Placental pathology lesions: International Society for Ultrasound in Obstetrics and Gynecology vs Society for Maternal-Fetal Medicine fetal growth restriction definitions.

BACKGROUND: Research on the definition of fetal growth restriction (FGR) has focused on predicting adverse perinatal outcomes. A significant limitation of this approach is that the individual outcomes of interest could be related to the condition and the treatment. Evaluation of outcomes that reflect the pathophysiology of FGR may overcome this limitation. OBJECTIVE: To compare the diagnostic performance of the FGR definitions established by the International Society for Ultrasound in Obstetrics and Gynecology (ISUOG) and the Society for Maternal-Fetal Medicine (SMFM) to predict placental histopathological findings associated with placental insufficiency and a composite adverse neonatal outcome (ANeO). STUDY DESIGN: In this retrospective cohort study of singleton pregnancies, the ISUOG and the SMFM guidelines were used to identify pregnancies with FGR and a corresponding control group. The primary outcome was the prediction of placental histopathological findings associated with placental insufficiency, defined as lesions associated with maternal vascular malperfusion (MVM). A composite ANeO (ie, umbilical artery pH≤7.1, Apgar score at 5 minutes ≤4, neonatal intensive care unit admission, hypoglycemia, respiratory distress syndrome requiring mechanical ventilation, intrapartum fetal distress requiring expedited delivery, and perinatal death) was investigated as a secondary outcome. Sensitivity, specificity, positive and negative predictive values, and the areas under the receiver-operating-characteristics curves were determined for each FGR definition. Logistic regression models were used to assess the association between each definition and the studied outcomes. A subgroup analysis of the diagnostic performance of both definitions stratifying the population in early and late FGR was also performed. RESULTS: Both societies' definitions showed a similar diagnostic performance as well as a significant association with the primary (ISUOG adjusted odds ratio 3.01 [95% confidence interval 2.42, 3.75]; SMFM adjusted odds ratio 2.85 [95% confidence interval 2.31, 3.51]) and secondary outcomes (ISUOG adjusted odds ratio 1.95 [95% confidence interval 1.56, 2.43]; SMFM adjusted odds ratio 2.12 [95% confidence interval 1.70, 2.65]). Furthermore, both FGR definitions had a limited discriminatory capacity for placental histopathological findings of MVM and the composite ANeO (area under the receiver-operating-characteristics curve ISUOG 0.63 [95% confidence interval 0.61, 0.65], 0.59 [95% confidence interval 0.56, 0.61]; area under the receiver-operating-characteristics SMFM 0.63 [95% confidence interval 0.61, 0.66], 0.60 [95% confidence interval 0.57, 0.62]). CONCLUSION: The ISUOG and the SMFM FGR definitions have limited discriminatory capacity for placental histopathological findings associated with placental insufficiency and a composite ANeO.

Preeclampsia and STOX1 (storkhead-box protein 1): Molecular evaluation of STOX1 in preeclampsia.

Preeclampsia (PE) is clinically defined as a part of pregnancy characterized by hypertension and multiple organ failure. PE is broadly categorized into two types: "placental" and "maternal". Placental PE is associated with fetal growth restriction and adverse maternal and neonatal outcomes. STOX1 (Storkhead box 1), a transcription factor, discovered through a complete transcript analysis of the PE susceptibility locus of 70,000 bp on chromosome 10q22.1. So far, studies investigating the relationship between STOX1 and PE have focused on STOX1 overexpression, STOX1 isoform imbalance, and STOX1 variations that could have clinical consequence. Initially, the Y153H variation of STOX was associated with the placental form of PE. Additionally, studies focusing on the maternal and fetal interface have shown that NODAL and STOX1 variations play a role together in the unsuccessful remodeling of the spiral arteries. Research specifically addressing the overexpression of STOX1 has shown that its disruption of cellular hemoastasis, leading to impaired hypoxia response, disruption of the cellular antioxidant system, and nitroso/redox imbalance. Furthermore, functional studies have been conducted showing that the imbalance between STOX1 isoforms contributes to the pathogenesis of placental PE. Research indicates that STOX1B competes with STOX1A and that the overexpression of STOX1B reverses cellular changes that STOX1A induces to the pathogenesis of PE. In this review, we aimed at elucidating the relationship between STOX1 and PE as well as function of STOX1. In conclusion, based on a comprehensive literature review, numerous studies support the role of STOX1 in the pathogenesis of PE.

