Cells In Human Decidua Research Articles

Evidence for the existence of CD34+ angiogenic stem cells in human first-trimester decidua and their therapeutic for ischaemic heart disease.

Stem cell transplantation is nearly available for clinical application in the treatment of ischaemic heart disease (IHD), where it may be joined traditional methods (intervention and surgery). The angiogenic ability of seed cells is essential for this applicability. The aim of this study was to reveal the presence of CD34+ angiogenic stem cells in human decidua at the first trimester and to use their strong angiogenic capacity in the treatment of IHD. In vitro, human decidual CD34+ (dCD34+) cells from the first trimester have strong proliferation and clonality abilities. After ruling out the possibility that they were vascular endothelial cells and mesenchymal stem cells (MSCs), dCD34+ cells were found to be able to form tube structures after differentiation. Their angiogenic capacity was obviously superior to that of bone marrow mesenchymal stem cells (BMSCs). At the same time, these cells had immunogenicity similar to that of BMSCs. Following induction of myocardial infarction (MI) in adult rats, infarct size decreased and cardiac function was significantly enhanced after dCD34+ cell transplantation. The survival rate of cells increased, and more neovasculature was found following dCD34+ cell transplantation. Therefore, this study confirms the existence of CD34+ stem cells with strong angiogenic ability in human decidua from the first trimester, which can provide a new option for cell‐based therapies for ischaemic diseases, especially IHD.

An Anti-inflammatory microRNA Signature Distinguishes Group 3 Innate Lymphoid Cells From Natural Killer Cells in Human Decidua.

Innate lymphoid cells (ILCs) are a heterogeneous subset of lymphocytes deeply implicated in the innate immune responses to different pathogens, in lymphoid organogenesis and in the maintenance of tissue homeostasis. Group 3 innate lymphoid cells (ILC3) have been detected in human decidua, where they play a role in the early inflammatory phase favoring implantation and tissue remodeling as well as in the subsequent regulatory phase preventing fetal rejection and supporting neoangiogenesis. A balance between inflammation and immune tolerance is required to maintain pregnancy, thus maternal immune system must be controlled by finely tuned mechanisms. microRNAs (miRNAs) are small non-coding RNAs with important regulatory roles in immune cells, but their function in decidual ILC3 (dILC3) and in decidual NK (dNK) cells is still undefined. Here, we examined the miRNome by microarray in these cells during the first trimester of pregnancy and compared with miRNA profiles of peripheral blood NK (pbNK) cells from pregnant women. We show that distinct miRNA profiles could clearly distinguish dILC3 from NK cells. Correlation analyses revealed that dNK and pbNK miRNome profiles are more similar to each other as compared to dILC3. In particular, we identified 302 and 279 mature miRNAs differentially expressed in dILC3 as compared to dNK and pbNK, respectively. The expression of miR-574-3p and the miR-99b/let-7e/miR-125a miRNA cluster resulted the most increased in dILC3. Remarkably, gene ontology analysis and pathway enrichments of miRNA targets revealed an involvement of these miRNAs in the promotion of anti-inflammatory responses. In agreement to this finding, we also found a higher expression of the anti-inflammatory miR-146a-5p in dILC3 with respect to NK cells. Overall, our data identified specific miRNA signatures distinguishing dILC3, dNK, and pbNK cells. Our data suggest the existence of a tight epigenetic control mediated by miRNAs in dILC3, potentially acting as a brake to prevent exaggerated inflammatory responses and to maintain the immune homeostasis in the early phases of pregnancy.

