Transcriptomics‐determined chemokine‐cytokine pathway presents a common pathogenic mechanism in pregnancy loss and spontaneous preterm birth

Abstract

Problem: Various etiological factors, such as infection and inflammation, may induce the adverse outcomes of pregnancy of miscarriage, stillbirth, or preterm birth. The pathogenic mechanisms associated with these adverse pregnancies are yet unclear.We hypothesized that a common pathogenic mechanism may underlie variant adverse outcomes of pregnancy, which are induced by genetic-environmental factors. The specific objective of the current study is to uncover the common molecular mechanism(s) by identifying the specific transcripts that are present in variant subtypes of pregnancy loss and preterm birth. Method of Study:Transcriptomic profiling was performed with RNA expression microarray or RNA sequencing of placentas derived from pregnancy loss (which includes spontaneous miscarriage, recurrent miscarriage, and stillbirth) and spontaneous preterm birth, followed by bioinformatic analysis of multi-omic integration to identify pathogenic molecules and pathways involved in pathological pregnancies. Results:The enrichment of common differentially expressed genes between fullterm birth and preterm birth and pregnancy loss of miscarriage and stillbirth revealed different pathophysiological pathway(s), including cytokine signaling dysregulated in spontaneous preterm birth, defense response, graft-versus-host disease, antigen processing and presentation, and T help cell differentiation in spontaneous miscarriage. Thirty-three genes shared between spontaneous preterm birth and spontaneous miscarriage were engaged in pathways of interferon gamma-mediated signaling and of antigen processing and presentation. For spontaneous miscarriage, immune response was enriched in the fetal tissue of chorionic villi and in the maternal facet of the placental sac. The transcript of nerve growth factor receptor was identified as the common molecule that is differentially expressed in all adverse pregnancies: spontaneous preterm birth, stillbirth, spontaneous miscarriage, and recurrent miscarriage.Superoxide dismutase 2 was up-regulated in all adverse outcomes of pregnancy except for recurrent miscarriage. Cytokine-cytokine receptor interaction was the common pathway in spontaneous preterm birth and spontaneous miscarriage. Defense How to cite this article: Wang P, Pan J, Tian X, et al.Transcriptomics-determined chemokine-cytokine pathway presents a common pathogenic mechanism in pregnancy loss and spontaneous preterm birth. Am J Reprod Immunol.

Characterization of placental and decidual cell development in early pregnancy loss by single-cell RNA sequencing

“…EPL has been grouped into three main categories according to causative factors: 1) resulting primarily from villous maldevelopment (such as in aneuploidy and/or lethal fetal anomalies), 2) resulting mainly from abnormal CTB invasion (such as in the antiphospholipid antibody syndrome), and 3) resulting from the abnormalities at the uteroplacental interface (such as in luteal phase deficiency or chronic inflammatory reaction) [ 59 ]. Among these three categories, EPL is increasingly considered a placentation disorder, resulting from placental oxidative stress, which may cause a thinner and fragmented trophoblast shell, reduced cytotrophoblast invasion of the endometrium and incomplete plugging of the lumen at the tips of the spiral arteries, and premature onset of the maternal circulation and loss of periphery-center coordination, with blood flow occurring throughout the placenta.…”

The landscape of circular RNA in preterm birth

“…IL-1b, TNF-a) to activate inflammatory signaling pathways (e.g. NF-kB) in various tissues and organs throughout the body as well as a full range of complement proteins to amplify the inflammatory effects, while infiltrating maternal-fetal interface tissues across the vascular wall under the stimulation of chemokines, causing progressively increasing inflammatory damage and thus leading to PTB (30,(60)(61)(62)(63)(64)(65). Coincidentally, we found that PTB-related DECs in monocytes were mainly involved in this complex series of immune-inflammatory responses, including NF-kappa B signaling pathway, complement receptor-mediated signaling pathway, chemokine receptor activity, and interleukin signaling.…”

Regulation and Function of Chemokines at the Maternal–Fetal Interface

“…Interestingly, a prospective immunohistochemical analysis of 203 chorionic villus sampling specimens showed that the scores of syndecan-1, a regulator of chemokine function, are correlated with PTB (Schmedt et al, 2012). Recently, a transcriptomic analysis has also reported that the chemokine pathway may present a common pathogenic mechanism in spontaneous PTB (Wang et al, 2021). Taken together, these studies implied that chemokines play important roles in the pathological mechanism of PTB.…”

“…RSA is defined as two or more times consecutive miscarriages before 20 weeks of gestation and impacts approximately 5% of childbearing-age women (Pereza et al, 2017; Practice Committee of the American Society for Reproductive Medicine, 2020). A recent transcriptomic analysis proposed chemokines as a common pathogenic mechanism in pregnancy loss (Wang et al, 2021). Abnormal secretion of CXCL5 was reported as an early indicator of miscarriage risk (Whitcomb et al, 2007).…”

“…Emerging evidence has identified chemokines and chemokine receptors as essential contributors in pregnancy, participating in trophoblast invasion, decidualization, and immune cell recruitment (Hannan and Salamonsen, 2007;Ramhorst et al, 2016;Ashley et al, 2021). Moreover, the aforementioned functional abnormalities of chemokines have been reported in several pregnancy complications, including preeclampsia (PE), recurrent spontaneous abortion (RSA), and preterm birth (PTB) (Whitcomb et al, 2007;Kwak et al, 2014;Ali et al, 2021;Wang et al, 2021;Zheng et al, 2021). In this review, we summarized the crucial regulatory roles of chemokines in pregnancy in detail and highlighted their importance on specific cellular processes at the maternal-fetal interface.…”