Sex Differences Across the Lifespan: A Focus on Cardiometabolism.

Women's health and sex differences research remain understudied. In 2022, to address the topic of sex differences, the Ludeman Family Center for Women's Health Research (LFCWHR) at the University of Colorado (LudemanCenter.org) held its third National Conference, "Sex Differences Across the Lifespan: A Focus on Metabolism." The research presentations and discussions from the 2022 conference addressed cardiometabolic sex differences across the lifespan and included sessions focusing on scientific methods with which to study sex differences, effects of estrogen on metabolism, and sex differences in cardiovascular disease-implications for women and policy among others. Over 100 participants, including basic scientists, clinical scientists, policymakers, advocacy group leaders, and federal agency leadership participated. The meeting proceedings reveal that although exciting advances in the area of sex differences have taken place, significant questions and gaps remain about women's health and sex differences in critical areas of health. Identifying these gaps and the subsequent research that will result may lead to important breakthroughs.

Umbilical Cord Hemangiomas: A Multi-Institutional Case Series With Literature Review.

Umbilical cord hemangiomas are rare lesions, for which data on pregnancy outcome is lacking. This study combines a multi-institution 4-case series with a systematic literature search (n = 52) to determine possible pathologic lesion parameters which may have an effect on pregnancy outcome. Of all 56 pregnancies, lesion size ranged from 0.2 to 23.0 cm with pregnancy outcomes ranging from healthy liveborns (58.9%), liveborns with severe complications largely due to prematurity and/or fluid overload (12.5%), intrauterine/neonatal demise (25.0%), and pregnancy termination (3.6%). Of the 52 cases included for statistical analysis, there was no significant association between fetal outcome and vascular lesion location (P = .12) or fetal outcome and single umbilical artery involvement versus involvement of other vasculature (P = .29). The mean length of vascular lesions that resulted in healthy liveborns did not significantly differ from those resulting in severe fetal complications and/or demise (P = .72). Cases resulting in severe complications and/or demise were significantly earlier at delivery than those resulting in healthy liveborns (P < .001). Combined findings suggest that functional lesion characteristics, such as the degree of turbulent flow generated, have more significance than size, especially in early gestation losses. Moving forward, standardized reporting of pathologic lesion characteristics is paramount to better predict pregnancy prognosis.

Placental ACE2 Expression: A Possible Pathogenetic Mechanism for Infantile Hemangiomas.

ACE2 is a mono-carboxypeptidase with remarkable vasculo-protective properties, and its expression in the human placenta plays a central role in blood pressure homeostasis and fetal perfusion. Therefore, an alteration in the placental expression of ACE2 could be responsible for reduced placental perfusion and infantile hemangioma (IH) development. Study placentae were collected from patients affected by IHs who were referred to our Dermatology Clinic from 2016 to 2022, while control placentae were randomly collected while matching cases for gestational age. Immunohistochemical investigations were performed with a recombinant anti-ACE2 rabbit monoclonal antibody. A total of 47 placentae were examined, including 20 study placentae and 27 control ones. The mean placental weight was significantly lower in the study group (380.6 g vs. 502.3 g; p = 0.005), while subclinical chorioamnionitis occurred more frequently in the study group (20% vs. 0%, p = 0.03). The mean ACE2 expression was dramatically lower in the study group (χ2 = 42.1 p < 0.001), and the mean placental weight was significantly lower when ACE2 was not expressed compared to the 25-75% and >75% classes of expression (p < 0.05). This study demonstrated that ACE2, as a marker for tissue hypoxia, is dramatically hypo-expressed in placentae belonging to mothers who delivered one or more babies with IH compared to the controls.