Distinctive phenotypes and functions of innate lymphoid cells in human decidua during early pregnancy

During early pregnancy, decidual innate lymphoid cells (dILCs) interact with surrounding maternal cells and invading fetal extravillous trophoblasts (EVT). Here, using mass cytometry, we characterise five main dILC subsets: decidual NK cells (dNK)1–3, ILC3s and proliferating NK cells. Following stimulation, dNK2 and dNK3 produce more chemokines than dNK1 including XCL1 which can act on both maternal dendritic cells and fetal EVT. In contrast, dNK1 express receptors including Killer-cell Immunoglobulin-like Receptors (KIR), indicating they respond to HLA class I ligands on EVT. Decidual NK have distinctive organisation and content of granules compared with peripheral blood NK cells. Acquisition of KIR correlates with higher granzyme B levels and increased chemokine production in response to KIR activation, suggesting a link between increased granule content and dNK1 responsiveness. Our analysis shows that dILCs are unique and provide specialised functions dedicated to achieving placental development and successful reproduction.

Alternatively Activated Macrophages Are the Primary Retinoic Acid-Producing Cells in Human Decidua.

In situ production and metabolism of all-trans retinoic acid (RA) in decidual tissue are critically important for endometrial stromal differentiation, embryo implantation, and healthy placentation. However, the cellular source(s) of RA in this tissue has yet to be determined. To identify the primary RA-producing cells in human term decidua, we isolated cells from decidua basalis of delivered placenta and quantified cellular retinal dehydrogenase (RALDH) activity, a major biosynthetic enzyme whose activity determines the synthesis of RA from retinol, using an Aldefluor assay and flow cytometry. RA production in decidual tissue and sorted cell subpopulations was evaluated by liquid chromatography-tandem mass spectrometry. CD14+ cells (macrophages/monocytes) showed > 4-fold higher RALDH activity than stromal cells (CD10+), T cells (CD3+), or non-T lymphocytes (CD3-negative). CD11c+ cells that did not co-express CD14 showed about one-third the RALDH activity of their CD14 co-expressing counterparts. The highest RALDH activity was found in "alternatively activated" M2 macrophages delineated by the simultaneous expression of CD14 and CD163. The greater RA synthesizing capacity of M2 versus CD14+CD163-ve (M1) cells was confirmed by direct quantitation of RA biosynthesis from retinol. RA levels in whole decidua were correlated with M2 cell density but not with stromal cell (CD10+) number, the major cell type comprising the decidua. These results identified M2 monocyte/macrophages as the primary source of RA in human term decidua. This finding may have implications for certain pregnancy complications that are known to be associated with reduced numbers of decidual M2 cells.

PD-1 is expressed by and regulates human group 3 innate lymphoid cells in human decidua.

Group 3 innate lymphoid cells (ILC3) have been detected in both murine and human decidual tissues where they are thought to play a relevant role in the induction and maintenance of pregnancy. However, limited information exists on the molecular mechanisms that regulate these cells, including immune checkpoints. Here, we show that ILC3 express the inhibitory checkpoints programmed cell death (PD-1) and T cell immunoglobulin and mucin domain containing protein 3 (TIM-3) during the first trimester of pregnancy and that these receptors could regulate production of cytokines, including IL-22, IL-8, and TNF-α, induced by IL-23. We also show that the intermediate extravillous trophoblast (iEVT) expresses high levels of the PD-1-ligand PD-L1, suggesting that PD-1/PD-L1 interaction may regulate ILC3 function at the feto-maternal interface. Our present data provide the first evidence that human decidual ILC3 express a functional PD-1. It is possible that an altered expression or function of PD-1 may break the immune-tolerance resulting in pregnancy failure.

Progesterone and cyclic adenosine monophosphate down-regulate CD90 in the stromal cells of human decidua. In vitro evidence and in situ findings.

CD90 is a glycoprotein involved in leukocyte relocation and cell differentiation. CD90 is expressed in endothelial and stromal cells in human endometrium; however, its role in the remodeling of the decidual tissue during pregnancy is poorly understood. Here, we investigate how CD90 expression in decidual stromal cells (DSCs) is regulated. The native CD90 receptor in stromal cells in decidua was investigated via histology. We further develop in vitro culture of DSCs which allows us to test the effects of hormones and paracrine signals on CD90 expression. Stromal cells in first-trimester human decidua display heterogeneous levels of CD90 expression. In vitro analyses reveal that progesterone, a factor normally secreted by trophoblast cells in the placenta, and extracellular cyclic adenosine monophosphate, a known downstream signaling messenger of progesterone, reduce CD90 expression in DSCs by ~30%. This reduction in CD90 expression correlates with a change toward a more highly differentiated cell state. DSCs in early pregnancy show different levels of CD90 expression, suggesting different DSC differentiation and selective interactions with cells during decidual morphogenesis.

