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Frontiers in Immunology 2020During pregnancy, the placenta forms the anatomical barrier between the mother and developing fetus. Infectious agents can potentially breach the placental barrier... (Review)
Review
During pregnancy, the placenta forms the anatomical barrier between the mother and developing fetus. Infectious agents can potentially breach the placental barrier resulting in pathogenic transmission from mother to fetus. Innate immune responses, orchestrated by maternal and fetal cells at the decidual-placental interface, are the first line of defense to avoid vertical transmission. Here, we outline the anatomy of the human placenta and uterine lining, the decidua, and discuss the potential capacity of pathogen pattern recognition and other host defense strategies present in the innate immune cells at the placental-decidual interface. We consider major congenital infections that access the placenta from hematogenous or decidual route. Finally, we highlight the challenges in studying human placental responses to pathogens and vertical transmission using current experimental models and identify gaps in knowledge that need to be addressed. We further propose novel experimental strategies to address such limitations.
Topics: Animals; Decidua; Disease Models, Animal; Female; Humans; Immunity, Innate; Infections; Infectious Disease Transmission, Vertical; Placenta; Pregnancy
PubMed: 33013876
DOI: 10.3389/fimmu.2020.02070 -
American Journal of Reproductive... Mar 2024Autophagy is a bulk degradation system that maintains cellular homeostasis by producing energy and/or recycling excess proteins. During early placentation, extravillous... (Review)
Review
Autophagy is a bulk degradation system that maintains cellular homeostasis by producing energy and/or recycling excess proteins. During early placentation, extravillous trophoblasts invade the decidua and uterine myometrium, facing maternal immune cells, which participate in the immune suppression of paternal and fetal antigens. Regulatory T cells will likely increase in response to a specific antigen before and during early pregnancy. Insufficient expansion of antigen-specific Treg cells, which possess the same T cell receptor, is associated with the pathophysiology of preeclampsia, suggesting sterile systemic inflammation. Autophagy is involved in reducing inflammation through the degradation of inflammasomes and in the differentiation and function of regulatory T cells. Autophagy dysregulation induces protein aggregation in trophoblasts, resulting in placental dysfunction. In this review, we discuss the role of regulatory T cells in normal pregnancies. In addition, we discuss the association between autophagy and regulatory T cells in the development of preeclampsia based on reports on the role of autophagy in autoimmune diseases.
Topics: Pregnancy; Female; Humans; Placenta; Pre-Eclampsia; Placentation; Trophoblasts; Autophagy; Inflammation; Decidua
PubMed: 38467995
DOI: 10.1111/aji.13835 -
Frontiers in Immunology 2020The human decidua and placenta form a distinct environment distinguished for its promotion of immunotolerance to infiltrating semiallogeneic trophoblast cells to enable... (Review)
Review
The human decidua and placenta form a distinct environment distinguished for its promotion of immunotolerance to infiltrating semiallogeneic trophoblast cells to enable successful pregnancy. The maternal-fetal interface also successfully precludes transmission of most pathogens. This barrier function occurs in conjunction with a diverse influx of decidual immune cells including natural killer cells, macrophages and T cells. However, several viruses, among other microorganisms, manage to escape destruction by the host adaptive and innate immune system, leading to congenital infection and adverse pregnancy outcomes. In this review, we describe mechanisms of pathogenicity of two such viral pathogens, Human cytomegalovirus (HCMV) and Zika virus (ZIKV) at the maternal-fetal interface. Host decidual immune cell responses to these specific pathogens will be considered, along with their interactions with other cell types and the ways in which these immune cells may both facilitate and limit infection at different stages of pregnancy. Neither HCMV nor ZIKV naturally infect commonly used animal models [e.g., mice] which makes it challenging to understand disease pathogenesis. Here, we will highlight new approaches using placenta-on-a-chip and organoids models that are providing functional and physiologically relevant ways to study viral-host interaction at the maternal-fetal interface.
Topics: Cytomegalovirus; Cytomegalovirus Infections; Decidua; Female; Humans; Infectious Disease Transmission, Vertical; Pregnancy; Pregnancy Complications, Infectious; Trophoblasts; Zika Virus; Zika Virus Infection
PubMed: 33117336
DOI: 10.3389/fimmu.2020.522047 -
American Journal of Reproductive... Dec 2021Mucosal-Associated Invariant T (MAIT) cells have been recently identified at the maternal-fetal interface. However, transcriptional programming of decidual MAIT cells in...