Reference Ranges of 2-Dimensional Placental Biometry and 3-Dimensional Placental Volume between 11 and 14 Weeks of Gestation.

OBJECTIVE: The purpose of this study was to provide gestational age (GA) specific reference ranges for 2-dimensional (2D) placental biometry and 3-dimensional (3D) placental volume between 11 and 14 weeks of gestation. METHODS: Placental biometry including 2D and 3D variables was calculated in 1142 first-trimester singleton pregnancies with non-complicated outcome between September 2016 and February 2020. Ultrasound datasets were obtained at the time of the first-trimester ultrasound, and 2D basal plate (BP), chorionic plate (CP), placental thickness (PT), and 3D placental volume (PV) were measured following a standardized methodology. Reference ranges for each variable were calculated according to GA and crown-rump-length (CRL). RESULTS: A total of 1142 uncomplicated pregnancies were considered for analysis. All placental measurements increased significantly between 11 and 14 weeks, especially for PT (39.64%) and PV (64.4%). Reference ranges were constructed for each 2D and 3D first-trimester placental variable using the best-fit regression model for the predicted mean and SD as a function of GA and CRL. CONCLUSIONS: Reference ranges of 2D placental biometry and 3D placental volume between 11 and 14 weeks of gestation were constructed, generating reference values. Placental biometry showed a progressive increase during the first trimester. This highlights the importance of using reference range charts according to GA.

Effect of Mediterranean diet or mindfulness-based stress reduction during pregnancy on placental volume and perfusion: A subanalysis of the IMPACT BCN randomized clinical trial.

INTRODUCTION: The IMPACT BCN trial-a parallel-group randomized clinical trial where 1221 pregnant women at high risk for small-for-gestational age (SGA) newborns were randomly allocated at 19- to 23-week gestation into three groups: Mediterranean diet, Mindfulness-based Stress reduction or non-intervention-has demonstrated a positive effect of Mediterranean diet and Stress reduction in the prevention of SGA. However, the mechanism of action of these interventions remains still unclear. The aim of this study is to investigate the effect of Mediterranean diet and Stress reduction on placental volume and perfusion. MATERIAL AND METHODS: Participants in the Mediterranean diet group received monthly individual and group educational sessions, and free provision of extra-virgin olive oil and walnuts. Women in the Stress reduction group underwent an 8-week Stress reduction program adapted for pregnancy, consisting of weekly 2.5-h and one full-day sessions. Non-intervention group was based on usual care. Placental volume and perfusion were assessed in a subgroup of randomly selected women (n = 165) using magnetic resonance (MR) at 36-week gestation. Small placental volume was defined as MR estimated volume <10th centile. Perfusion was assessed by intravoxel incoherent motion. RESULTS: While mean MR placental volume was similar among the study groups, both interventions were associated with a lower prevalence of small placental volume (3.9% Mediterranean diet and 5% stress reduction vs. 17% non-intervention; p = 0.03 and p = 0.04, respectively). Logistic regression showed that small placental volume was significantly associated with higher risk of SGA in both study groups (OR 7.48 [1.99-28.09] in Mediterranean diet and 20.44 [5.13-81.4] in Stress reduction). Mediation analysis showed that the effect of Mediterranean diet on SGA can be decomposed by a direct effect and an indirect effect (56.6%) mediated by a small placental volume. Similarly, the effect of Stress reduction on SGA is partially mediated (45.3%) by a small placental volume. Results on placental intravoxel incoherent motion perfusion fraction and diffusion coefficient were similar among the study groups. CONCLUSIONS: Structured interventions during pregnancy based on Mediterranean diet or Stress reduction are associated with a lower proportion of small placentas, which is consistent with the previously observed beneficial effects of these interventions on fetal growth.

Mtnr1b deletion disrupts placental angiogenesis through the VEGF signaling pathway leading to fetal growth restriction.

