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      Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology

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          Significance

          We provide evidence of a decidualization defect in the endometrium of women with severe preeclampsia (PE) that was detected at the time of delivery and persisted years after the affected pregnancy. We went on to link this defect to impaired cytotrophoblast invasion. The transcriptional signature of the defect could enable its detection before (or after) conception, which would aid the development of therapies focused on improving decidualization and perhaps preventing severe PE.

          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.

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          Circulating angiogenic factors and the risk of preeclampsia.

          Richard J. Levine, Sharon E. Maynard, Cong Qian … (2004)
          The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role. We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia. During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant. Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia. Copyright 2004 Massachusetts Medical Society
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            Cyclic decidualization of the human endometrium in reproductive health and failure.

            Birgit Gellersen, Jan J Brosens (2014)
            Decidualization denotes the transformation of endometrial stromal fibroblasts into specialized secretory decidual cells that provide a nutritive and immunoprivileged matrix essential for embryo implantation and placental development. In contrast to most mammals, decidualization of the human endometrium does not require embryo implantation. Instead, this process is driven by the postovulatory rise in progesterone levels and increasing local cAMP production. In response to falling progesterone levels, spontaneous decidualization causes menstrual shedding and cyclic regeneration of the endometrium. A growing body of evidence indicates that the shift from embryonic to maternal control of the decidual process represents a pivotal evolutionary adaptation to the challenge posed by invasive and chromosomally diverse human embryos. This concept is predicated on the ability of decidualizing stromal cells to respond to individual embryos in a manner that either promotes implantation and further development or facilitates early rejection. Furthermore, menstruation and cyclic regeneration involves stem cell recruitment and renders the endometrium intrinsically capable of adapting its decidual response to maximize reproductive success. Here we review the endocrine, paracrine, and autocrine cues that tightly govern this differentiation process. In response to activation of various signaling pathways and genome-wide chromatin remodeling, evolutionarily conserved transcriptional factors gain access to the decidua-specific regulatory circuitry. Once initiated, the decidual process is poised to transit through distinct phenotypic phases that underpin endometrial receptivity, embryo selection, and, ultimately, resolution of pregnancy. We discuss how disorders that subvert the programming, initiation, or progression of decidualization compromise reproductive health and predispose for pregnancy failure.
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              Purification, characterization, and in vitro differentiation of cytotrophoblasts from human term placentae.

