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1. Integrin α4-positive human trophoblast progenitors: functional characterization and transcriptional regulation.

Author

Genbacev, O, Larocque, N, Ona, K, Prakobphol, A, Garrido-Gomez, T, Kapidzic, M, Bárcena, A, Gormley, Matthew, and Fisher, S

Subjects
GATA4, HMGA2, progenitor cells, self-renewal, smooth chorion, trophoblast, Cell Differentiation, Cell Line, Chorion, Coculture Techniques, Flow Cytometry, GATA4 Transcription Factor, Gene Expression Regulation, Developmental, HMGA2 Protein, Humans, Integrin alpha4, Regulatory Elements, Transcriptional, Trophoblasts
Abstract

STUDY QUESTION: What are the functional characteristics and transcriptional regulators of human trophoblast progenitor cells (TBPCs)? SUMMARY ANSWER: TBPC lines established from the human smooth chorion by cell sorting for integrin α4 expressed markers of stemness and trophoblast (TB) stage-specific antigens, invaded Matrigel substrates and contributed to the cytotrophoblasts (CTBs) layer of smooth chorion explants with high-mobility group protein HMGI-C (HMGA2) and transcription factor GATA-4 (GATA4) controlling their progenitor state and TB identity. WHAT IS KNOWN ALREADY: Previously, we reported the derivation of TBPC lines by trypsinization of colonies that formed in cultures of chorionic mesenchyme cells that were treated with an activin nodal inhibitor. Microarray analyses showed that, among integrins, α4 was most highly expressed, and identified HMGA2 and GATA4 as potential transcriptional regulators. STUDY DESIGN, SIZE, DURATION: The aim of this study was to streamline TBPC derivation across gestation. High-cell surface expression of integrin α4 enabled the use of a fluorescence-activated cell sorter (FACS) approach for TBPC isolation from the human smooth chorion (n = 6 lines). To confirm their TBPC identity, we profiled their expression of stemness and TB markers, and growth factor receptors. At a functional level, we assayed their invasive capacity (n = 3) and tropism for the CTB layer of the smooth chorion (n = 3). At a molecular level, we studied the roles of HMGA2 and GATA4. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Cells were enzymatically disassociated from the human smooth chorion across gestation. FACS was used to isolate the integrin α4-positive population. In total, we established six TBPC lines, two per trimester. Their identity was determined by immunolocalization of a suite of antigens. Function was assessed via Matrigel invasion and co-culture with explants of the human smooth chorion. An siRNA approach was used to down-regulate HMGA2 and GATA4 expression and the results were confirmed by immunoblotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses. The endpoints analyzed included proliferation, as determined by 5-bromo-2-deoxyuridine (BrDU) incorporation, and the expression of stage-specific antigens and hormones, as determined by qRT-PCR and immunostaining approaches. MAIN RESULTS AND THE ROLE OF CHANCE: As with the original cell lines, the progenitors expressed a combination of human embryonic stem cell and TB markers. Upon differentiation, they primarily formed CTBs, which were capable of Matrigel invasion. Co-culture of the cells with smooth chorion explants enabled their migration through the mesenchyme after which they intercalated within the chorionic CTB layer. Down-regulation of HMGA2 showed that this DNA-binding protein governed their self-renewal. Both HMGA2 and GATA4 had pleitropic effects on the cells progenitor state and TB identity. LIMITATIONS, REASONS FOR CAUTION: This study supported our hypothesis that TBPCs from the chorionic mesenchyme can contribute to the subpopulation of CTBs that reside in the smooth chorion. In the absence of in vivo data, which is difficult to obtain in humans, the results have the limitations common to all in vitro studies. WIDER IMPLICATIONS OF THE FINDINGS: The accepted view is that progenitors reside among the villous CTB subpopulation. Here, we show that TBPCs also reside in the mesenchymal layer of the smooth chorion throughout gestation. We theorize that they can contribute to the CTB layer in this region. This phenomenon may be particularly important in pathological situations when CTBs of the smooth chorion might provide a functional reserve for CTBs of the placenta proper. STUDY FUNDING/COMPETING INTERESTS: Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award P50HD055764. O.G., N.L., K.O., A.P., T.G.-G., M.K., A.B., M.G. have nothing to disclose. S.J.F. received licensing fees and royalties from SeraCare Life Sciences for trisomic TBPC lines that were derived according to the methods described in this manuscript. TRIAL REGISTRATION NUMBER: N/A.