Unique Cytokine Profile of Novel Innate Lymphoid Cells in Human Decidua

Abstract Immune cells at the maternal-fetal interface play a complex role in regulation of vascular remodeling, fetal tolerance and protection from infection. We have previously presented the identification of two novel CD56highNKs based on Eomes expression (Eomeslo/hi). Activation of these subsets revealed preferential production of IL-8 and IL-17A by decidual innate lymphoid cells (ILCs). Decidual specimens were dissected from term placentas and mononuclear cells (MCs) were isolated by mechanical (GentleMACS) and enzymatic (Collagenase, DNAse) disruption. MCs were then simulated with PMA/ionomycin or IL-23, then labeled by flurochrome-conjugate antibodies against surface CD3, 14, 16, 19, 34, 45, 49a, 56, 94, 117, 127, 335 and intracellular Granzyme B, IL-8, IL-17A, IL-22, INFγ, TNFα. Data acquisition was performed using BD Fortessa flow cytometer in a 5 laser, 18 detector configuration and data analysis was performed using FlowJo 10.2. Activation of decidual ILCs revealed a unique milieu of cytokine production. The novel subsets, CD56high Eomeslo/hi, preferentially produced IL-8 and IL-17A, while decreasing production of INFγ, Granzyme B, and TNFα. In addition, as expected, ILC3s and LTi-like cells produced IL-17A and IL-22. Furthermore, differences in response were observed between decidual basalis and decidual parietalis ILCs, with decidual parietalis ILCs being more responsive to stimulation. Preliminary results suggest that both CD56high Eomeslo/hi subsets demonstrate a similar altered cytokine profile that is conducive to decidual remodeling. Further gene expression analysis will reveal if these novel subsets represent a truly unique population or are members of the expanding tissue-resident NK cell family.

Distinct Transcriptional and Alternative Splicing Signatures of Decidual CD4+ T Cells in Early Human Pregnancy.

Decidual CD4+ T (dCD4 T) cells are crucial for the maternal-fetal immune tolerance required for a healthy pregnancy outcome. However, their molecular and functional characteristics are not well elucidated. In this study, we performed the first analysis of transcriptional and alternative splicing (AS) landscapes for paired decidual and peripheral blood CD4+ T (pCD4 T) cells in human early pregnancy using high throughput mRNA sequencing. Our data showed that dCD4 T cells are endowed with a unique transcriptional signature when compared to pCD4 T cells: dCD4 T cells upregulate 1,695 genes enriched in immune system process whereas downregulate 1,011 genes mainly related to mRNA catabolic process and the ribosome. Moreover, dCD4 T cells were observed to be at M phase, and show increased activation, proliferation, and cytokine production, as well as display an effector-memory phenotype and a heterogenous nature containing Th1, Th17, and Treg cell subsets. However, dCD4 T cells undergo a comparable number of upregulated and downregulated AS events, both of which are enriched in the genes related to cellular metabolic process. And the changes at the AS event level do not reflect measurable differences at the gene expression level in dCD4 T cells. Collectively, our findings provide a comprehensive portrait of the unique transcriptional signature and AS profile of CD4+ T cells in human decidua and help us gain more understanding of the functional characteristic of these cells during early pregnancy.

Do prorenin-synthesizing cells release active, 'open' prorenin?

