoing suction dilation and curettage. Cell motility was evaluated with invasion and migration assays. The mechanisms of EGF and GnRH-II were performed using real-time PCR and immunoblot analysis. The results showed that human decidual tissue and stromal cells expressed the EGF and GnRH-I receptors. GnRH-II-mediated cell motility was enhanced by EGF and was suppressed by the knockdown of the endogenous GnRH-I receptor and EGF receptor with siRNA, revealing that GnRH-II promoted the cell motility of human decidual endometrial stromal cells through the GnRH-I receptor and the activation of Twist and N-cadherin signaling. This new concept regarding the coaction of EGF- and GnRH-promoted cell motility suggests that EGF and GnRH-II potentially affect embryo implantation and the decidual programming of human pregnancy.

Novel therapies for graft versus host disease with a focus on cell therapies.

Graft versus host disease (GVHD) can occur at any period post allogeneic hematopoietic stem cell transplantation as a common clinical complication contributing to significant morbidity and mortality. Acute GVHD develops in approximately 30-50% of patients receiving transplants from matched related donors. High doses of steroids are used as first-line treatment, but are unsuccessful in around 40% of patients, resulting in the diagnosis of steroid-refractory acute GVHD. Consensus has yet to develop for the management of steroid-refractory acute GVHD, and prognosis at six months has been estimated at around 50%. Thus, it is critical to find effective treatments that increase survival of steroid-refractory acute GVHD. This article describes the currently known characteristics, pathophysiology, and treatments for GVHD, with a special focus on recent advances in cell therapies. In particular, a novel cell therapy using decidua stromal cells (DSCs) was recently shown to have promising results for acute GVHD, with improved effectiveness over previous treatments including mesenchymal stromal cells. At the Karolinska Institute, severe acute GVHD patients treated with placenta-derived DSCs supplemented with either 5% albumin or 10% AB plasma displayed a one-year survival rate of 76% and 47% respectively. Furthermore, patients with steroid-refractory acute GVHD, displayed survival rates of 73% with albumin and 31% with AB plasma-supplemented DSCs, compared to the 20% survival rate in the mesenchymal stromal cell control group. Adverse events and deaths were found to be attributed only to complications of hematopoietic stem cell transplant and GVHD, not to the study intervention. ASC Therapeutics, Inc, in collaboration with the Karolinska Institute, will soon initiate a phase 2 multicenter, open-label study to further assess the efficacy and safety of intravenous DSC treatment in sixty patients with Grade II-IV steroid-refractory acute GVHD. This novel cell therapy represents a promising treatment to combat the poor prognosis that steroid-refractory acute GVHD patients currently face.