Browsing by Author "Pique-Regi, Roger"

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    A single-cell atlas of murine reproductive tissues during preterm labor
    (2023) Garcia-Flores, Valeria; Romero, Roberto; Peyvandipour, Azam; Galaz, Jose; Pusod, Errile; Panaitescu, Bogdan; Miller, Derek; Xu, Yi; Tao, Li; Liu, Zhenjie; Tarca, Adi L.; Pique-Regi, Roger; Gomez-Lopez, Nardhy
    Preterm birth, the leading cause of perinatal morbidity and mortality worldwide, frequently results from the syndrome of preterm labor. The best-established causal link to preterm labor is intra-amniotic infection, which involves premature activation of the parturition cascade in the reproductive tissues. Herein, we utilize single-cell RNA sequencing (scRNA-seq) to generate a single-cell atlas of the murine uterus, decidua, and cervix in a model of infection-induced preterm labor. We show that preterm labor affects the transcriptomic profiles of specific immune and non-immune cell subsets. Shared and tissue-specific gene expression sig-natures are identified among affected cells. Determination of intercellular communications implicates spe-cific cell types in preterm labor-associated signaling pathways across tissues. In silico comparison of murine and human uterine cell-cell interactions reveals conserved signaling pathways implicated in labor. Thus, our scRNA-seq data provide insights into the preterm labor-driven cellular landscape and communications in reproductive tissues.
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    Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes
    (2023) Farias-Jofre, Marcelo; Romero, Roberto; Galaz, Jose; Xu, Yi; Miller, Derek; Garcia-Flores, Valeria; Arenas-Hernandez, Marcia; Winters, Andrew D.; Berkowitz, Bruce A.; Podolsky, Robert H.; Shen, Yimin; Kanninen, Tomi; Panaitescu, Bogdan; Glazier, Catherine R.; Pique-Regi, Roger; Theis, Kevin R.; Gomez-Lopez, Nardhy
    Background Preterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment.Methods Proteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1 alpha in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1 alpha. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment were tested. The neonatal gut immune-microbiome was evaluated using metagenomic sequencing and immunophenotyping.Findings IL-6 plays a critical role in the human intra-amniotic inflammatory response, which is associated with elevated concentrations of the alarmin IL-1 alpha. Intra-amniotic injection of IL-1 alpha resembles SIAI, inducing preterm birth (7% vs. 50%, p = 0.03, Fisher's exact test) and neonatal mortality (18% vs. 56%, p = 0.02, Mann-Whitney U-test). QUEST-MRI revealed no foetal brain oxidative stress upon in utero IL-1 alpha exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1 alpha-induced preterm birth (50% vs. 7%, p = 0.03, Fisher's exact test) by dampening inflammatory processes associated with the common pathway of labour. Importantly, aIL-6R reduces neonatal mortality (56% vs. 22%, p = 0.03, Mann-Whitney U-test) by crossing from the mother to the amniotic cavity, dampening foetal organ inflammation and improving growth. Beneficial effects of prenatal IL -6R blockade carried over to neonatal life, improving survival, growth, neurodevelopment, and gut immune homeostasis.Interpretation IL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes.
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    Deciphering maternal-fetal cross-talk in the human placenta during parturition using single-cell RNA sequencing
    (2024) Garcia-Flores, Valeria; Romero, Roberto; Tarca, Adi L.; Peyvandipour, Azam; Xu, Yi; Galaz, Jose; Miller, Derek; Chaiworapongsa, Tinnakorn; Chaemsaithong, Piya; Berry, Stanley M.; Awonuga, Awoniyi O.; Bryant, David R.; Pique-Regi, Roger; Gomez-Lopez, Nardhy
    Labor is a complex physiological process requiring a well-orchestrated dialogue between the mother and fetus. However, the cellular contributions and communications that facilitate maternal-fetal cross-talk in labor have not been fully elucidated. Here, single-cell RNA sequencing (scRNA-seq) was applied to decipher maternal-fetal signaling in the human placenta during term labor. First, a single-cell atlas of the human placenta was established, demonstrating that maternal and fetal cell types underwent changes in transcriptomic activity during labor. Cell types most affected by labor were fetal stromal and maternal decidual cells in the chorioamniotic membranes (CAMs) and maternal and fetal myeloid cells in the placenta. Cell-cell interaction analyses showed that CAM and placental cell types participated in labor-driven maternal and fetal signaling, including the collagen, C-X-C motif ligand (CXCL), tumor necrosis factor (TNF), galectin, and interleukin-6 (IL-6) pathways. Integration of scRNA-seq data with publicly available bulk transcriptomic data showed that placenta-derived scRNA-seq signatures could be monitored in the maternal circulation throughout gestation and in labor. Moreover, comparative analysis revealed that placenta-derived signatures in term labor were mirrored by those in spontaneous preterm labor and birth. Furthermore, we demonstrated that early in gestation, labor-specific, placenta-derived signatures could be detected in the circulation of women destined to undergo spontaneous preterm birth, with either intact or prelabor ruptured membranes. Collectively, our findings provide insight into the maternal-fetal cross-talk of human parturition and suggest that placenta-derived single-cell signatures can aid in the development of noninvasive biomarkers for the prediction of preterm birth.
