Corrigendum: Editorial: Immunological role of the maternal microbiome in pregnancy.

[This corrects the article DOI: 10.3389/fimmu.2021.703009.]

Human trophoblast differentiation: possible role for trophoblast cell surface antigen 2

Human trophoblast cell surface antigen 2 (Trop2) is a 40-kDa transmembrane glycoprotein, encoded by TACSTD2 gene and identified for the first time in human trophoblast and choriocarcinoma cell lines. Trop2 has a short intracytoplasmic tail essential for the control of several pathways that regulate cellular functions such as cell- cell adhesion, cell proliferation and mobility [1]. We analysed the expression of Trop2 in human normal placentas during gestation and in placentas complicated by preeclampsia (PE). Trop2 protein expression and miR125b1 were analysed by morphological and bio-molecular techniques. Trop2 increased during gestation, i.e. from first to third trimester of gestation while it was low expressed in placental tissues collected from patients with PE. Since PE is a pathology associated with placental hypoxia, we demonstrated that Trop2 is downregulated in hypoxic conditions by in vitro model. Our study suggests a possible involvement of Trop2 in maintaining trophoblast morphology and function during placental development in normal and PE conditions

Synthetic PreImplantation Factor (sPIF) reduces inflammation and prevents preterm birth.

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality and spontaneous PTB is a major contributor. The preceding inflammation/infection contributes not only to spontaneous PTB but is associated with neonatal morbidities including impaired brain development. Therefore, control of exaggerated immune response during pregnancy is an attractive strategy. A potential candidate is synthetic PreImplantation Factor (sPIF) as sPIF prevents inflammatory induced fetal loss and has neuroprotective properties. Here, we tested maternal sPIF prophylaxis in pregnant mice subjected to a lipopolysaccharides (LPS) insult, which results in PTB. Additionally, we evaluated sPIF effects in placental and microglial cell lines. Maternal sPIF application reduced the LPS induced PTB rate significantly. Consequently, sPIF reduced microglial activation (Iba-1 positive cells) and preserved neuronal migration (Cux-2 positive cells) in fetal brains. In fetal brain lysates sPIF decreased IL-6 and INFγ concentrations. In-vitro, sPIF reduced Iba1 and TNFα expression in microglial cells and reduced the expression of pro-apoptotic (Bad and Bax) and inflammatory (IL-6 and NLRP4) genes in placental cell lines. Together, maternal sPIF prophylaxis prevents PTB in part by controlling exaggerated immune response. Given the sPIF`FDA Fast Track approval in non-pregnant subjects, we envision sPIF therapy in pregnancy

Protective role of complement factor H against the development of preeclampsia

Pregnancy is an immunologically regulated, complex process. A tightly controlled complement system plays a crucial role in the successful establishment of pregnancy and parturition. Complement inhibitors at the feto-maternal interface are likely to prevent inappropriate complement activation to protect the fetus. In the present study, we aimed to understand the role of Factor H (FH), a negative regulator of complement activation, in normal pregnancy and in a model of pathological pregnancy, i.e. preeclampsia (PE). The distribution and expression of FH was investigated in placental tissues, various placental cells, and in the sera of healthy (CTRL) or PE pregnant women via immunohistochemistry, RT-qPCR, ELISA, and Western blot. Our results showed a differential expression of FH among the placental cell types, decidual stromal cells (DSCs), decidual endothelial cells (DECs), and extravillous trophoblasts (EVTs). Interestingly, FH was found to be considerably less expressed in the placental tissues of PE patients compared to normal placental tissue both at mRNA and protein levels. Similar results were obtained by measuring circulating FH levels in the sera of third trimester CTRL and PE mothers. Syncytiotrophoblast microvesicles, isolated from the placental tissues of PE and CTRL women, downregulated FH expression by DECs. The present study appears to suggest that FH is ubiquitously present in the normal placenta and plays a homeostatic role during pregnancy

Obstetric antiphospholipid syndrome: A recent classification for an old defined disorder