Published
2016

3. Decidualization resistance in the origin of preeclampsia

Author

Garrido-Gomez T, Castillo-Marco N, Cordero T, and Simon C

Subjects
embryonic structures
Abstract

Preeclampsia (PE) is a major obstetric complication with short- and long-term life-threatening consequences for both mother and child. Shallow cytotrophoblast (CTB) invasion through the uterine decidua into the spiral arteries is implicated in the pathogenesis of preeclampsia, though the cause of deficient arterial invasion remains unknown. Research focused on the "soil"-the maternal decidua-highlights the importance of this poorly understood but influential uterine layer. Decidualization of endometrial cells regulates embryo invasion, which is essential for spiral artery remodeling and establishing the maternal-fetal interface. Exploration of the association between impaired decidualization and PE revealed suboptimal endometrial maturation and uNK cells present in the decidua before PE development. Further, decidualization defects in the endometrium of women with severe PE (sPE), characterized by impaired CTB invasion, were detected at the time of delivery and persisted 5 years after the affected pregnancy. Recently, a maternal deficiency of Annexin A2 (ANXA2) expression was found to influence aberrant decidualization and shallow CTB invasion, suggesting that decidualization resistance, defective endometrial cell differentiation during the menstrual cycle, could underly shallow trophoblast invasion and the poor establishment of the maternal-fetal interface. Based on these findings, the transcriptional signature in the endometrium that promotes decidualization deficiency could be detected before (or after) conception. This would serve to identify women at risk of developing sPE and aid the development of therapies focused on improving decidualization, perhaps also preventing severe PE. Here, we discuss decidualization deficiency as contributor to the pathogenesis of pregnancy disorders with particular attention to sPE. We also review current diagnostic strategies and discuss future directions in diagnostic methods based on decidualization.

Published
2022

5. Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia

Author

Garrido-Gomez T, Castillo-Marco N, Clemente-Ciscar M, Cordero T, Munoz-Blat I, Amadoz A, Jimenez-Almazan J, Monfort-Ortiz R, Climent R, Perales-Marin A, and Simon C

Subjects
Preeclampsia, chromosomes, decidua, defective decidualization, gene expression, hormonal receptor, human, human endometrium, medicine, transcriptomic fingerprint
Abstract

Background: Decidualization of the uterine mucosa drives the maternal adaptation to invasion by the placenta. Appropriate depth of placental invasion is needed to support a healthy pregnancy; shallow invasion is associated with the development of severe preeclampsia (sPE). Maternal contribution to sPE through failed decidualization is an important determinant of placental phenotype. However, the molecular mechanism underlying the in vivo defect linking decidualization to sPE is unknown. Methods: Global RNA sequencing was applied to obtain the transcriptomic profile of endometrial biopsies collected from nonpregnant women who suffer sPE in a previous pregnancy and women who did not develop this condition. Samples were randomized in two cohorts, the training and the test set, to identify the fingerprinting encoding defective decidualization in sPE and its subsequent validation. Gene Ontology enrichment and an interaction network were performed to deepen in pathways impaired by genetic dysregulation in sPE. Finally, the main modulators of decidualization, estrogen receptor 1 (ESR1) and progesterone receptor B (PGR-B), were assessed at the level of gene expression and protein abundance. Results: Here, we discover the footprint encoding this decidualization defect comprising 120 genes-using global gene expression profiling in decidua from women who developed sPE in a previous pregnancy. This signature allowed us to effectively segregate samples into sPE and control groups. ESR1 and PGR were highly interconnected with the dynamic network of the defective decidualization fingerprint. ESR1 and PGR-B gene expression and protein abundance were remarkably disrupted in sPE. Conclusions: Thus, the transcriptomic signature of impaired decidualization implicates dysregulated hormonal signaling in the decidual endometria in women who developed sPE. These findings reveal a potential footprint that could be leveraged for a preconception or early prenatal screening of sPE risk, thus improving prevention and early treatments. Funding: This work has been supported by the grant PI19/01659 (MCIU/AEI/FEDER, UE) from the Spanish Carlos III Institute awarded to TGG. NCM was supported by the PhD program FDGENT/2019/008 from the Spanish Generalitat Valenciana. IMB was supported by the PhD program PRE2019-090770 and funding was provided by the grant RTI2018-094946-B-100 (MCIU/AEI/FEDER, UE) from the Spanish Ministry of Science and Innovation with CS as principal investigator. This research was funded partially by Igenomix S.L.

