bims-reprim 2022-03-13 papers

Issue of 2022–03–13
five papers selected by
Iva Filipovic, Karolinska Institutet

JCI Insight. 2022 Mar 08. pii: e153921. [Epub ahead of print]7(5):

A single-cell atlas of the myometrium in human parturition.

Roger Pique-Regi, Roberto Romero, Valeria Garcia-Flores, Azam Peyvandipour, Adi L Tarca, Errile Pusod, Jose Galaz, Derek Miller, Gaurav Bhatti, Robert Para, Tomi Kanninen, Ola Hadaya, Carmen Paredes, Kenichiro Motomura, Jeffrey R Johnson, Eunjung Jung, Chaur-Dong Hsu, Stanley M Berry, Nardhy Gomez-Lopez.

Parturition is a well-orchestrated process characterized by increased uterine contractility, cervical ripening, and activation of the chorioamniotic membranes; yet, the transition from a quiescent to a contractile myometrium heralds the onset of labor. However, the cellular underpinnings of human parturition in the uterine tissues are still poorly understood. Herein, we performed a comprehensive study of the human myometrium during spontaneous term labor using single-cell RNA sequencing (scRNA-Seq). First, we established a single-cell atlas of the human myometrium and unraveled the cell type-specific transcriptomic activity modulated during labor. Major cell types included distinct subsets of smooth muscle cells, monocytes/macrophages, stromal cells, and endothelial cells, all of which communicated and participated in immune (e.g., inflammation) and nonimmune (e.g., contraction) processes associated with labor. Furthermore, integrating scRNA-Seq and microarray data with deconvolution of bulk gene expression highlighted the contribution of smooth muscle cells to labor-associated contractility and inflammatory processes. Last, myometrium-derived single-cell signatures can be quantified in the maternal whole-blood transcriptome throughout pregnancy and are enriched in women in labor, providing a potential means of noninvasively monitoring pregnancy and its complications. Together, our findings provide insights into the contributions of specific myometrial cell types to the biological processes that take place during term parturition.

Keywords: Bioinformatics; Cell Biology; Obstetrics/gynecology; Reproductive Biology

DOI: https://doi.org/10.1172/jci.insight.153921

Am J Reprod Immunol. 2022 Mar 07.

CD158a+ /CD158b+ NK cell imbalance correlates with hypertension in patients with pre-eclampsia.

Xiuxiu Xu, Xirui Zhao, Ling Chen, Muziying Liu, Ziming Hu, Jieqi Ke, Binqing Fu, Yonggang Zhou, Haiming Wei.

PROBLEM: Preeclampsia, a pregnancy complication with hypertension and proteinuria, seriously threats the health and lives of the mother and the baby. The pathogenesis of pre-eclampsia remains incompletely understood. The role of peripheral natural killer cells (NK cells) in the pre-eclampsia is unclear.
METHOD OF STUDY: Flow cytometry was performed to detect the expression of CD158a (KIR2DL1) and CD158b (KIR2DL2/3) in peripheral NK cells of healthy pregnant women (HP) and patients with pre-eclampsia (PE). Differentially expressed genes (DEGs) in CD158a+ and CD158b+ NK cells were identified by RNA-sequencing and real-time PCR. Protein array analysis was used to identify altered protein levels in the serum of study participants.
RESULTS: CD158a+ NK cell numbers were increased in the peripheral blood of patients while the number of CD158b+ NK cells was reduced. In addition, the percentage of CD158a+ NK cells within the peripheral NK subset was positively correlated with systolic blood pressure while the percentage of CD158b+ NK cells was negatively correlated with systolic blood pressure. RNA-seq and real-time PCR showed that the expression of ERAP2 and GCH1, the genes that regulate blood pressure and angiogenesis, was decreased in CD158a+ compared to CD158b+ NK cells. Consistently, the level of proteins involved in angiogenesis was altered in the serum of pre-eclampsia patients compared to healthy individuals.
CONCLUSIONS: CD158a+ NK cells increased while CD158b+ NK cells decreased in the peripheral blood of patients with pre-eclampsia compared to healthy individuals. The change in the frequency of CD158a+ /CD158b+ NK cells is related to the increase in blood pressure. This article is protected by copyright. All rights reserved.