              H J Kliman, J E Nestler, E Sermasi … (1986)
              Highly purified functional cytotrophoblasts have been prepared from human term placentae by adding a Percoll gradient centrifugation step to a standard trypsin-DNase dispersion method. The isolated mononuclear trophoblasts averaged 10 microns in diameter, with occasional cells measuring up to 20-30 microns. Viability was greater than 90%. Transmission electron microscopy revealed that the cells had fine structural features typical of trophoblasts. In contrast to syncytial trophoblasts of intact term placentae, these cells did not stain for hCG, human placental lactogen, pregnancy-specific beta 1-glycoprotein or low mol wt cytokeratins by immunoperoxidase methods. Endothelial cells, fibroblasts, or macrophages did not contaminate the purified cytotrophoblasts, as evidenced by the lack of immunoperoxidase staining with antibodies against vimentin or alpha 1-antichymotrypsin. The cells produced progesterone (1 ng/10(6) cells . 4 h), and progesterone synthesis was stimulated up to 8-fold in the presence of 25-hydroxycholesterol (20 micrograms/ml). They also produced estrogens (1360 pg/10(6) cells . 4 h) when supplied with androstenedione (1 ng/ml) as a precursor. When placed in culture, the cytotrophoblasts consistently formed aggregates, which subsequently transformed into syncytia within 24-48 h after plating. Time lapse cinematography revealed that this process occurred by cell fusion. The presumptive syncytial groups were proven to be true syncytia by microinjection of fluorescently labeled alpha-actinin, which diffused completely throughout the syncytial cytoplasm within 30 min. Immunoperoxidase staining of cultured trophoblasts between 3.5 and 72 h after plating revealed a progressive increase in cytoplasmic pregnancy-specific beta 1-glycoprotein, hCG, and human placental lactogen concomitant with increasing numbers of aggregates and syncytia. At all time points examined, occasional single cells positive for these markers were identified. RIA of the spent culture media for hCG revealed a significant increase in secreted hCG, paralleling the increase in hCG-positive cells and syncytia identified by immunoperoxidase methods. We conclude that human cytotrophoblasts differentiate in culture and fuse to form functional syncytiotrophoblasts.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Proc Natl Acad Sci U S A
                Journal ID (iso-abbrev): Proc. Natl. Acad. Sci. U.S.A
                Journal ID (hwp): pnas
                Journal ID (pmc): pnas
                Journal ID (publisher-id): PNAS
                Title: Proceedings of the National Academy of Sciences of the United States of America
                Publisher: National Academy of Sciences
                ISSN (Print): 0027-8424
                ISSN (Electronic): 1091-6490
                Publication date (Print): 3 October 2017
                Publication date (Electronic): 18 September 2017
                Publication date PMC-release: 18 September 2017
                Volume: 114
                Issue: 40
                Pages: E8468-E8477
                Affiliations
                [1] a Fundación Igenomix , 46980 Valencia, Spain;
                [2] bInstituto Universitario IVI, Instituto de Investigación Sanitaria Hospital Clinico de Valencia INCLIVA, 46010 Valencia, Spain;
                [3] cCenter for Reproductive Sciences, University of California, San Francisco , CA 94143;
                [4] dDepartment of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco , CA 94143;
                [5] eDepartment of Obstetrics and Gynecology, Hospital Universitario La Fe , 46026 Valencia, Spain;
                [6] fDepartment of Cell and Tissue Biology, University of California, San Francisco , CA 94143;
                [7] gDepartment of Obstetrics and Gynecology, School of Medicine, Valencia University , 46010 Valencia, Spain;
                [8] hThe Eli & Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco , CA 94143;
                [9] iDepartment of Anatomy, University of California, San Francisco , CA 94143;
                [10] jDepartment of Obstetrics and Gynecology, School of Medicine, Stanford University , Palo Alto, CA 94305
                Author notes
                2To whom correspondence may be addressed. Email: carlos.simon@ 123456igenomix.com or susan.fisher@ 123456ucsf.edu .

                Edited by R. Michael Roberts, University of Missouri-Columbia, Columbia, MO, and approved August 11, 2017 (received for review April 20, 2017)

                Author contributions: O.G., A.P., S.J.F., and C.S. designed research; T.G.-G., F.D., A.Q., M.K., K.O., P.P.-I., O.G., and A.P. performed research; P.D.-G. and M.G. contributed new reagents/analytic tools; T.G.-G., M.G., S.J.F., and C.S. analyzed data; P.P.-I. collected samples; and T.G.-G., M.M., S.J.F., and C.S. wrote the paper.

                1S.J.F. and C.S. contributed equally to this work.

                Author information
                http://orcid.org/0000-0001-7745-4850
                Article
                Accession ID: PMC5635883 Pmcid ID: PMC5635883 Pmc-uid ID: 5635883 Publisher ID: 201706546
                DOI: 10.1073/pnas.1706546114
                PMC ID: 5635883
                PubMed ID: 28923940
                SO-VID: c27e6e95-8e25-43cc-9628-9645c1d8da2f
                License:

                Freely available online through the PNAS open access option.

                History
                Page count
                Pages: 10
                Funding
                Funded by: HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) 100009633
                Award ID: R37 HD0762353
                Categories
                Subject: PNAS Plus
                Subject: Biological Sciences
                Subject: Medical Sciences
                Series title: PNAS Plus

                Keywords: decidua,preeclampsia,human endometrial stromal cells,cytotrophoblast,transcriptomics
                Data availability:
                Keywords: decidua, preeclampsia, human endometrial stromal cells, cytotrophoblast, transcriptomics

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