Published
2021

6. Preeclampsia: a defect in decidualization is associated with deficiency of Annexin A2

Author

Garrido-Gomez T, Quinonero A, Dominguez F, Rubert L, Perales A, Hajjar K, and Simon C

Subjects
human endometrial stromal cells, ANXA2 deficiency, ANXA2-null mice, decidualization resistance, human endometrial stromal cells, placentation defect, severe preeclampsia, decidualization resistance, placentation, severe preeclampsia, ANXA2 deficiency, ANXA2-null mice
Abstract

BACKGROUND: Decidualization defects in the endometrium have been demonstrated at the time of delivery in women with severe preeclampsia (sPE) and linger for years, suggesting a maternal contribution to the pathogenesis of this condition. Global transcriptional profiling reveals alterations in gene expression, including downregulation of Annexin A2 (ANXA2) in sPE patients with decidualization resistance.; OBJECTIVE: We investigated the functional role of ANXA2 deficiency during endometrial decidualization and its potential contribution to shallow trophoblast invasion during implantation and subsequent placentation using in vitro and in vivo modeling.; STUDY DESIGN: ANXA2 gene and protein levels were assessed during in vitro decidualization of human endometrial stromal cells (hESCs) isolated from biopsies collected from women with previous severe preeclampsia (sPE) (n=5) or normal obstetric outcomes (n=5). Next, ANXA2 was inhibited with small interference RNA (siRNA) in control hESC cells isolated from endometrial biopsies (n=15) as an in vitro model to analyze decidualization defects at the morphological level as well as secretion of prolactin (PRL) and insulin-like growth binding protein-1 (IGFPB1). ANXA2-inhibited cells were used to evaluate motility and promotion of embryo invasion. Decidualization and placentation defects of ANXA2 deficiency were confirmed using an ANXA2-null mouse model.; RESULTS: ANXA2 gene and protein levels were downregulated during in vitro decidualization of hESCs from women with prior sPE compared to control individuals. To assess its role in the endometrial stroma, we inhibited ANXA2 expression and detected decidualization failure as evidenced by impaired morphological transformation, which was associated with altered actin polymerization and low PRL and IGFBP1 secretions. Functionally, in vitro models demonstrated that ANXA2 inhibition failed to support embryo invasion. This finding was corroborated by reduced trophoblast spreading through hESCs, lack of motility of these cells, and reduced trophoblast invasion in the presence of conditioned media from ANXA2-inhibited cells. Extending our discovery to an animal model, we detected that ANXA2-null mice have a functional deficiency in decidualization and placentation that impairs fetal growth as a feature associated with sPE.; CONCLUSIONS: Together, in vitro and in vivo results suggest that endometrial defects in ANXA2 expression impair decidualization of endometrial stromal cells as well as the uterine microenvironment that promotes embryo implantation and placentation. Our findings highlight the maternal contribution to the pathogenesis of sPE and suggest that evaluation of ANXA2 may provide a novel strategy to assess a woman's risk of developing this pathology and perhaps discover therapeutic interventions to improve decidualization. Copyright © 2019 Elsevier Inc. All rights reserved.