PROBLEM
Mucosal-Associated Invariant T (MAIT) cells have been recently identified at the maternal-fetal interface. However, transcriptional programming of decidual MAIT cells in pregnancy remains poorly understood.
METHOD OF STUDY
We employed a multiomic approach to address this question. Mononuclear cells from the decidua basalis and parietalis, and control PBMCs, were analyzed via flow cytometry to investigate MAIT cells in the decidua and assess their transcription factor expression. In a separate study, both decidual and matched peripheral MAIT cells were analyzed using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) coupled with gene expression analysis. Lastly, decidual MAIT cells were stimulated with E.coli and expression of MR1 by antigen presenting cells was measured to evaluate decidual MAIT cell function.
RESULTS
First, we identified MAIT cells in both the decidua basalis and parietalis. CITE-seq, coupled with scRNA-seq gene expression analysis, highlighted transcriptional programming differences between decidual and matched peripheral MAIT cells at a single cell resolution. Transcription factor expression analysis further highlighted transcriptional differences between decidual MAIT cells and non-matched peripheral MAIT cells. Functionally, MAIT cells are skewed towards IFNγ and TNFα production upon stimulation, with E.coli leading to IFNγ production. Lastly, we demonstrate that MR1, the antigen presenting molecule restricting MAIT cells, is expressed by decidual APCs.
CONCLUSION
MAIT cells are present in the decidua basalis and obtain a unique gene expression profile. The presence of MR1 on APCs coupled with in vitro activation by E.coli suggests that MAIT cells might be involved in tissue-repair mechanisms at the maternal-fetal interface.
Topics: Decidua; Female; Flow Cytometry; Humans; Leukocytes; Mucosal-Associated Invariant T Cells; Placenta; Pregnancy
PubMed: 34411378
DOI: 10.1111/aji.13495 -
Placenta Sep 2023High yield and integrity of placental RNA are crucial for placental transcriptomics studies. We assessed the effects of time to placental collection post-delivery;...
High yield and integrity of placental RNA are crucial for placental transcriptomics studies. We assessed the effects of time to placental collection post-delivery; tissue storage, amount and method used for extraction; mode of delivery; and tissue type on total RNA yield. The optimal protocol for RNA extraction from placental tissue includes cryofreezing of the sample upon collection and RNA extraction from 50 mg of tissue using TRIzol reagent. Decidua yielded highest RNA quantity/mg of tissue, followed by villous tissue and the chorion. Comparisons with murine kidney and HEK293T show lower placental RNA yield, likely due to highly dense and heterogeneous tissue make-up and potential high placental nuclease activity.
Topics: Humans; Pregnancy; Female; Animals; Mice; Placenta; RNA; Decidua; HEK293 Cells; Chorion
PubMed: 37549440
DOI: 10.1016/j.placenta.2023.08.002 -
Scientific Reports Mar 2022Placental function requires organized growth, transmission of nutrients, and an anti-inflammatory milieu between the maternal and fetal interface, but placental factors...
Placental function requires organized growth, transmission of nutrients, and an anti-inflammatory milieu between the maternal and fetal interface, but placental factors important for its function remain unclear. Renalase is a pro-survival, anti-inflammatory flavoprotein found to be critical in other tissues. We examined the potential role of renalase in placental development. PCR, bulk RNA sequencing, immunohistochemistry, and immunofluorescence for renalase and its binding partners, PMCA4b and PZP, were performed on human placental tissue from second-trimester and full-term placentas separated into decidua, placental villi and chorionic plates. Quantification of immunohistochemistry was used to localize renalase across time course from 17 weeks to term. Endogenous production of renalase was examined in placental tissue and organoids. Renalase and its receptor PMCA4b transcripts and proteins were present in all layers of the placenta. Estimated RNLS protein levels did not change with gestation in the decidual samples. However, placental villi contained more renalase immunoreactive cells in fetal than full-term placental samples. RNLS co-labeled with markers for Hofbauer cells and trophoblasts within the placental villi. Endogenous production of RNLS, PMCA4b, and PZP by trophoblasts was validated in placental organoids. Renalase is endogenously expressed throughout placental tissue and specifically within Hofbauer cells and trophoblasts, suggesting a potential role for renalase in placental development and function. Future studies should assess renalase's role in normal and diseased human placenta.
