Novel role of human chorionic gonadotropin in differentiation of human cytotrophoblasts.

Shi, Qian; Lei, Zhenmin; Rao, Ch.V.; Lin, Jing

doi:10.1210/endo.132.3.7679981

Cited by 210 publications

(49 citation statements)

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“…In a second step, we analyzed whether CTB and STB exhibit physiological features similar to in vivo conditions [31,32,33]. Therefore, we compared the gene expression and secretion of human chorionic gonadotropin ( hCG ), human placental lactogen ( hPL ), and endoglin between CTB and STB.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we compared the gene expression and secretion of human chorionic gonadotropin ( hCG ), human placental lactogen ( hPL ), and endoglin between CTB and STB. The abundances of hCG and hPL were determined because it has been demonstrated that the expression of these genes increases with trophoblast differentiation and syncytium formation [31,33]. Endoglin is strongly expressed on the apical membrane of STB with a possible role in syncytial invasiveness and angiogenesis [32,34].…”

Section: Resultsmentioning

confidence: 99%

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Novel Insights into Concepts and Directionality of Maternal–Fetal Cholesterol Transfer across the Human Placenta

Kallol

Huang

Müller

et al. 2018

IJMS

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Cholesterol is indispensable for cellular membrane composition and function. It is also a precursor for the synthesis of steroid hormones, which promote, among others, the maturation of fetal organs. A role of the ATP-binding-cassette-transporter-A1 (ABCA1) in the transport of maternal cholesterol to the fetus was suggested by transferring cholesterol to apolipoprotein-A-1 (apo-A1), but the directionality of the apoA-1/ABCA1-dependent cholesterol transport remains unclear. We isolated primary trophoblasts from term placentae to test the hypotheses that (1) apoA-1/ABCA1 dispatches cholesterol mainly towards the fetus to support fetal developmental maturation at term, and (2) differentiated syncytiotrophoblasts (STB) exert higher cholesterol transport activity than undifferentiated cytotrophoblasts (CTB). As experimental models, we used (1) trophoblast monolayers grown on Transwell® system consisting of apical (maternal-like) and basal (fetal-like) compartments, and (2) trophoblasts grown on conventional culture plates at CTB and STB stages. Surprisingly, apoA-1-mediated cholesterol efflux operated almost exclusively at the apical-maternal side, where ABCA1 was also localized by immunofluorescence. We found greater cholesterol efflux capacity in STB, which was increased by liver-X-receptor agonist treatment and decreased by ABCA1 inhibition. We conclude that at term the apoA-1/ABCA1 pathway is rather involved in cholesterol transport to the mother than in transfer to the fully developed fetus.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Novel Insights into Concepts and Directionality of Maternal–Fetal Cholesterol Transfer across the Human Placenta

Kallol

Huang

Müller

et al. 2018

IJMS

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“…Some embryonic signals modulating this dialogue have been identified 7–9 . Among them, human chorionic gonadotrophin synthesized early by the trophoblast cells acts on the uterine environment via the luteinizing hormone/hCG receptor and exerts both autocrine effects, promoting differentiation 10 and migration of trophoblasts 11 , and paracrine effects on the maternal endometrium 12 . Another molecule identified in embryo culture media and supposed to be involved in the regulation of local maternal immune response is represented by sHLA-G 13 .…”

Section: Introductionmentioning

confidence: 99%

Secretome of in vitro cultured human embryos contains extracellular vesicles that are uptaken by the maternal side

Giacomini

Vago

Sánchez

et al. 2017

Sci Rep

119

135

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Communication between embryo and maternal endometrium occurs during a specific time frame in which implantation is possible. Here we demonstrate for the first time that conditioned media from non-manipulated human embryos cultured in vitro for 3 days or up to the blastocyst stage contain extracellular vesicles (EVs) with a diameter of 50 to 200 nm and bearing the traditional microvesicle and exosome marker proteins CD63, CD9 and ALIX. The embryonic origin of these EVs has been confirmed by the presence of stemness gene transcripts and their enrichment in the non-classical HLA-G protein. NANOG and POU5F1 transcripts were shown to be contained in vesicles deriving from embryos at different stages of development. In line with a higher detection rate of the HLA-G protein in blastocysts compared to cleavage stage embryos, a significantly higher amount of HLA-G was found in vesicles accumulated in spent media from day 3 to day 5 of development compared to those isolated from the earlier stage. Uptake of dye-labeled embryo-derived EVs by human primary endometrial epithelial and stromal cells was also demonstrated with a fluorescence intensity signal significantly higher for cells treated with vesicles derived from blastocysts. Based on these findings, EV exchange may be suggested as an emerging way of communication at the maternal-fetal interface.Since the first gestation reported in 1976 1 , more than five million pregnancies have been achieved worldwide by in vitro fertilization and its modifications, known generically as assisted reproductive technologies (ARTs). Currently, ART accounts for 1 to 3 percent of live births in the United States and Europe. Despite significant advances in the understanding of infertility mechanisms and the overcoming of many deficiencies in human fertility by evolving ART, the number of 'take-home' babies still remains low 2 . Research in this area is moving toward the improvement of success rates through a better understanding of embryo and uterine physiology 3 .Embryo implantation and consequent pregnancy is thought to involve a two-way communication between maternal uterus and the blastocyst, a dialogue whose success seems essential for the progression through the processes of embryo apposition, adhesion, attachment and penetration [4][5][6] . Some embryonic signals modulating this dialogue have been identified 7-9 . Among them, human chorionic gonadotrophin synthesized early by the trophoblast cells acts on the uterine environment via the luteinizing hormone/hCG receptor and exerts both autocrine effects, promoting differentiation 10 and migration of trophoblasts 11 , and paracrine effects on the maternal endometrium 12 . Another molecule identified in embryo culture media and supposed to be involved in the regulation of local maternal immune response is represented by sHLA-G 13 . HLA-G1/G5 protein expression has been detected in human preimplantation embryos in association with β2-microglobulin and the soluble spliced isoform has been proposed as a noninvasive tool for embryo select...

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“…The observation that CTBs and the STB layer express hCG and its receptor suggests that hCG may impose an autocrine and/or a paracrine effect on trophoblastic differentiation through cAMP and PKA (12). Shi et al (13) showed that inhibition of PKA by H89 blocks hCG-induced trophoblastic differentiation.…”

mentioning

confidence: 99%

A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGβ Expression and Cell Differentiation

Cheong

Wang

Chuang

et al. 2016

Molecular and Cellular Biology

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e Human chorionic gonadotropin (hCG) is composed of a common ␣ subunit and a placenta-specific ␤ subunit. Importantly, hCG is highly expressed in the differentiated and multinucleated syncytiotrophoblast, which is formed via trophoblast cell fusion and stimulated by cyclic AMP (cAMP). Although the ubiquitous activating protein 2 (AP2) transcription factors TFAP2A and TFAP2C may regulate hCG␤ expression, it remains unclear how cAMP stimulates placenta-specific hCG␤ gene expression and trophoblastic differentiation. Here we demonstrated that the placental transcription factor glial cells missing 1 (GCM1) binds to a highly conserved promoter region in all six hCG␤ paralogues by chromatin immunoprecipitation-on-chip (ChIPchip) analyses. We further showed that cAMP stimulates GCM1 and the CBP coactivator to activate the hCG␤ promoter through a GCM1-binding site (GBS1), which also constitutes a previously identified AP2 site. Given that TFAP2C may compete with GCM1 for GBS1, cAMP enhances the association between the hCG␤ promoter and GCM1 but not TFAP2C. Indeed, the hCGcAMP-protein kinase A (PKA) signaling pathway also stimulates Ser269 and Ser275 phosphorylation of GCM1, which recruits CBP to mediate GCM1 acetylation and stabilization. Consequently, hCG stimulates the expression of GCM1 target genes, including the fusogenic protein syncytin-1, to promote placental cell fusion. Our study reveals a positive feedback loop between GCM1 and hCG regulating placental hCG␤ expression and cell differentiation. Successful pregnancy requires a variety of hormones, growth factors, and cytokines to regulate uterine decidualization, embryo implantation, and pregnancy maintenance. For instance, progesterone and estrogen steroid hormones from the ovary prepare the uterine endometrium for embryo implantation. Human chorionic gonadotropin (hCG) is a critical hormone for pregnancy maintenance in humans. hCG is a glycoprotein hormone comprising ␣ and ␤ subunits. The hCG␣ subunit is shared with other glycoprotein hormones, including thyroid-stimulating hormone, follicle-stimulating hormone, and luteinizing hormone (LH), whereas the hCG␤ subunit is specifically expressed in placenta and is unique to hCG. While hCG␣ is encoded by a single gene on chromosome 6, hCG␤ can be encoded by a gene cluster of six (hCG␤1, -2, -3, -5, -7, and -8) paralogues on chromosome 19 (1). Recent studies have suggested that the expression of hCG␤5 and -8 may account for the majority of hCG␤ transcripts given that all hCG␤ paralogues share high sequence homology in their promoter regions (2, 3).hCG expression can be detected in early 6-to 8-cell embryos, and this may serve as an embryonic signal for the rendering of appropriate maternal physiology for pregnancy (1). After implantation, the serum hCG level increases dramatically as pregnancy proceeds, reaching its peak at 9 or 10 weeks of gestation, and then decreases and remains at ϳ20% of the peak value until term (4). One of the crucial hCG functions is to stimulate progesterone synthesis from the corpus luteu...

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Novel role of human chorionic gonadotropin in differentiation of human cytotrophoblasts.

Cited by 210 publications

References 0 publications

Novel Insights into Concepts and Directionality of Maternal–Fetal Cholesterol Transfer across the Human Placenta

Novel Insights into Concepts and Directionality of Maternal–Fetal Cholesterol Transfer across the Human Placenta

Secretome of in vitro cultured human embryos contains extracellular vesicles that are uptaken by the maternal side

A Positive Feedback Loop between Glial Cells Missing 1 and Human Chorionic Gonadotropin (hCG) Regulates Placental hCGβ Expression and Cell Differentiation

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