Published
2020

14. SESSION 17: STEM CELLS AND ART: A NEVER-ENDING STORY

Author

Pourret, E., primary, Assou, S., additional, Monzo, C., additional, Haouzi, D., additional, Dechaud, H., additional, Hamamah, S., additional, Capalbo, A., additional, Wright, G., additional, Elliott, T., additional, Ubaldi, F. M., additional, Rienzi, L., additional, Nagy, Z. P., additional, Gil-Sanchis, C., additional, Cervello, I., additional, Santamaria, X., additional, Mas, A., additional, Faus, A., additional, Garrido-Gomez, T., additional, Quinonero, A., additional, Pellicer, A., additional, Simon, C., additional, Katsiani, E., additional, Garas, A., additional, Skentou, C., additional, Tsezou, A., additional, Dafopoulos, K., additional, Messinis, I. E., additional, Barraud-Lange, V., additional, Firlej, V., additional, Lassale, B., additional, Fouchet, P., additional, and Wolf, J. P., additional

Published
2012
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15. ANDROLOGY

Author

Hu, J. C. Y., primary, Seo, B. K., additional, Neri, Q. V., additional, Rozenwaks, Z., additional, Palermo, G. D., additional, Fields, T., additional, Monahan, D., additional, Rosenwaks, Z., additional, Szkodziak, P., additional, Plewka, K., additional, Wozniak, S., additional, Czuczwar, P., additional, Mroczkowski, A., additional, Lorenzo Leon, C., additional, Hernandez, J., additional, Chinea Mendez, E., additional, Concepcion Lorenzo, C., additional, Sanabria Perez, V., additional, Puopolo, M., additional, Palumbo, A., additional, Toth, B., additional, Franz, C., additional, Montag, M., additional, Boing, A., additional, Strowitzki, T., additional, Nieuwland, R., additional, Griesinger, G., additional, Schultze-Mosgau, A., additional, Cordes, T., additional, Depenbusch, M., additional, Diedrich, K., additional, Vloeberghs, V., additional, Verheyen, G., additional, Camus, M., additional, Van de Velde, H., additional, Goossens, A., additional, Tournaye, H., additional, Coppola, G., additional, Di Caprio, G., additional, Wilding, M., additional, Ferraro, P., additional, Esposito, G., additional, Di Matteo, L., additional, Dale, R., additional, Dale, B., additional, Daoud, S., additional, Auger, J., additional, Wolf, J. P., additional, Dulioust, E., additional, Lafuente, R., additional, Lopez, G., additional, Brassesco, M., additional, Hamad, M., additional, Montenarh, M., additional, Hammadeh, M., additional, Robles, F., additional, Magli, M. C., additional, Crippa, A., additional, Pescatori, E., additional, Ferraretti, A. P., additional, Gianaroli, L., additional, Zahiri, M., additional, Movahedin, M., additional, Mowla, S. J., additional, Noruzinia, M., additional, Crivello, A. M., additional, Sermondade, N., additional, Dupont, C., additional, Hafhouf, E., additional, Cedrin-Durnerin, I., additional, Poncelet, C., additional, Benzacken, B., additional, Levy, R., additional, Sifer, C., additional, Ferfouri, F., additional, Boitrelle, F., additional, Clement, P., additional, Molina Gomes, D., additional, Bailly, M., additional, Selva, J., additional, Vialard, F., additional, Yaprak, E., additional, Basar, M., additional, Guzel, E., additional, Arda, O., additional, Irez, T., additional, Norambuena, P., additional, Krenkova, P., additional, Tuettelmann, F., additional, Kliesch, S., additional, Paulasova, P., additional, Stambergova, A., additional, Macek, M., additional, Rivera, R., additional, Garrido-Gomez, T., additional, Galletero, S., additional, Meseguer, M., additional, Dominguez, F., additional, Garrido, N., additional, Mallidis, C., additional, Sanchez, V., additional, Weigeng, L., additional, Redmann, K., additional, Wistuba, J., additional, Gross, P., additional, Wuebbelling, F., additional, Fallnich, C., additional, Burger, M., additional, Schlatt, S., additional, San Celestino Carchenilla, M., additional, Pacheco Castro, A., additional, Simon Sanjurjo, P., additional, Molinero Ballesteros, A., additional, Rubio Garcia, S., additional, Garcia Velasco, J. A., additional, Macanovic, B., additional, Otasevic, V., additional, Korac, A., additional, Vucetic, M., additional, Garalejic, E., additional, Ivanovic