Topics: Chorionic Villi; Decidua; Female; Humans; Monoamine Oxidase; Placenta; Placentation; Plasma Membrane Calcium-Transporting ATPases; Pregnancy; Trophoblasts
PubMed: 35322081
DOI: 10.1038/s41598-022-08817-6 -
The International Journal of... 2020The eutherian species evolved an elaborate uterus to allow viviparity. For successful pregnancy, the uterus must not only be differentiated, but must also function... (Review)
Review
The eutherian species evolved an elaborate uterus to allow viviparity. For successful pregnancy, the uterus must not only be differentiated, but must also function optimally and any defects in uterus differentiation and/or function can lead to infertility. The homoebox gene HOXA10 has emerged to be a key player in both uterine development and its optimal functioning in adulthood. Within the Abd-B family, the posterior Hoxa genes play a dominant role in anterio-posterior segmentation of the Müllerian ducts in mammals, with Hoxa10 having a central role in uterine segmentation. In the adult endometrium, HOXA10 is expressed by endometrial cells and is regulated in a cyclic manner under the influence of ovarian steroids. During embryo implantation, expression of HOXA10 is increased in endometrial stromal cells by signals from the embryo to govern stromal cell transformation to decidual cells. Once decidualization is initiated, HOXA10 is rapidly downregulated to activate expression of pro-invasive factors to promote trophoblast invasion. We propose that HOXA10 governs embryo implantation in a three-step process: 1) acquisition of endometrial receptivity, 2) responding to signals from the blastocyst to modify receptive endometrium for decidualization 3) making the decidua conductive for trophoblast invasion and placentation. There is currently ample evidence that expression of HOXA10 is deregulated in a variety of "endometriopathies" such as endometriosis and endometrial cancers. Overall, HOXA10 appears to be the master regulator of endometrial health and a central determinant of fertility in mammals.
Topics: Animals; Cell Differentiation; Decidua; Embryo Implantation; Endometrium; Female; Gene Expression Regulation, Developmental; Homeobox A10 Proteins; Humans; Placentation; Pregnancy
PubMed: 32659011
DOI: 10.1387/ijdb.190120dm -
Reproduction (Cambridge, England) May 2023Hypoxia is vital for the establishment of the maternal-fetal interface during early pregnancy. This study shows that decidual macrophages (dMφ) could be recruited and...
IN BRIEF
Hypoxia is vital for the establishment of the maternal-fetal interface during early pregnancy. This study shows that decidual macrophages (dMφ) could be recruited and reside in decidua under the regulation of hypoxia/VEGFA-CCL2 axis.
ABSTRACT
Infiltration and residence of decidual macrophages (dMφ) are of great significance to pregnancy maintenance for their role in angiogenesis, placental development, and inducing immune tolerance. Besides, hypoxia has now been acknowledged as an important biological event at maternal-fetal interface in the first trimester. However, whether and how hypoxia regulates biofunctions of dMφ remain elusive. Herein, we observed increased expression of C-C motif chemokine ligand 2 (CCL2) and residence of macrophages in decidua compared to secretory-phase endometrium. Moreover, hypoxia treatment on stromal cells improved the migration and adhesion of dMφ. Mechanistically, these effects might be mediated by upregulated CCL2 and adhesion molecules (especially ICAM2 and ICAM5) on stromal cells in the presence of endogenous vascular endothelial growth factor-A (VEGFA) in hypoxia. These findings were also verified by recombinant VEGFA and indirect coculture, indicating that the interaction between stromal cells and dMφ in hypoxia condition may facilitate dMφ recruitment and residence. In conclusion, VEGFA derived from a hypoxic environment may manipulate CCL2/CCR2 and adhesion molecules to enhance the interactions between dMφ and stromal cells and thus contribute to the enrichment of macrophages in decidua early during normal pregnancy.