The placenta, as a "transit station" between mother and fetus, has functions delivering nutrients, excreting metabolic wastes and secreting hormones. A healthy placenta is essential for fetal growth and development while the melatonergic system seems to play a critical physiological role in this organ since melatonin, its synthetic enzymes and receptors are present in the placenta. In current study, Mtnr1a and Mtnr1b knockout mice were constructed to explore the potential roles of melatonergic system played on the placental function and intrauterine growth retardation (IUGR). The result showed that Mtnr1a knockout had little effect on placental function while Mtnr1b knockout reduced placental efficiency and increased IUGR. Considering the extremely high incidence of IURG in sows, the pregnant sows were treated with melatonin. This treatment reduced the incidence of IUGR. All the evidence suggests that the intact melatonergic system in placenta is required for its function. Mechanistical studies uncovered that Mtnr1b knockout increased placental oxidative stress and apoptosis but reduced the angiogenesis. The RNA sequencing combined with histochemistry study identified the reduced angiogenesis and placental vascular density in Mtnr1b knockout mice. These alterations were mediated by the disrupted STAT3/VEGFR2/PI3K/AKT pathway, i.e., Mtnr1b knockout reduced the phosphorylation of STAT3 which is the promotor of VEGFR2. The downregulated VEGFR2 and its downstream elements of PI3K and AKT expressions, then, jeopardizes the angiogenesis and placental development.

Unexpected placental tumor: A case report.

INTRODUCTION AND IMPORTANCE: Placental non-trophoblastic tumors (PNTT) are uncommon, consisting mainly of chorangiomas, placental teratomas (PT) and haemangiomas. PT are exceedingly rare, with less than 40 cases reported in the literature. We, herein, present a case of mature PT arising within the membranes, and we aim to discuss the clinico-pathological characteristics of this rare entity. CASE PRESENTATION: A 30-year-old female patient, gravida 1, para 1, with no medical history, was admitted at 40 weeks' gestational age. Ultrasound in the third trimester of pregnancy revealed agenesis of the left fetal kidney and a fundal placenta with increased uterine artery resistance. A cesarean section was performed for failure of labor's induction. Gross examination of the placenta revealed a solid polypoid mass, measuring 4 × 2 cm, attached to the membranes and covered by a smooth cutaneous coating. The cut surface was soft, yellowish, and focally heterogenous, with areas of adipose tissue and cartilage. Microscopic examination revealed that the mass was made up of a mature keratinized squamous layer, with skin appendages, adipose and cartilaginous tissues. The diagnosis of PT was established. CLINICAL DISCUSSION: PT are rarely suspected on prenatal ultrasonography and the diagnosis is made after delivery. Only pathological examination allows the diagnosis of certainty. Their histogenesis is still poorly understood. CONCLUSION: We presented a rare case of mature PT arising within the membranes. PT are extremely uncommon tumors. Usually, they are benign, and no fetal or maternal complications. A better knowledge of these uncommon tumors is mandatory to not miss the diagnosis.

Placental somatic mutation in human stillbirth and live birth: A pilot case-control study of paired placental, fetal, and maternal whole genomes.

INTRODUCTION: A high frequency of single nucleotide somatic mutations in the placenta has been recently described, but its relationship to placental dysfunction is unknown. METHODS: We performed a pilot case-control study using paired fetal, maternal, and placental samples collected from healthy live birth controls (n = 10), live births with fetal growth restriction (FGR) due to placental insufficiency (n = 7), and stillbirths with FGR and placental insufficiency (n = 11). We quantified single nucleotide and structural somatic variants using bulk whole genome sequencing (30-60X coverage) in four biopsies from each placenta. We also assessed their association with clinical and histological evidence of placental dysfunction. RESULTS: Seventeen pregnancies had sufficiently high-quality placental, fetal, and maternal DNA for analysis. Each placenta had a median of 473 variants (range 111-870), with 95 % arising in just one biopsy within each placenta. In controls, live births with FGR, and stillbirths, the median variant counts per placenta were 514 (IQR 381-779), 582 (450-735), and 338 (245-441), respectively. After adjusting for depth of sequencing coverage and gestational age at birth, the somatic mutation burden was similar between groups (FGR live births vs. controls, adjusted diff. 59, 95 % CI -218 to +336; stillbirths vs controls, adjusted diff. -34, -351 to +419), and with no association with placental dysfunction (p = 0.7). DISCUSSION: We confirmed the high prevalence of somatic mutation in the human placenta and conclude that the placenta is highly clonal. We were not able to identify any relationship between somatic mutation burden and clinical or histologic placental insufficiency.