The function of prorenin, the inactive precursor of renin, remains unclear after many decades of research. The discovery of a (pro)renin receptor suggested that prorenin, by binding to this receptor, would become active, that is, obtain an 'open' conformation. However, the receptor only interacted with prorenin at levels that were many orders of magnitude above its normal levels, making such interaction in-vivo unlikely. Prorenin occurs in two conformations, an open, active form, and a closed, inactive form. Under physiological conditions (pH 7.4, 37 °C), virtually all prorenin occurs in the closed conformation. This study investigated to what degree prorenin-synthesizing cells release prorenin in an open conformation. Renin plus prorenin-synthesizing human mast cells, and prorenin-synthesizing HEK293 cells (transfected with the mammalian expression vector pRhR1100, containing human prorenin) and human decidua cells were incubated with the renin inhibitor VTP-27999. This inhibitor will trap open prorenin, as after VTP-27999 binding, prorenin can no longer return to its closed conformation, thus allowing its detection in a renin immunoradiometric assay. No evidence for the release of open prorenin was found. Moreover, incubating decidua cells with angiotensinogen yielded low angiotensin levels, corresponding with the activity of ≈1% of prorenin in the medium, that is, the amount of open prorenin expected based upon the equilibrium between open and closed prorenin under physiological conditions. Our study does not reveal evidence for the release of open, active prorenin by prorenin-synthesizing cells, at least under cell culture conditions. This argues against prorenin activity at the site of its release.

Expression and regulation of 11β-hydroxysteroid dehydrogenase type 1 in first trimester human decidua cells: Implication in preeclampsia

Glucocorticoids are implicated in successful blastocyst implantation, whereas alterations in glucocorticoid levels are associated with various pregnancy disorders including preeclampsia. Tissue concentration of active glucocorticoids depends on the expression of 11β-hydroxysteroid dehydrogenase (11β-HSD). This study investigated the contribution of first trimester decidua to glucocorticoid availability at the fetal-maternal interface by assessing the expression and regulation of 11β-HSD in human first trimester decidual tissues and cells and by evaluating 11β-HSD levels in preeclamptic vs. gestational age-matched decidua. 11β-HSD1 was the predominant isoform in first trimester decidua. In vitro, decidual cell 11β-HSD1 levels and enzymatic activity were up-regulated by ovarian steroids and inflammatory cytokines. Higher levels of 11β-HSD1 were found in preeclamptic decidua compared to controls. The present study indicates the predominance of 11β-HSD oxoreductase isoform in early decidua. Observations that ovarian hormones and inflammatory cytokines up-regulate 11β-HSD1, together with increased 11β-HSD1 expression in preeclampsia, highlight a role for decidual cells in controlling biologically active glucocorticoids in early pregnancy.

Characterization of a new subset of CD8+HLA-DR+ T cells in human decidua

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Characterization of a new subset of CD8+HLA-DR+ T cells in human decidua

Characterization of a new subset of CD8+HLA-DR+ T cells in human decidua

Galectin-1 reduced the effect of LPS on the IL-6 production in decidual cells by inhibiting LPS on the stimulation of IκBζ

Pregnancy is a complex process where several physiological pathways interact. The down-regulated inflammatory response and the abundance of anti-inflammatory molecules during gestation may explain the acceptance of the fetus and the lack of immune response against it, even though it is a foreign tissue for the mother. NF-κB is a key regulator of the transcription of inflammatory genes, such as IL-8, IL-1β, TNF-α, or IL-6. Increased NF-κB activity that leads to the production of proinflammatory cytokines may induce obstetric disorders, such as preterm birth or abortion. Low activity of this transcription factor is associated with the beneficial anti-inflammatory environment during fetus development until delivery. Galectin-1 (Gal-1) is a lectin-type glycan-binding protein that is able to down-regulate inflammation. It has been shown that Gal-1 is abundantly expressed at the feto-maternal interface in humans, where it promotes maternal immune tolerance to the fetal semi-allograft. Gal-1 tolerance-promoting mechanisms have been established for adaptive immune cells, such as T cells and dendritic cells. However, the role of this lectin has not been established in non-immune cells at the feto-maternal interface. Here, we determined that Gal-1 is able to block the stimulating effect of LPS on IL-6 in human decidua cells. Our results show that Gal-1 acts by inhibiting the stimulation of the LPS-induced IκBζ expression, an NF-κB regulator involved in IL-6 gene transcription.