Burmazovic, I., additional, Filipovic, M. R., additional, Buzadzic, B., additional, Stancic, A., additional, Jankovic, A., additional, Velickovic, K., additional, Golic, I., additional, Markelic, M., additional, Korac, B., additional, Gosalvez, J., additional, Ruiz-Jorro, M., additional, Garcia-Ochoa, C., additional, Sachez-Martin, P., additional, Martinez-Moya, M., additional, Caballero, P., additional, Hasegawa, N., additional, Fukunaga, N., additional, Nagai, R., additional, Kitasaka, H., additional, Yoshimura, T., additional, Tamura, F., additional, Kato, M., additional, Nakayama, K., additional, Oono, H., additional, Kojima, E., additional, Yasue, K., additional, Watanabe, H., additional, Asano, E., additional, Hashiba, Y., additional, Asada, Y., additional, Das, M., additional, Al-Hathal, N., additional, San-Gabriel, M., additional, Phillips, S., additional, Kadoch, I. J., additional, Bissonnette, F., additional, Holzer, H., additional, Zini, A., additional, Zebitay, A. G., additional, Ocal, P., additional, Sahmay, S., additional, Karahuseyinoglu, S., additional, Usta, T., additional, Repping, S., additional, Silber, S., additional, Van Wely, M., additional, Datta, A., additional, Nayini, K., additional, Eapen, A., additional, Barlow, S., additional, Lockwood, G., additional, Tavares, R., additional, Baptista, M., additional, Publicover, S. J., additional, Ramalho-Santos, J., additional, Vaamonde, D., additional, Rodriguez, I., additional, Diaz, A., additional, Darr, C., additional, Chow, V., additional, Ma, S., additional, Smith, R., additional, Jeria, F., additional, Rivera, J., additional, Gabler, F., additional, Nicolai, H., additional, Cunha, M., additional, Viana, P., additional, Goncalves, A., additional, Silva, J., additional, Oliveira, C., additional, Teixeira da Silva, J., additional, Ferraz, L., additional, Madureira, C., additional, Doria, S., additional, Sousa, M., additional, Barros, A., additional, Herrero, M. B., additional, Delbes, G., additional, Troueng, E., additional, Chan, P. T. K., additional, Vingris, L., additional, Setti, A. S., additional, Braga, D. P. A. F., additional, Figueira, R. C. S., additional, Iaconelli, A., additional, Borges, E., additional, Sargin Oruc, A., additional, Gulerman, C., additional, Zeyrek, T., additional, Yilmaz, N., additional, Tuzcuoglu, D., additional, Cicek, N., additional, Scarselli, F., additional, Terribile, M., additional, Franco, G., additional, Zavaglia, D., additional, Dente, D., additional, Zazzaro, V., additional, Riccio, T., additional, Minasi, M. G., additional, Greco, E., additional, Cejudo-Roman, A., additional, Ravina, C. G., additional, Candenas, L., additional, Gallardo-Castro, M., additional, Martin-Lozano, D., additional, Fernandez-Sanchez, M., additional, Pinto, F. M., additional, Balasuriya, A., additional, Serhal, P., additional, Doshi, A., additional, Harper, J., additional, Romany, L., additional, Fernandez, J. L., additional, Pellicer, A., additional, Ribas-Maynou, J., additional, Garcia-Peiro, A., additional, Fernandez-Encinas, A., additional, Prada, E., additional, Jorda, I., additional, Cortes, P., additional, Llagostera, M., additional, Navarro, J., additional, Benet, J., additional, Kesici, H., additional, Cayli, S., additional, Erdemir, F., additional, Karaca, Z., additional, Aslan, H., additional, Ocakli, S., additional, Tas, U., additional, Ozdemir, A. A., additional, Aktas, R. G., additional, Tok, O. E., additional, Li, S., additional, Lu, C., additional, Hwu, Y., additional, Lee, R. K., additional, Landaburu, I., additional, Gonzalvo, M. C., additional, Clavero, A., additional, Ramirez, J. P., additional, Pedrinaci, S., additional, Serrano, M., additional, Montero, L., additional, Carrillo, S., additional, Weiss, J., additional, Ortiz, A. P., additional, Castilla, J. A., additional, Sahin, O., additional, Bakircioglu, E., additional, Serdarogullari, M., additional, Bayram, A., additional, Yayla, S., additional, Ulug, U., additional, Tosun, S. B., additional, Bahceci, M., additional, Yoon, S. Y., additional, Shin, D. H., additional, Shin, T. E., additional, Park, E. A., additional, Won, H. J., additional, Kim, Y. S., additional, Lee, W. S., additional, Yoon, T. K., additional, Lee, D. R., additional, Hattori, H., additional, Nakajo, Y., additional, Kyoya, T., additional, Kuchiki, M., additional, Kanto, S., additional, Kyono, K., additional, Park, M., additional, Park, M. R., additional, Lim, E. J., additional, Choi, Y., additional, Mitra, A., additional, Bhattacharya, J., additional, Kundu, A., additional, Mukhopadhaya, D., additional, Pal, M., additional, Enciso, M., additional, Alfarawati, S., additional, Wells, D., additional, Abad, C., additional, Amengual, M. J., additional, Esmaeili, V., additional, Safiri, M., additional, Shahverdi, A. H., additional, Alizadeh, A. R., additional, Ebrahimi, B., additional, Brucculeri, A. M., additional, Ruvolo, G., additional, Giovannelli, L., additional, Schillaci, R., additional, Cittadini, E., additional, Scaravelli, G., additional, Perino, A., additional, Cortes Gallego, S., additional, Gabriel Segovia, A., additional, Nunez Calonge, R., additional, Guijarro Ponce, A., additional, Ortega Lopez, L., additional, Caballero Peregrin, P., additional, Heindryckx, B., additional, Kashir, J., additional, Jones, C., additional, Mounce, G., additional, Ramadan, W. M., additional, Lemmon, B., additional, De Sutter, P., additional, Parrington, J., additional, Turner, K., additional, Child, T., additional, McVeigh, E., additional, Coward, K., additional, Tosun, S., additional, Ciray, N., additional, Saeidi, S., additional, Shapouri, F., additional, Hoseinifar, H., additional, Sabbaghian, M., additional, Pacey, A., additional, Aflatoonian, R., additional, Bosco, L., additional, Carrillo, L., additional, Pane, A., additional, Manno, M., additional, Roccheri, M. C., additional, Selles, E., additional, Garcia-Herrero, S., additional, Martinez, J. A., additional, Munoz, M., additional, Durmaz, A., additional, Dikmen, N., additional, Gunduz, C., additional, Tavmergen Goker, E., additional, Tavmergen, E., additional, Gozuacik, D., additional, Vatansever, H. S., additional, Kara, B., additional, Calimlioglu, N., additional, Yasar, P., additional, Semerci, B., additional, Baka, M., additional, Ozbilgin, K., additional, Karabulut, A., additional, Tekin, A., additional, Sabah, B., additional, Cottin, V., additional, Kottelat, D., additional, Fellmann, M., additional, Halm, S., additional, Rosenthaler, E., additional, Kisida, T., additional, Kojima, F., additional, Sakamoto, T., additional, Makutina, V. A., additional, Balezin, S. L., additional, Rosly, O. F., additional, Slishkina, T. V., additional, Hatzi, E., additional, Lazaros, L., additional, Xita, N., additional, Makrydimas, G., additional, Sofikitis, N., additional, Kaponis, A., additional, Stefos, T., additional, Zikopoulos, K., additional, Georgiou, I., additional, Hibi, H., additional, Ohori, T., additional, Sumitomo, M., additional, Anarte, C., additional, Calvo, I., additional, Domingo, A., additional, Presilla, N., additional, Aleman, M., additional, Bou, R., additional, Guardiola, F., additional, Agirregoikoa, J. A., additional, De Pablo, J. L., additional, Barrenetxea, G., additional, Zhylkova, I., additional, Feskov, O., additional, Feskova, I., additional, Zozulina, O., additional, Somova, O., additional, Nabi, A., additional, Khalili, M. A., additional, Roudbari, F., additional, Parmegiani, L., additional, Cognigni, G. E., additional, Bernardi, S., additional, Taraborrelli, S., additional, Troilo, E., additional, Ciampaglia, W., additional, Pocognoli, P., additional, Infante, F. E., additional, Tabarelli de fatis, C., additional, Arnone, A., additional, Maccarini, A. M., additional, Filicori, M., additional, Silva, L., additional, Oliveira, J. B. A., additional, Petersen, C. G., additional, Mauri, A. L., additional, Massaro, F. C., additional, Cavagna, M., additional, Baruffi, R. L. R., additional, Franco, J. G., additional, Fujii, Y., additional, Endou, Y., additional, Mtoyama, H., additional, Shokri, S., additional, and Aitken, R. J., additional

