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Decidual Cells at Implantation
Abstracts / Placenta 57 (2017) 225e335
inflammation, which may exacerbate placental dysfunction and predispose to stillbirth. The profile of inflammatory cytokines released, particularly IL-1, suggests activation of the NLRP3 inflammasome as a potential underlying mechanism.[1] Girard et al, 2014, AJRI; 72: 422-434
http://dx.doi.org/10.1016/j.placenta.2017.07.049
S7.5. AN INFLAMMATORY ROLE FOR NOD1 IN DECIDUA AND PLACENTA OF NORMAL AND PREECLAMPTIC PREGNANCIES Lobke Gierman 1, Gabriela Silva 1, 2, Guro Johanne Rakner 1, 1, 2 3 2 Stødle , Mattijs Elschot , Unn Elin Dahlberg , Liv Cecilie Vestrheim Thomsen 1, 4, Line Bjørge 4, 5, Ann-Charlotte Iversen 1. 1 Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 2 St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 3 Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 4 Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway; 5 Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway Objectives: Inflammation at the maternal-fetal interface is part of normal pregnancy and further increased in preeclampsia (PE), but underlying mechanisms are largely unknown. Maternal-fetal interaction occurs at two sites; in the inner uterine wall layer (decidua) and at the fetal syncytiotrophoblast layer covering all placental structures. The intracellular pattern recognition receptor NOD1 is shown to be expressed in the decidua and placenta and can mount an inflammatory response to specific danger signals. The precise role of NOD1 during normal pregnancies and in the development of PE is unknown. This study aimed to characterize the expression and function of NOD1 in decidua and placenta of normal and preeclamptic pregnancies. Methods: Women with normal (n¼44) or preeclamptic pregnancies (n¼48) were included at delivery. Decidual samples from all, and placental samples from some (n¼4 normal pregnancies, n¼4 PE) of the pregnancies were analyzed for NOD1 expression by immunohistochemistry. For functional response, decidual and placental explants from normal term placentas (n¼5) were incubated with or without the specific NOD1-agonist iE-DAP (10mg/mL) and the NOD1-antagonist iE-lys (10mg/mL) for 24 hours. Cytokine responses (IL-6 and IL-8) were measured by ELISA. Results: NOD1 was strongly expressed by decidual trophoblasts and in the syncytiotrophoblast layer in both normal and preeclamptic pregnancies. The expression levels will be compared by quantitative analyses. NOD1 activation of decidual explants induced a significantly increased IL-8 response when compared to unstimulated explants, and activation of placental explants induced a significant upregulation of IL-6 and IL-8. The NOD1-antagonist iE-lys did not influence the release of IL-6 or IL-8. Conclusion: The NOD1 expression pattern points to the importance of this inflammatory mechanism for maternal and fetal interaction both in decidua and placenta. The inflammatory response to in vitro stimulation of NOD1 suggests a functional role in placental inflammation in normal and preeclamptic pregnancies. http://dx.doi.org/10.1016/j.placenta.2017.07.050
235
immunoprotective matrix that controls trophoblast invasion. Although decidualization of the endometrium is an evolutionarily conserved process in all mammals with invasive placentae, there are important inter-species difference. By contrast to the mouse, the window of implantation in the human endometrium is not dependent on a nidatory oestrogen surge nor is the decidual process triggered by an implanting embryo. Instead, this remodelling process is initiated in the human endometrium during the mid-luteal phase of the cycle in response to convergence of progesterone and cAMP signalling pathways and induction and activation of FOXO1, a core regulatory transcription factor of decidual cells. Here we show that FOXO1 also causes senescence of a subpopulation of decidualizing human endometrial stromal cells in an IL-8 dependent manner. Selective depletion or enrichment of this subpopulation revealed that decidual senescence drives a transient inflammatory response that mimics the nidatory oestrogen surge in mice. Further, senescent cells also prevent differentiation of endometrial mesenchymal stem cells in decidualizing cultures. As the cycle progresses, IL-15 activated uterine natural killer (uNK) cells selectively target and clear senescent decidual cells through granule exocytosis. These findings reveal that decidual senescence governs endometrial remodeling at embryo implantation, and suggest a critical role for uNK cells in maintaining cellular homeostasis in cycling endometrium. http://dx.doi.org/10.1016/j.placenta.2017.07.051