Dehydrated Amnion Chorion Membrane versus standard of care for diabetic foot ulcers: a randomised controlled trial.

OBJECTIVE: Diabetic foot ulcers (DFUs) continue to challenge wound care practitioners. This prospective, multicentre, randomised controlled trial (RCT) evaluated the effectiveness of a dehydrated Amnion Chorion Membrane (dACM) (Organogenesis Inc., US) versus standard of care (SoC) alone in complex DFUs in a challenging patient population. METHOD: Subjects with a DFU extending into dermis, subcutaneous tissue, tendon, capsule, bone or joint were enrolled in a 12-week trial. They were allocated equally to two treatment groups: dACM (plus SoC); or SoC alone. The primary endpoint was frequency of wound closure determined by a Cox analysis that adjusted for duration and wound area. Kaplan-Meier analysis was used to determine median time to complete wound closure (CWC). RESULTS: The cohort comprised 218 patients, and these were split equally between the two treatment groups with 109 patients in each. A Cox analysis showed that the estimated frequency of wound closure for the dACM plus SoC group was statistically superior to the SoC alone group at week 4 (12% versus 8%), week 6 (22% versus 11%), week 8 (31% versus 21%), week 10 (42% versus 27%) and week 12 (50% versus 35%), respectively (p=0.04). The computed hazard ratio (1.48 (confidence interval: 0.95, 2.29) showed a 48% greater probability of wound closure in favour of the dACM group. Median time to wound closure for dACM-treated ulcers was 84 days compared to 'not achieved' in the SoC-treated group (i.e., ≥50% of SoC-treated DFUs failed to heal by week 12; p=0.04). CONCLUSION: In an adequately powered DFU RCT, dACM increased the frequency, decreased the median time, and improved the probability of CWC when compared with SoC alone. dACM demonstrated beneficial effects in DFUs in a complex patient population. DECLARATION OF INTEREST: This study was funded by Organogenesis Inc., US. JC serves as a consultant and speaker for Organogenesis. RDD serves as a speaker for Organogenesis. OMA and MLS serve as consultants for Organogenesis. The authors have no other conflicts of interest to declare.

Intravenous Immunoglobulins for Recurrent Chronic Histiocytic Intervillositis: A Series of Case Studies.

INTRODUCTION: Chronic histiocytic intervillositis (CHI) is a rare inflammatory placental disease characterized by diffuse infiltration of monocytes into the intervillous space and is associated with adverse pregnancy outcomes. No treatment is currently validated and although in some small reports, steroids with hydroxychloroquine have been described. There are no data for other therapies in refractory cases. PATIENTS AND METHODS: We here report four cases of patients with a history of CHI treated with immunoglobulins during a subsequent pregnancy. The four patients with recurrent CHI had failed to previous immunomodulatory therapies with steroids and hydroxychloroquine. All patients had at least four pregnancy losses with histopathological confirmation of CHI for at least one pregnancy loss. The usual pregnancy-loss etiology screening and immunological screening were negative for all the patients. RESULTS: For three patients, intravenous immunoglobulins were initiated at the ßHCG positivity at 1 g/kg every 15 days until delivery. In one case with combined therapy since the beginning of the pregnancy, intravenous immunoglobulins were introduced at 20 WG because of severe growth restriction. Two patients had live births at 36 WG and one patient at 39 WG. One patient, who presented early first-trimester hypertension and severe placental lesions, failed to intravenous immunoglobulins and had a pregnancy loss at 15 WG. CONCLUSION: This is the first report demonstrating the potential benefit of intravenous immunoglobulins in recurrent chronic intervillositis. Larger studies are needed to confirm this potential benefit for patients presenting severe cases of recurrent CHI.