Topics: Pregnancy; Female; Humans; Placenta; Decidua; Vascular Endothelial Growth Factor A; Chemotaxis; Ligands; Macrophages; Chemokines; Chemokine CCL2
PubMed: 36809184
DOI: 10.1530/REP-22-0473 -
Placenta Feb 2021Inflammation is a normal physiological process that increases to harmful levels in preeclampsia. It affects the interaction between maternal immune cells and fetal...
INTRODUCTION
Inflammation is a normal physiological process that increases to harmful levels in preeclampsia. It affects the interaction between maternal immune cells and fetal trophoblasts at both sites of the maternal-fetal interface; decidua and placenta. The pattern recognition receptor nucleotide-binding oligomerization domain-containing protein (NOD)1 is expressed at both sites. This study aimed to characterize the cellular expression and functionality of NOD1 at the maternal-fetal interface of normal and preeclamptic pregnancies.
METHODS
Women with normal or preeclamptic pregnancies delivered by caesarean section were included. Decidual (n = 90) and placental (n = 91) samples were analyzed for NOD1 expression by immunohistochemistry and an automated image-based quantification method. Decidual and placental explants were incubated with or without the NOD1-agonist iE-DAP and cytokine responses measured by ELISA.
RESULTS
NOD1 was markedly expressed by maternal cells in the decidua and by fetal trophoblasts in both decidua and placenta, with trophoblasts showing the highest NOD1 expression. Preeclampsia with normal fetal growth was associated with a trophoblast-dependent increase in decidual NOD1 expression density. Compared to normal pregnancies, preeclampsia demonstrated stronger correlation between decidual and placental NOD1 expression levels. Increased production of interleukin (IL)-6 or IL-8 after in vitro explant stimulation confirmed NOD1 functionality.
DISCUSSION
These findings suggest that NOD1 contributes to inflammation at the maternal-fetal interface in normal pregnancies and preeclampsia and indicate a role in direct maternal-fetal communication. The strong expression of NOD1 by all trophoblast types highlights the importance of combined assessment of decidua and placenta for overall understanding of pathophysiological processes at the maternal-fetal interface.
Topics: Adult; Cytokines; Decidua; Female; Humans; Inflammation; Nod1 Signaling Adaptor Protein; Placenta; Pre-Eclampsia; Pregnancy; Trophoblasts; Young Adult
PubMed: 33529885
DOI: 10.1016/j.placenta.2021.01.014 -
American Journal of Reproductive... Oct 2022A tight immune and metabolic regulation underlies the early maternal-placental interaction to assist the energetic dynamic demands of the fetus throughout pregnancy. The... (Review)
Review
BACKGROUND
A tight immune and metabolic regulation underlies the early maternal-placental interaction to assist the energetic dynamic demands of the fetus throughout pregnancy. The vasoactive intestinal peptide (VIP) holds biochemical, metabolic and immune properties consistent with a regulatory role during pregnancy.
AIM
Here we overview critical aspects of embryo implantation and placental development with special focus on the immune and metabolic effects of VIP expressed by decidual and trophoblast cells.
CONTENT
During decidualization, endometrial stromal cells undergo reticular stress and trigger unfolded protein response (UPR) that enable expansion of their endoplasmic reticulum and immunomodulatory factor synthesis. These processes appear differentially affected in recurrent abortion and in vitro fertilization failure suggesting their relevance in reproductive pathologies. Similarly, defective placentation associates with altered immune, vascular and trophoblast interaction resulting in complicated pregnancies that threaten maternal and neonatal health and underlie metabolic programming of adult life. We discuss the most recent research on decidual, trophoblast and immune cell interaction on the light of VIP regulation. Its role in decidualization and UPR associated with a sterile inflammatory response and angiogenesis is discussed. Evidence on VIP modulation of cytotrophoblast cell function, metabolism and immune profile is revised as well as the shaping of decidual leukocyte phenotype and function from decidualization to term.
IMPLICATIONS
The broad spectrum of effects of VIP from implantation to term in normal and pathological conditions summarized here might contribute to the identification of novel biomarkers for diagnosis and pharmacological targeting.
Topics: Biomarkers; Decidua; Embryo Implantation; Female; Humans; Placenta; Placentation; Pregnancy; Stromal Cells; Trophoblasts; Vasoactive Intestinal Peptide
PubMed: 35810353
DOI: 10.1111/aji.13601