S8.2. HEMATOPOIESIS VASCULOGENESIS AND ANGIOGENESIS IN FIRST TRIMESTER PLACENTA John Aplin. Maternal and Fetal Health Centre, University of Manchester, Manchester, UK In the first weeks of gestation, rapid vasculogenesis and angiogenesis occur to populate the chorionic plate (CP) and villous tree with a rich network of vessels and cords. As vili grow and branches form, vasculogenesis continues to be detectable at villous tips in late first trimester. At the same time, in the superficial CP that abuts the capsular decidua, vessels regress from both the villi and the plate. Mid first trimester placenta contains morphologically identifiable sites of hematopoiesis both in the villous tree and the CP. These occur in clusters of villi that are rich in angiogenic cords and developing vessels, but other extensive and well vascularised parts of the villous tree lack them altogether. The foci comprise crypts containing close-packed cells, mostly erythroid, that indent the trophoblast layer and connect to channels that seem to feed the maturing blood cells into the vascular network. They display a discontinuous CD31+/CD34+ endothelium. CD34+ cells isolated from first trimester placenta can produce endothelium in vitro as VECAD+/CD31+ monolayers, with progressive appearance of both erythroid and myeloid cells. We hypothesise that a mesodermal precursor gives rise to haemogenic endothelium that in turn produces both fetal microvascular endothelium and blood cells. http://dx.doi.org/10.1016/j.placenta.2017.07.052
S8.3. HUMAN PLACENTAL MULTIPOTENT MESENCHYMAL STROMAL CELLS AND PLACENTAL ANGIOGENESIS Chie-Pein Chen. MacKay Memorial Hospital, Taipei, Taiwan
S8.1. DECIDUAL CELLS AT IMPLANTATION Jan Brosens. University of Warwick, Warwick, UK Decidualization denotes the transformation of endometrial stromal cells into specialized decidual cells, which form the nutritive and
Whether human placental multipotent mesenchymal stromal cells (PMSCs) have the endothelial cell differentiation capability and the angiogenesis-promoting potential through interaction with endothelial cells are not known. PMSCs can be isolated from term placenta. The PMSCs were positive for the multipotent mesenchymal stromal cell markers CD13, CD29, CD44, CD49e, CD54, CD73, CD90, CD105, CD166, Oct-4, and HLA-ABC. Flow cytometric analysis further showed these cells expressed CD146, SSEA-4, NG2, CD140a, and CD140b, but negative for the
inflammation, which may exacerbate placental dysfunction and predispose to stillbirth. The profile of inflammatory cytokines released, particularly IL-1, suggests activation of the NLRP3 inflammasome as a potential underlying mechanism.[1] Girard et al, 2014, AJRI; 72: 422-434
http://dx.doi.org/10.1016/j.placenta.2017.07.049
S7.5. AN INFLAMMATORY ROLE FOR NOD1 IN DECIDUA AND PLACENTA OF NORMAL AND PREECLAMPTIC PREGNANCIES Lobke Gierman 1, Gabriela Silva 1, 2, Guro Johanne Rakner 1, 1, 2 3 2 Stødle , Mattijs Elschot , Unn Elin Dahlberg , Liv Cecilie Vestrheim Thomsen 1, 4, Line Bjørge 4, 5, Ann-Charlotte Iversen 1. 1 Centre of Molecular Inflammation Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 2 St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; 3 Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; 4 Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway; 5 Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway Objectives: Inflammation at the maternal-fetal interface is part of normal pregnancy and further increased in preeclampsia (PE), but underlying mechanisms are largely unknown. Maternal-fetal interaction occurs at two sites; in the inner uterine wall layer (decidua) and at the fetal syncytiotrophoblast layer covering all placental structures. The intracellular pattern recognition receptor NOD1 is shown to be expressed in the decidua and placenta and can mount an inflammatory response to specific danger signals. The precise role of NOD1 during normal pregnancies and in the development of PE is unknown. This study aimed to characterize the expression and function of NOD1 in decidua and placenta of normal and preeclamptic pregnancies. Methods: Women with normal (n¼44) or preeclamptic pregnancies (n¼48) were included at delivery. Decidual samples from all, and placental samples from some (n¼4 normal pregnancies, n¼4 PE) of the pregnancies were analyzed for NOD1 expression by immunohistochemistry. For functional response, decidual and placental explants from normal term placentas (n¼5) were incubated with or without the specific NOD1-agonist iE-DAP (10mg/mL) and the NOD1-antagonist iE-lys (10mg/mL) for 24 hours. Cytokine responses (IL-6 and IL-8) were measured by ELISA. Results: NOD1 was strongly expressed by decidual trophoblasts and in the syncytiotrophoblast layer