Human CD56+CD39+ dNK cells support fetal survival through controlling trophoblastic cell fate: immune mechanisms of recurrent early pregnancy loss.

Decidual natural killer (dNK) cells are the most abundant immune cells at the maternal-fetal interface during early pregnancy in both mice and humans, and emerging single-cell transcriptomic studies have uncovered various human dNK subsets that are disrupted in patients experiencing recurrent early pregnancy loss (RPL) at early gestational stage, suggesting a connection between abnormal proportions or characteristics of dNK subsets and RPL pathogenesis. However, the functional mechanisms underlying this association remain unclear. Here, we established a mouse model by adoptively transferring human dNK cells into pregnant NOG (NOD/Shi-scid/IL-2Rγnull) mice, where human dNK cells predominantly homed into the uteri of recipients. Using this model, we observed a strong correlation between the properties of human dNK cells and pregnancy outcome. The transfer of dNK cells from RPL patients (dNK-RPL) remarkably worsened early pregnancy loss and impaired placental trophoblast cell differentiation in the recipients. These adverse effects were effectively reversed by transferring CD56+CD39+ dNK cells. Mechanistic studies revealed that CD56+CD39+ dNK subset facilitates early differentiation of mouse trophoblast stem cells (mTSCs) towards both invasive and syncytial pathways through secreting macrophage colony-stimulating factor (M-CSF). Administration of recombinant M-CSF to NOG mice transferred with dNK-RPL efficiently rescued the exacerbated pregnancy outcomes and fetal/placental development. Collectively, this study established a novel humanized mouse model featuring functional human dNK cells homing into the uteri of recipients and uncovered the pivotal role of M-CSF in fetal-supporting function of CD56+CD39+ dNK cells during early pregnancy, highlighting that M-CSF may be a previously unappreciated therapeutic target for intervening RPL.

Fibroblasts activation by embryonic signal switching: A novel mechanism of placental growth factor-induced cardiac remodeling.

INTRODUCTION: Cardiac remodeling is defined as cellular interstitial changes that lead dysfunction of the heart after injury. Placental growth factor (PlGF), a member of the VEGF family, has been reported to regulate cardiac hypertrophy in hemodynamic state. We therefore analyze the function of PlGF during cardiac remodeling using cardiac cells and fibroblasts, under Angiotensin II (AngII) stimulation. METHODS: PlGF overexpressed mouse embryonic fibroblasts derived from C57BL/6 mice, were made by deficient retrovirus vector, designated as C57/PlGF. Only retrovirus vector introduced C57 cells (C57/EV) were used as control. After AngII stimulation, wound scratching assay and MTT proliferation assay with or without p38 MAPK inhibitor, SB205580 were performed in retrovirally-introduced C57 cells. Reactive oxygen species (ROS) production, NF-kB activation, IL-6 and TNF-α production were also measured. Then we assessed AngII-induced cell proliferation of mouse cardiac fibroblasts (CFs) and rat primary cardiomyocytes incubating with C57/PlGF conditioned-medium. RESULTS: The PlGF production in C57/PlGF were confirmed by ELISA (1093.48 ± 3.5 pg/ml, ±SE). AngII-induced cell migration, proliferation and H2O2 production were increased in C57/PlGF compared with C57/EV. SB205580 inhibited the AngII-induced cell proliferation in C57/PlGF. In C57/PlGF cells, NF-kB activation was higher, followed by up-regulation of IL-6 and TNF-α production. CFs and cardiomyocytes proliferation increased when stimulated with C57/PlGF conditioned-medium. DISCUSSION: The activation of fibroblast is stimulated by PlGF signaling via p38 MAPK/NF-kB pathway accompanied by elevation of ROS and inflammatory response. Furthermore, these signals stimulate the activation of CFs and cardiomyocytes, indicating that high circulating level of PlGF have a potential to regulate cardiac remodeling.

LIM homeobox 1 (LHX1) induces endoplasmic reticulum stress and promotes preterm birth.