Keywords: Blood pressure; CD158a; CD158b; Natural killer cells; Pre-eclampsia

DOI: https://doi.org/10.1111/aji.13532

Front Immunol. 2021 ;12 756035

Placental Macrophage (Hofbauer Cell) Responses to Infection During Pregnancy: A Systematic Scoping Review.

Georgia Fakonti, Paschalia Pantazi, Vladimir Bokun, Beth Holder.

Background: Congenital infection of the fetus via trans-placental passage of pathogens can result in severe morbidity and mortality. Even without transmission to the fetus, infection of the placenta itself is associated with pregnancy complications including pregnancy loss and preterm birth. Placental macrophages, also termed Hofbauer cells (HBCs), are fetal-origin macrophages residing in the placenta that are likely involved in responding to placental infection and protection of the developing fetus. As HBCs are the only immune cell present in the villous placenta, they represent one of the final opportunities for control of infection and prevention of passage to the developing fetus.
Objective and Rationale: The objective of this review was to provide a systematic overview of the literature regarding HBC responses during infection in pregnancy, including responses to viral, bacterial, and parasitic pathogens.
Methods: PubMed and Scopus were searched on May 20th, 2021, with no limit on publication date, to identify all papers that have studied placental macrophages/Hofbauer cells in the context of infection. The following search strategy was utilized: (hofbauer* OR "hofbauer cells" OR "hofbauer cell" OR "placental macrophage" OR "placental macrophages") AND [infect* OR virus OR viral OR bacteri* OR parasite* OR pathogen* OR LPS OR "poly(i:c)" OR toxoplasm* OR microb* OR HIV)].
Outcomes: 86 studies were identified for review. This included those that investigated HBCs in placentas from pregnancies complicated by maternal infection and in vitro studies investigating HBC responses to pathogens or Pathogen-Associated Molecular Patterns (PAMPs). HBCs can be infected by a variety of pathogens, and HBC hyperplasia was a common observation. HBCs respond to pathogen infection and PAMPs by altering their transcriptional, translational and secretion profiles. Co-culture investigations demonstrate that they can replicate and transmit pathogens to other cells. In other cases, they may eliminate the pathogen through a variety of mechanisms including phagocytosis, cytokine-mediated pathogen elimination, release of macrophage extracellular traps and HBC-antibody-mediated neutralization. HBC responses differ across gestation and may be influenced by pre-existing immunity. Clinical information, including gestational age at infection, gestational age of the samples, mode of sample collection and pregnancy outcome were missing for the majority of studies.

Keywords: Hofbauer cells; congenital infection; placenta; placental macrophages; virus

DOI: https://doi.org/10.3389/fimmu.2021.756035

Mol Hum Reprod. 2022 Mar 08. pii: gaac006. [Epub ahead of print]

GAS6-mediated dialogue between decidual stromal cells and macrophages is essential for early pregnancy maintenance by inducing M2-like polarization and cell proliferation of decidual macrophages.

Jing-Cong Dai, Jia-Yan Yang, Rui-Qi Chang, Yan Liang, Xiao-Yu Hu, Hu Li, Shuang You, Fan He, Li-Na Hu.

Maternal immunotolerance toward the semi-allogeneic fetus is critical for normal pregnancy. As a secretory protein, growth arrest-specific factor 6 (GAS6) promotes cancer progression by inducing the conversion of tumour-associated macrophages to an immunosuppressive M2-like phenotype. However, little is known about whether GAS6 regulates decidual macrophages (dMφs) in early maternal-fetal interface. In this study, first-trimester decidual tissues were obtained from normal pregnant women undergoing elective terminations and patients with miscarriages. The expression of GAS6 and its receptors (AXL, TYRO3 and MERTK) in decidua and GAS6 secretion by decidual stromal cells (DSCs) was measured. Then, we investigated the effect of recombinant human GAS6 (rhGAS6) on dMφs isolated from normal pregnancy and THP-1 cells, and revealed the underlying mechanism. Both the expression of GAS6 in DSCs and MERTK in dMφs, in addition to GAS6 secretion by DSCs, was found to be significantly decreased in miscarriage patients compared to that in normal pregnancy. Additionally, we observed that rhGAS6 polarized dMφs and THP-1 cells toward an M2-like phenotype, as evidenced by the up-regulated CD163 expression. Moreover rhGAS6 enhanced the clearance of toxic cell-free hemoglobin by dMφs by up-regulating CD163 expression, and rhGAS6 also boosted cell proliferation of dMφs and THP-1 cells. Finally, we demonstrated that rhGAS6 stimulated CD163 expression and cell proliferation by activating the PI3K/Akt signaling pathway. Collectively, these findings suggest that GAS6-mediated dialogue between DSCs and dMφs is crucial for the establishment and maintenance of maternal-fetal immunotolerance, and decreased GAS6 secretion by DSCs may lead to the occurrence of miscarriage in first trimester.