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    Homeostatic Macrophages Prevent Preterm Birth and Improve Neonatal Outcomes by Mitigating In Utero Sterile Inflammation in Mice
    (2024) García-Flores, Valeria; Liu, Zhenjie; Romero, Roberto; Pique-Regi, Roger; Xu, Yi; Miller, Derek; Levenson, Dustyn; Galaz Alarcón, José Carlo; Winters, Andrew D.; Farias Jofré, Marcelo Enrique; Panzer, Jonathan J.; Theis, Kevin R.; Gómez-López, Nardhy
    Copyright © 2024 by The American Association of Immunologists, Inc.Preterm birth (PTB), often preceded by preterm labor, is a major cause of neonatal morbidity and mortality worldwide. Most PTB cases involve intra-amniotic inflammation without detectable microorganisms, termed in utero sterile inflammation, for which there is no established treatment. In this study, we propose homeostatic macrophages to prevent PTB and adverse neonatal outcomes caused by in utero sterile inflammation. Single-cell atlases of the maternal-fetal interface revealed that homeostatic maternal macrophages are reduced with human labor. M2 macrophage treatment prevented PTB and reduced adverse neonatal outcomes in mice with in utero sterile inflammation. Specifically, M2 macrophages halted premature labor by suppressing inflammatory responses in the amniotic cavity, including inflammasome activation, and mitigated placental and offspring lung inflammation. Moreover, M2 macrophages boosted gut inflammation in neonates and improved their ability to fight systemic bacterial infections. Our findings show that M2 macrophages are a promising strategy to mitigate PTB and improve neonatal outcomes resulting from in utero sterile inflammation.
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    Homeostatic Macrophages Prevent Preterm Birth and Improve Neonatal Outcomes by Mitigating In Utero Sterile Inflammation in Mice
    (2024) García-Flores, Valeria; Liu, Zhenjie; Romero, Roberto; Pique-Regi, Roger; Xu, Yi; Miller, Derek; Levenson, Dustyn; Galaz Alarcón, José Carlo; Winters, Andrew D.; Farias Jofré, Marcelo Enrique; Panzer, Jonathan J.; Theis, Kevin R.; Gómez-López, Nardhy
    Preterm birth (PTB), often preceded by preterm labor, is a major cause of neonatal morbidity and mortality worldwide. Most PTB cases involve intra-amniotic inflammation without detectable microorganisms, termed in utero sterile inflammation, for which there is no established treatment. In this study, we propose homeostatic macrophages to prevent PTB and adverse neonatal outcomes caused by in utero sterile inflammation. Single-cell atlases of the maternal-fetal interface revealed that homeostatic maternal macrophages are reduced with human labor. M2 macrophage treatment prevented PTB and reduced adverse neonatal outcomes in mice with in utero sterile inflammation. Specifically, M2 macrophages halted premature labor by suppressing inflammatory responses in the amniotic cavity, including inflammasome activation, and mitigated placental and offspring lung inflammation. Moreover, M2 macrophages boosted gut inflammation in neonates and improved their ability to fight systemic bacterial infections. Our findings show that M2 macrophages are a promising strategy to mitigate PTB and improve neonatal outcomes resulting from in utero sterile inflammation.
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    Single-Cell Immunobiology of the Maternal-Fetal Interface
    (2022) Miller, Derek; Garcia-Flores, Valeria; Romero, Roberto; Galaz, Jose; Pique-Regi, Roger; Gomez-Lopez, Nardhy
    Pregnancy success requires constant dialogue between the mother and developing conceptus. Such crosstalk is facil-itated through complex interactions between maternal and fetal cells at distinct tissue sites, collectively termed the "maternal -fetal interface." The emergence of single-cell technologies has enabled a deeper understanding of the unique processes taking place at the maternal -fetal interface as well as the discovery of novel pathways and immune and nonimmune cell types. Single-cell approaches have also been applied to decipher the cellular dynamics through-out pregnancy, in parturition, and in obstetrical syndromes such as recurrent spontaneous abortion, preeclampsia, and preterm labor. Furthermore, single-cell technologies have been used during the recent COVID-19 pandemic to eval-uate placental viral cell entry and the impact of SARS-CoV-2 infection on maternal and fetal immunity. In this brief review, we summarize the current knowledge of cellular immunobiology in pregnancy and its complica-tions that has been generated through single-cell investi-gations of the maternal -fetal interface. The Journal of Immunology, 2022, 209: 1450-1464.