Published
2012
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16. The human periconceptional maternal-embryonic space in health and disease.

Author

Moreno I, Capalbo A, Mas A, Garrido-Gomez T, Roson B, Poli M, Dimitriadis E, Santamaria X, Vilella F, and Simon C

Subjects
Pregnancy, Female, Child, Infant, Newborn, Humans, Blastocyst, Placenta, Embryo Implantation, Endometrium
Abstract

Pregnancy is established during the periconceptional period as a continuum beginning with blastocyst attachment to the endometrial epithelial surface followed by embryo invasion and placenta formation. This period sets the foundation for the child and mother's health during pregnancy. Emerging evidence indicates that prevention of downstream pathologies in both the embryo/newborn and pregnant mother may be possible at this stage. In this review, we discuss current advances in the periconceptional space, including the preimplantation human embryo and maternal endometrium. We also discuss the role of the maternal decidua, the periconceptional maternal-embryonic interface, the dialogue between these elements, and the importance of the endometrial microbiome in the implantation process and pregnancy. Finally, we discuss the myometrium in the periconceptional space and review its role in determining pregnancy health.

Published
2023
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18. Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology.

Author

Garrido-Gomez T, Dominguez F, Quiñonero A, Diaz-Gimeno P, Kapidzic M, Gormley M, Ona K, Padilla-Iserte P, McMaster M, Genbacev O, Perales A, Fisher SJ, and Simón C

Subjects
Adult, Cells, Cultured, Decidua metabolism, Embryo Implantation, Endometrium metabolism, Female, Gene Expression Profiling, Gene Expression Regulation, Humans, Pre-Eclampsia pathology, Pregnancy, Pregnancy Trimester, First, Stromal Cells metabolism, Trophoblasts metabolism, Decidua pathology, Endometrium pathology, Pre-Eclampsia etiology, Stromal Cells pathology, Trophoblasts pathology
Abstract