CD1 Antigen Presentation and Autoreactivity in the Pregnant Human Uterus.

CD11c(HI) human decidual macrophages express several isoforms of CD1 molecules. Their expression pattern and function required investigation. CD11c(HI) macrophages were isolated from decidua. Expression of CD1 isoforms and their ability to present lipid antigens to T cells was studied. CD1a, CD1c, and CD1d were all expressed on CD11c(HI) dMϕ, a pattern differing from those previously observed. Exposure of peripheral monocytes and dendritic cells to lipid isolates from decidua led to increased surface CD1a levels only. The CD1a and CD1c on dMϕ were able to present the appropriate lipid antigens to lipid antigen-specific T cells. Finally, autoreactivity of decidual T cells to CD1a was observed. The unique pattern of expression of CD1 isoforms on CD11c(HI) dMϕ is consistent with organ-specific roles of CD1 in human T-cell responses. dMϕ are able to present lipid antigens to both peripheral and decidual T cells and are major antigen-presenting cells in human decidua.

Identification of diverse innate lymphoid cells in human decidua.

Innate lymphoid cells (ILCs) are developmentally related cells that play an important role in innate defenses and tissue remodeling. So far, only natural killer (NK) cells have been identified and functionally characterized in human decidua where they contribute to induction of immune suppression, neo-angiogenesis, and tissue building/remodeling. The presence of other ILC subsets in human decidua has not been yet characterized. Here we identify in human decidua, during early pregnancy, two subsets of decidual group 3 ILC (ILC3), including lymphoid tissue inducer (LTi)-like cells and natural cytotoxicity receptors (NCRs)(+)ILC3 and interferon-(IFN)γ-producing ILC1, different from NK cells. Decidual LTi-like cells produced interleukin -17 (IL-17) and tumor necrosis factor (TNF), while NCR(+)ILC3 released IL-22 and IL-8. Importantly, NCR(+)ILC3 and LTi-like cells established functional interactions with stromal cells. Decidual LTi-like cells differentiated into NCR(+)ILC3, whereas they marginally contributed to NK cell generation. Our data suggest that decidual ILC3 may play a role in innate defenses and in vessel and tissue building, thus contributing to maintenance of pregnancy.

HLA-G expressing DC-10 and CD4+ T cells accumulate in human decidua during pregnancy

Multiple mechanisms underlie the surprising willingness of mothers to tolerate the semi-allogeneic fetal tissues during pregnancy. Chief among these is the expression of the HLA-G molecules that has been largely demonstrated to be responsible for reprogramming the local maternal immune response towards tolerance. We recently identified a subset of tolerogenic dendritic cells, DC-10 that secrete high amounts of IL-10 and express high levels of HLA-G and its ligand ILT4. DC-10 are present in the peripheral blood and are essential in inducing adaptive regulatory T cells. We investigated the presence of DC-10 and HLA-G-expressing CD4+ T cells in human decidua in the first trimester of pregnancy. Results showed that these cells are highly represented in human decidua as compared to the peripheral blood. This is the first report describing decidual DC-10 and CD4+HLA-G+ T cells, strongly suggesting that they may accumulate or be induced at the fetal maternal interface to promote tolerance.