Background: Premature birth (PTB) is a major cause of neonatal mortality and has enduring consequences. LIM Homeobox 1 (LHX1) is vital in embryonic organogenesis, while Inositol-Requiring Enzyme 1 (IRE-1) regulates endoplasmic reticulum stress (ERS). This study explores whether IRE-1 impacts PTB via LHX1 modulation. Methods: We analyzed LHX1 expression in placental samples from PTB patients and examined its impact on the viability, migration, invasion, and apoptosis of the human placental trophoblast cell line HTR8/Svneo, particularly when treated with the ERS inducer tunicamycin (TM). We also assessed the levels of ERS-related genes and autophagy activation in response to LHX1 deficiency. To gain mechanistic insights, we evaluated the ERS-mediated activation of the IRE-1/XBP1/CHOP signaling pathway in LHX1-silenced HTR8/Svneo cells. Additionally, we examined the transcriptional activation of IRE-1 and the binding of LHX1 to the IRE-1 promoter in HTR8/Svneo cells. We overexpressed IRE-1 in LHX1-silenced HTR8/Svneo cells to assess its effects on cell viability, migration, invasion, apoptosis, and autophagy. Finally, we induced LHX1 knockdown in mice through intraperitoneal injections of tunicamycin (TM) and Sh-LHX1 over a 24-h period to evaluate PTB symptoms. Results: We observed LHX1 overexpression in placental tissue from PTB cases and TM-induced HTR8/Svneo cells. LHX1 depletion enhanced cell viability, migration, and invasion while reducing autophagy and apoptosis. This reduction in LHX1 led to decreased levels of IRE-1, XBP1, CHOP, and other ERS-related genes, indicating LHX1's role in ERS induction and the activation of the IRE-1/XBP1/CHOP pathway. Mechanistically, LHX1 was found to bind to the IRE-1 promoter, inducing its transcriptional activation. Notably, overexpressing IRE-1 counteracted the impact of LHX1 depletion on trophoblast cell behavior, suggesting that LHX1 modulates IRE-1. In line with our in vitro studies, LHX1 knockdown ameliorated PTB symptoms in TM-treated mice. Conclusion: LHX1 contributes to the progression of PTB by regulating the IRE-1-XBP1-CHOP pathway.

Human placental mesenchymal stromal cells promote the formation of CD8+CD122+PD-1+Tregs via CD73/Foxo1 to alleviate liver injury in graft-versus-host disease mice.

BACKGROUND: Human placental mesenchymal stromal cells (hPMSCs) are known to limit graft-versus-host disease (GVHD). CD8+CD122+PD-1+Tregs have been shown to improve the survival of GVHD mice. However, the regulatory roles of hPMSCs in this subgroup remain unclear. Here, the regulatory mechanism of hPMSCs in reducing liver fibrosis in GVHD mice by promoting CD8+CD122+PD-1+Tregs formation and controlling the balance of IL-6 and IL-10 were explored. METHODS: A GVHD mouse model was constructed using C57BL/6J and BALB/c mice and treated with hPMSCs. LX-2 cells were explored to study the effects of IL-6 and IL-10 on the activation of hepatic stellate cells (HSCs). The percentage of CD8+CD122+PD-1+Tregs and IL-10 secretion were determined using FCM. Changes in hepatic tissue were analysed by HE, Masson, multiple immunohistochemical staining and ELISA, and the effects of IL-6 and IL-10 on LX-2 cells were detected using western blotting. RESULTS: hPMSCs enhanced CD8+CD122+PD-1+Treg formation via the CD73/Foxo1 and promoted IL-10, p53, and MMP-8 levels, but inhibited IL-6, HLF, α-SMA, Col1α1, and Fn levels in the liver of GVHD mice through CD73. Positive and negative correlations of IL-6 and IL-10 between HLF were found in liver tissue, respectively. IL-6 upregulated HLF, α-SMA, and Col1α1 expression via JAK2/STAT3 pathway, whereas IL-10 upregulated p53 and inhibited α-SMA and Col1α1 expression in LX-2 cells by activating STAT3. CONCLUSIONS: hPMSCs promoted CD8+CD122+PD-1+Treg formation and IL-10 secretion but inhibited HSCs activation and α-SMA and Col1α1 expression by CD73, thus controlling the balance of IL-6 and IL-10, and alleviating liver injury in GVHD mice.