In preeclampsia (PE), cytotrophoblast (CTB) invasion of the uterus and spiral arteries is often shallow. Thus, the placenta's role has been a focus. In this study, we tested the hypothesis that decidual defects are an important determinant of the placental phenotype. We isolated human endometrial stromal cells from nonpregnant donors with a previous pregnancy that was complicated by severe PE (sPE). Compared with control cells, they failed to decidualize in vitro as demonstrated by morphological criteria and the analysis of stage-specific antigens (i.e., IGFBP1, PRL). These results were bolstered by global transcriptional profiling data that showed they were transcriptionally inert. Additionally, we used laser microdissection to isolate the decidua from tissue sections of the maternal-fetal interface in sPE. Global transcriptional profiling revealed defects in gene expression. Also, decidual cells from patients with sPE, which dedifferentiated in vitro, failed to redecidualize in culture. Conditioned medium from these cells failed to support CTB invasion. To mimic aspects of the uterine environment in normal pregnancy, we added PRL and IGFBP1, which enhanced invasion. These data suggested that failed decidualization is an important contributor to down-regulated CTB invasion in sPE. Future studies will be aimed at determining whether this discovery has translational potential with regard to assessing a woman's risk of developing this pregnancy complication., Competing Interests: The authors declare no conflict of interest.

Published
2017
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19. Modeling human endometrial decidualization from the interaction between proteome and secretome.

Author

Garrido-Gomez T, Dominguez F, Lopez JA, Camafeita E, Quiñonero A, Martinez-Conejero JA, Pellicer A, Conesa A, and Simón C

Subjects
Adolescent, Adult, Biomarkers analysis, Blotting, Western, Case-Control Studies, Cell Shape, Cells, Cultured, Computational Biology, Culture Media, Conditioned, Cytokines metabolism, Decidua cytology, Electrophoresis, Polyacrylamide Gel, Endometrium cytology, Enzyme-Linked Immunosorbent Assay, Female, Humans, Models, Biological, Protein Processing, Post-Translational, Proteomics, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Stromal Cells physiology, Stromal Cells ultrastructure, Young Adult, Decidua physiology, Endometrium physiology, Proteome genetics
Abstract

Context: Decidualization of the human endometrium, which involves morphological and biochemical modifications of the endometrial stromal cells (ESCs), is a prerequisite for adequate trophoblast invasion and placenta formation., Objective: This study aims to investigate the proteome and secretome of in vitro decidualized ESCs. These data were combined with published genomic information and integrated to model the human decidualization interactome., Design: Prospective experimental case-control study., Setting: A private research foundation., Patients: Sixteen healthy volunteer ovum donors., Intervention: Endometrial samples were obtained, and ESCs were isolated and decidualized in vitro., Main Outcome Measures: Two-dimensional difference in-gel electrophoresis, matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry, Western blot, human protein cytokine array, ELISA, and bioinformatics analysis were performed., Results: The proteomic analysis revealed 60 differentially expressed proteins (36 over- and 24 underexpressed) in decidualized versus control ESCs, including known decidualization markers (cathepsin B) and new biomarkers (transglutaminase 2, peroxiredoxin 4, and the ACTB protein). In the secretomic analysis, a total of 13 secreted proteins (11 up- and 2 down-regulated) were identified, including well-recognized markers (IGF binding protein-1 and prolactin) and novel ones (myeloid progenitor inhibitory factor-1 and platelet endothelial cell adhesion molecule-1). These proteome/secretome profiles have been integrated into a decidualization interactome model., Conclusions: Proteomic and secretomic have been used as hypothesis-free approaches together with complex bioinformatics to model the human decidual interactome for the first time. We confirm previous knowledge, describe new molecules, and we have built up a model for human in vitro decidualization as invaluable tool for the diagnosis, therapy, and interpretation of biological phenomena.

Published
2011
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