Keywords: CD163; M2-like polarization; cell proliferation; decidual macrophages; decidual stromal cells; growth arrest-specific factor 6; maternal-fetal interface; miscarriage; pregnancy

DOI: https://doi.org/10.1093/molehr/gaac006

Hum Reprod Update. 2022 Mar 09. pii: dmac006. [Epub ahead of print]

Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: a systematic review and meta-analysis.

Ee Von Woon, Orene Greer, Nishel Shah, Dimitrios Nikolaou, Mark Johnson, Victoria Male.

BACKGROUND: Uterine natural killer cells (uNK) are the most abundant lymphocytes found in the decidua during implantation and in first trimester pregnancy. They are important for early placental development, especially trophoblast invasion and transformation of the spiral arteries. However, inappropriate uNK function has been implicated in reproductive failure, such as recurrent miscarriage (RM) or recurrent implantation failure (RIF). Previous studies have mainly focussed on peripheral NK cells (pNK), despite the well-documented differences in pNK and uNK phenotype and function. In recent years, there has been an explosion of studies conducted on uNK, providing a more suitable representation of the immune environment at the maternal-foetal interface. Here, we summarize the evidence from studies published on uNK in women with RM/RIF compared with controls.
OBJECTIVE AND RATIONALE: The objectives of this systematic review and meta-analysis are to evaluate: differences in uNK level in women with RM/RIF compared with controls; pregnancy outcome in women with RM/RIF stratified by high and normal uNK levels; correlation between uNK and pNK in women with RM/RIF; and differences in uNK activity in women with RM/RIF compared with controls.
SEARCH METHODS: MEDLINE, EMBASE, Web of Science and Cochrane Trials Registry were searched from inception up to December 2020 and studies were selected in accordance with PRISMA guidelines. Meta-analyses were performed for uNK level, pregnancy outcome and uNK/pNK correlation. Narrative synthesis was conducted for uNK activity. Risk of bias was assessed by ROBINS-I and publication bias by Egger's test.
OUTCOMES: Our initial search yielded 4636 articles, of which 60 articles were included in our systematic review. Meta-analysis of CD56+ uNK level in women with RM compared with controls showed significantly higher levels in women with RM in subgroup analysis of endometrial samples (standardized mean difference (SMD) 0.49, CI 0.08, 0.90; P = 0.02; I2 88%; 1100 women). Meta-analysis of CD56+ uNK level in endometrium of women with RIF compared with controls showed significantly higher levels in women with RIF (SMD 0.49, CI 0.01, 0.98; P = 0.046; I2 84%; 604 women). There was no difference in pregnancy outcome in women with RM/RIF stratified by uNK level, and no significant correlation between pNK and uNK levels in women with RM/RIF. There was wide variation in studies conducted on uNK activity, which can be broadly divided into regulation and receptors, uNK cytotoxicity, cytokine secretion and effect of uNK on angiogenesis. These studies were largely equivocal in their results on cytokine secretion, but most studies found lower expression of inhibitory receptors and increased expression of angiogenic factors in women with RM.
WIDER IMPLICATIONS: The observation of significantly increased uNK level in endometrium of women with RM and RIF may point to an underlying disturbance of the immune milieu culminating in implantation and/or placentation failure. Further research is warranted to elucidate the underlying pathophysiology. The evidence for measuring pNK as an indicator of uNK behaviour is sparse, and of limited clinical use. Measurement of uNK level/activity may be more useful as a diagnostic tool, however, a standardized reference range must be established before this can be of clinical use.

Keywords: assisted reproduction; endometrium; flow cytometry; immunohistochemistry; immunology; natural killer cells; recurrent implantation failure; recurrent miscarriage; reproductive immunology

DOI: https://doi.org/10.1093/humupd/dmac006