in both normal and preeclamptic pregnancies. The expression levels will be compared by quantitative analyses. NOD1 activation of decidual explants induced a significantly increased IL-8 response when compared to unstimulated explants, and activation of placental explants induced a significant upregulation of IL-6 and IL-8. The NOD1-antagonist iE-lys did not influence the release of IL-6 or IL-8. Conclusion: The NOD1 expression pattern points to the importance of this inflammatory mechanism for maternal and fetal interaction both in decidua and placenta. The inflammatory response to in vitro stimulation of NOD1 suggests a functional role in placental inflammation in normal and preeclamptic pregnancies. http://dx.doi.org/10.1016/j.placenta.2017.07.050
235
immunoprotective matrix that controls trophoblast invasion. Although decidualization of the endometrium is an evolutionarily conserved process in all mammals with invasive placentae, there are important inter-species difference. By contrast to the mouse, the window of implantation in the human endometrium is not dependent on a nidatory oestrogen surge nor is the decidual process triggered by an implanting embryo. Instead, this remodelling process is initiated in the human endometrium during the mid-luteal phase of the cycle in response to convergence of progesterone and cAMP signalling pathways and induction and activation of FOXO1, a core regulatory transcription factor of decidual cells. Here we show that FOXO1 also causes senescence of a subpopulation of decidualizing human endometrial stromal cells in an IL-8 dependent manner. Selective depletion or enrichment of this subpopulation revealed that decidual senescence drives a transient inflammatory response that mimics the nidatory oestrogen surge in mice. Further, senescent cells also prevent differentiation of endometrial mesenchymal stem cells in decidualizing cultures. As the cycle progresses, IL-15 activated uterine natural killer (uNK) cells selectively target and clear senescent decidual cells through granule exocytosis. These findings reveal that decidual senescence governs endometrial remodeling at embryo implantation, and suggest a critical role for uNK cells in maintaining cellular homeostasis in cycling endometrium. http://dx.doi.org/10.1016/j.placenta.2017.07.051
S8.2. HEMATOPOIESIS VASCULOGENESIS AND ANGIOGENESIS IN FIRST TRIMESTER PLACENTA John Aplin. Maternal and Fetal Health Centre, University of Manchester, Manchester, UK In the first weeks of gestation, rapid vasculogenesis and angiogenesis occur to populate the chorionic plate (CP) and villous tree with a rich network of vessels and cords. As vili grow and branches form, vasculogenesis continues to be detectable at villous tips in late first trimester. At the same time, in the superficial CP that abuts the capsular decidua, vessels regress from both the villi and the plate. Mid first trimester placenta contains morphologically identifiable sites of hematopoiesis both in the villous tree and the CP. These occur in clusters of villi that are rich in angiogenic cords and developing vessels, but other extensive and well vascularised parts of the villous tree lack them altogether. The foci comprise crypts containing close-packed cells, mostly erythroid, that indent the trophoblast layer and connect to channels that seem to feed the maturing blood cells into the vascular network. They display a discontinuous CD31+/CD34+ endothelium. CD34+ cells isolated from first trimester placenta can produce endothelium in vitro as VECAD+/CD31+ monolayers, with progressive appearance of both erythroid and myeloid cells. We hypothesise that a mesodermal precursor gives rise to haemogenic endothelium that in turn produces both fetal microvascular endothelium and blood cells. http://dx.doi.org/10.1016/j.placenta.2017.07.052
S8.3. HUMAN PLACENTAL MULTIPOTENT MESENCHYMAL STROMAL CELLS AND PLACENTAL ANGIOGENESIS Chie-Pein Chen. MacKay Memorial Hospital, Taipei, Taiwan
S8.1. DECIDUAL CELLS AT IMPLANTATION Jan Brosens. University of Warwick, Warwick, UK Decidualization denotes the transformation of endometrial stromal cells into specialized decidual cells, which form the nutritive and
Whether human placental multipotent mesenchymal stromal cells (PMSCs) have the endothelial cell differentiation capability and the angiogenesis-promoting potential through interaction with endothelial cells are not known. PMSCs can be isolated from term placenta. The PMSCs were positive for the multipotent mesenchymal stromal cell markers CD13, CD29, CD44, CD49e, CD54, CD73, CD90, CD105, CD166, Oct-4, and HLA-ABC. Flow cytometric analysis further showed these cells expressed CD146, SSEA-4, NG2, CD140a, and CD140b, but negative for the