The influence of the oral microbiota in full-term pregnant women on immune regulation during pregnancy.

BACKGROUND: This study aims to conduct a preliminary exploration of the correlation between the oral microbiota of full-term pregnant women and both local placental immunity and the systemic immune system of the mother. METHODS: A total of 26 pregnant women participated in this study, with samples collected from oral swabs, placental tissue, and peripheral venous blood. High-throughput sequencing was used to examine the oral microbial community. Flow cytometry was employed to assess immune cells in placental tissue and peripheral venous blood. ELISA and Luminex liquid bead chip technology were utilized to detect cytokines in both placental tissue and peripheral venous blood. RESULTS: In placental tissue, The oral microbial community is primarily negatively correlated with placental CD3+CD4+CD8+T cells and positively correlated with placental IL-5. In the peripheral blood, The oral microbial community is primarily positively correlated with maternal systemic immune parameters, including CD3+CD4+ T cells and the CD4+/CD8+ ratio, as well as positively correlated with peripheral IL-18. CONCLUSIONS: The oral microbiota of full-term pregnant women participates in the regulatory function of the maternal immune system. Meanwhile, the oral microbial community may also be an important factor mediating local immune regulation in the placenta.

Unlocking the secrets of Hofbauer cells in placental (patho-) physiology: Isolation and quality assessment in human term placenta.

INTRODUCTION: Hofbauer cells (HBCs) are macrophages of fetal origin that reside in the villous tissue. They are the only immune cells within healthy villi. While HBCs perform innate immune functions such as phagocytosis and antigen presentation, they are increasingly recognized for their diverse roles in placental physiology e.g. vascular functionality, tissue homeostasis, tolerance. Consequently, HBCs are of utmost interest in a variety of non-physiological placental conditions. ISOLATION: Villous tissue is collected freshly after delivery and finely minced. The resulting tissue is digested in a two-step process, using Trypsin/DNase to separate cytotrophoblasts and collagenase/DNase to penetrate deeper into the villous stroma, containing HBCs, and obtain a single cell suspension. After a density gradient centrifugation, the corresponding cell layer is collected and subjected to negative immune selection of HBCs, yielding unaffected cells that have not been activated during the isolation process. QUALITY CONTROL: In addition to a classical immunocytochemistry (ICC) approach including macrophage markers, and markers for potentially contaminating cell types (e.g. fibroblasts, muscle, mesenchymal cells), we have developed a multi-color flow cytometry (FC) panel. This panel assesses Hofbauer cell purity and polarization states more accurately and comprehensively than qualitative ICC, using percentage analysis of parent cells to estimate the expression levels of specific markers. DISCUSSION: The presented protocol allows us to isolate HBCs in significant numbers and high purity, even from placentae compromised by preeclampsia (PE) with limited placental volume. We have successfully developed and implemented this protocol to study healthy, diabetic and PE macrophages, aiding a better understanding of the underlying placental pathophysiology at the cellular level.

Therapeutic effect of E-Lip-siRNA-sFlt1 on pre-eclampsia: targeted gene silencing and improved pregnancy outcomes.

Aim: To evaluate a liposome complex conjugated with anti-epidermal growth factor receptor (EGFR) antibodies for the treatment of pre-eclampsia (PE). Methods: In in vitro experiments, the transfection rate, silencing effect and cytotoxicity were determined. In the in vivo PE model, the siRNA distribution, mean arterial pressure, 24-h urine protein concentration, serum sFlt1 concentration, number of viable fetuses and placental weight were measured. Results: The nanomedicine effectively reduced the expression of sFIt1 and had a strong ability to target placental tissues. It could significantly reduce the symptoms of pre-eclampsia and improve pregnancy outcomes in PE model rats. Conclusion: The constructed nanomedicine can improve pregnancy outcomes in a rat model of pre-eclampsia and provides a new strategy for the treatment of pre-eclampsia.

[Box: see text].