Obstetric antiphospholipid syndrome (APS) is nowbeing recognized as a distinct entity fromvascular APS. Pregnancy morbidity includes N3 consecutive and spontaneous early miscarriages before 10 weeks of gestation; at least one unexplained fetal death after the 10thweek of gestation of a morphologically normal fetus; a premature birth before the 34thweek of gestation of a normal neonate due to eclampsia or severe pre-eclampsia or placental insufficiency. It is not well understood how antiphospholipid antibodies (aPLs), beyond their diagnostic and prognostic role, contribute to pregnancy manifestations. Indeed aPL-mediated thrombotic events cannot explain the obstetric manifestations and additional pathogenic mechanisms, such as a placental aPL mediated complement activation and a direct effect of aPLs on placental development, have been reported. Still debated is the possible association between aPLs and infertility and the effect of maternal autoantibodies on non-vascular manifestations in the babies. Combination of low dose aspirin and unfractionated or low molecular weight heparin is the effective treatment in most of the cases. However, pregnancy complications, in spite of this therapy, can occur in up to 20% of the patients. Novel alternative therapies able to abrogate the aPL pathogenic action either by interfering with aPL binding at the placental level or by inhibiting the aPL-mediated detrimental effect are under active investigation

Resistin modulates glucose uptake and glucose transporter-1 (GLUT-1) expression in trophoblast cells

The adipocytokine resistin impairs glucose tolerance and insulin sensitivity. Here, we examine the effect of resistin on glucose uptake in human trophoblast cells and we demonstrate that transplacental glucose transport is mediated by glucose transporter (GLUT)-1. Furthermore, we evaluate the type of signal transduction induced by resistin in GLUT-1 regulation. BeWo choriocarcinoma cells and primary cytotrophoblast cells were cultured with increasing resistin concentrations for 24 hrs. The main outcome measures include glucose transport assay using [3H]-2-deoxy glucose, GLUT-1 protein expression by Western blot analysis and GLUT-1 mRNA detection by quantitative real-time RT-PCR. Quantitative determination of phospho(p)-ERK1/2 in cell lysates was performed by an Enzyme Immunometric Assay and Western blot analysis. Our data demonstrate a direct effect of resistin on normal cytotrophoblastic and on BeWo cells: resistin modulates glucose uptake, GLUT-1 messenger ribonucleic acid (mRNA) and protein expression in placental cells. We suggest that ERK1/2 phosphorylation is involved in the GLUT-1 regulation induced by resistin. In conclusion, resistin causes activation of both the ERK1 and 2 pathway in trophoblast cells. ERK1 and 2 activation stimulated GLUT-1 synthesis and resulted in increase of placental glucose uptake. High resistin levels (50–100 ng/ml) seem able to affect glucose-uptake, presumably by decreasing the cell surface glucose transporter

Human growth hormone enhances progesterone production by human luteal cells in vitro. II. Evidence of a distinct effect on two luteal cell types

OBJECTIVE: To examine the differential effect of human GH (hGH) on basal and hCG-stimulated production by cultured small and large human luteal cells. DESIGN: Distinct cultures of small and large luteal cells from early and midluteal phase. SETTING: All corpora lutea were obtained from the Obstetrics and Gynecology Department of the Catholic University, a public care center in Rome, Italy. PATIENTS, PARTICIPANTS: Ten nonpregnant women between 31 and 43 years of age underwent surgery for various nonendocrine disorders such as leiomyomatosis. INTERVENTIONS: Corpora lutea were obtained at the time of hysterectomy. MAIN OUTCOME MEASURES: Small and large luteal cells were incubated with or without hCG and/or hGH at different concentrations. RESULTS: Human GH neither at 250 nor at 500 micrograms/L increased basal P production by small luteal cells, whereas from 1,000 micrograms/L, P concentration in media was significantly increased. The concomitant treatment with ineffective doses of hCG (30 and 60 IU/L) and hGH (250 and 500 micrograms/L) enhanced P production to that obtained with the highest doses of hGH (1,000 micrograms/L or more) or hCG (125 to 250 IU/L) alone. Human GH addition did not change the amount of P release by large luteal cells at any concentration. CONCLUSIONS: These results indicate a distinct and differential effect of hGH on in vitro luteal steroidogenesis by the two luteal cell type