The decidual gamma-delta T cells up-regulate the biological functions of trophoblasts via IL-10 secretion in early human pregnancy

The functions of decidual γδT cells in early human pregnancy are not fully understood. The present study was undertaken to characterize the action of decidual γδT cells, and analyze their regulatory roles in proliferation and invasion of trophoblasts in early human pregnancy. It was revealed that decidual γδT cells were a CD4(-) and CD8(-) subset whose numbers increased significantly in either the decidua or peripheral blood. The main cytokines synthesized in decidual γδT cells in decreasing concentration were; IL-10>TGF-β>TNF-α≥IFN-γ, with little IL-2 or IL-4 being produced. Decidual γδT cells promoted trophoblast proliferation and invasion, and suppressed trophoblast apoptosis through IL-10 secretion in co-culture. These results suggest that γδT cells in human decidua might play an important role in the Th2 bias at maternal-fetal interface and in the development and progression of the placenta, which is beneficial to maternal immunotolerance toward the fetus in early human pregnancy.

Side population cells in the human decidua of early pregnancy exhibit stem/progenitor cell-like characteristics

It is proposed that human decidua contains a population of stem cells that are responsible for the proliferation ability during the process of embryo implantation and placenta formation and that factors in the crosstalk between the decidua and chorion may mediate decidual stem cell differentiation. This study analysed the phenotype of side population (SP) cells and investigated the clonogenicity and differentiation ability of SP cells in human decidua of early pregnancy. Serum-free culture-conditioned media of human decidua and chorion were obtained from decidua and chorion explant culture. Decidual SP cells were isolated by fluorescence-activated cell sorting. Different inducing media were added and the functional differentiation of decidual SP cells was examined. Decidual SP cells were negative for the mature decidual cell marker CD13 and prolactin and negative for CD34 and CD45 expression. Decidual SP cells formed clones after culture in colony-forming medium and they could form clones again. Differentiated cells expressing CD13 and prolactin were observed and stroma-like structures expressing CD13 were obtained. These results indicate that decidual SP cells are enriched for stem cell activity. Oestradiol, progesterone and factors in culture-conditioned media of human decidua and chorion induced their proliferation and differentiation.

Specific subsets of immune cells in human decidua differ between normal pregnancy and preeclampsia - a prospective observational study

BackgroundChanges in the balance of decidual leucocyte populations may lead to an unfavourable uterine microenvironment which may be associated with the development of preeclampsia (PE). In this study, we therefore investigated the leucocyte subpopulations in decidual tissues of 33 women with preeclampsia and 66 control patients.MethodsDecidua was either obtained via curettage during cesarean section or dissected from the surface of the basal plate of the placenta after spontaneous delivery. We used FACS analysis to quantify decidual leukocytes (CD45), NK cells (CD56+/CD16+ and CD56++/CD16-), antigen presenting cells (HLA-DR, DC-Sign, CD14) and T/B cells (CD8, CD4, alpha-beta-T-cell receptor, gamma-delta-T-cell receptor, CD25, CD19).ResultsThe number of decidual cytotoxic CD8+T-lymphocytes (P < 0.02), alpha-beta -T-cell receptor positive T cells (P < 0.03) and of CD56+/CD16+ NK cells (P < 0.03) was lower in decidua from women with PE than in decidua from control patients.ConclusionThe observed reduction of specific leucocyte subsets could create a microenvironment which is unfavourable for an appropriate placentation and could thereby be involved in the development of preeclamptic symptoms.

Identification and clonogenicity of side-population cells in human decidua of first trimester pregnancy

To explore the existence of side-population cells (SP cells) in human decidual tissues in early pregnancy, and its biological characteristics. Decidual cells were obtained by enzymatic digestion from the decidual tissues of human early pregnancy. The cells then were stained with Hoechst33342 dye either alone or in combination with verapamil. Fluorescence-activated cell sorter (FACS) analysis was used to identify and isolate SP cells. The isolated cells were cultured in conditioned media culture to observe the proliferation and ability to form colony. Stem cells were found in the decidual tissues of early pregnancy with a percentage of 0.78% +/- 0.71% (0% - 3.20%). These cells further proliferated and formed colonies during long-time culture in vitro. No significant statistical difference was found in contents of SP cells among different gestational week (P > 0.05). SP cells exist in human decidua that can further proliferate and have the clonogenicity in culture in vitro.