Novel function of pregnancy-associated plasma protein A: promotes endometrium receptivity by up-regulating N-fucosylation

Objectives Early pregnancy loss is a major clinical concern in animal and human reproduction, which is largely influenced by embryo implantation. The importance of methionine for embryo implantation is widely neglected. Materials and methods We performed a series of experiments with primiparous rats fed diets containing different levels of methionine during early pregnancy to investigate the role of methionine in embryonic implantation and pregnancy outcomes, and used them to perform in vivo metabolic assessments and in vitro uterine explant culture. In addition, through transcriptome analysis and silencing the expression of cystathionine β‐synthase (CBS, the key enzyme in transsulfuration pathway) and cell adhesion assay, we measured signalling within Ishikawa, pTr and JAR cells. Results We determined the relevance and underlying mechanism of methionine on embryo implantation. We showed that methionine deprivation sharply decreased embryo implantation sites, expression of CBS and transsulfuration pathway end products, which were reversed by maternal methionine supplementation during early pregnancy. Moreover, we found CBS improved methionine‐mediated cell proliferation and DNA synthesis by CBS inhibition or interference. In addition, transcriptome analysis also revealed that CBS influenced the signalling pathway‐associated cell proliferation and DNA synthesis, as well as a correlation between CBS and methionine adenosyltransferase 2A (MAT2A), implying that MAT2A was possibly involved in cell proliferation and DNA synthesis. Further analysis revealed that MAT2A influenced S‐adenosylmethionine receptor SAMTOR expression, and SAMTOR activated mTORC1 and its downstream S6K1 and CAD, ultimately enhancing DNA synthesis in the embryo and uterus. Conclusions Taken together, these studies demonstrate that CBS and MAT2A improve methionine‐mediated DNA synthesis through SAMTOR/mTORC1/S6K1/CAD pathway during embryo implantation.

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“…Embryo adhesion was performed as previously described 27 with minor changes. Briefly, Ishikawa and JAR cells were grown on 6‐well plates.…”

Section: Methodsmentioning

confidence: 99%

CBS and MAT2A improve methionine‐mediated DNA synthesis through SAMTOR/mTORC1/S6K1/CAD pathway during embryo implantation

Cai

Zeng

et al. 2020

Cell Proliferation

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“…The dynamic changes of specific fucosyltransferases are closely correlated with reproduction function. Accumulated evidence shows that variations in the fucosyltransferase gene expression levels play an important role in determining the implantation at the fetal-maternal interface [49,50]. Downregulation of FUT4 by miR-200c impairs uterine receptivity formation [52].…”

Section: Discussionmentioning

confidence: 99%

poFUT1 promotes endometrial decidualization by enhancing the O-fucosylation of Notch1

et al. 2019

Self Cite

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Background Endometrial stromal cell decidualization is critical for embryo implantation. Dysfunctional decidualization leads to implantation failure, miscarriage and even pregnancy associated disorders in subsequent pregnancy trimesters. Protein glycosylation is involved in many physiological and pathological processes. Protein O-fucosyltransferase 1 (poFUT1) is the key enzyme for the O-fucosylation of proteins. However, the role and mechanism of poFUT1 in human endometrial stromal cell decidualization remain elusive. Methods We employed immunohistochemistry to detect the level of poFUT1 in the uterine endometrium from those of the proliferative phase, secretory phase, early pregnancy women and miscarriage patients. Using human endometrial stromal cells (hESCs) and a mouse model, the underlying mechanisms of poFUT1 in decidualization was investigated. Findings The level of poFUT1 was increased in the stromal cells of the secretory phase relative to those in the proliferative phase of the menstrual cycle, and decreased in the stromal cells of miscarriage patients compared to women with healthy early pregnancies. Furthermore, we found that poFUT1 promoted hESCs decidualization. The results also demonstrated that poFUT1 increased O-fucosylation on Notch1 in hESCs, which activated Notch1 signaling pathway. Activated Notch1 (NICD), as a specific trans-factor of PRL and IGFBP1 promoters, enhanced PRL and IGFBP1 transcriptional activity, thus inducing hESCs decidualization. Interpretation Level of poFUT1 is lower in the uterine endometrium from miscarriage patients than early pregnancy women. poFUT1 is critical in endometrial decidualization by controlling the O-fucosylation on Notch1. Our findings provide a new mechanism perspective on poFUT1 in uterine decidualization that may be a useful diagnostic and therapeutic target for miscarriage. Fund National Natural Science Foundation of China (31770857, 31670810 and 31870794). Liaoning Provincial Program for Top Discipline of Basic Medical Sciences.

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“…If a reliable marker can be used, as early as the embryonic stage for in vitro fertilization (IVF) cases, to predict the likelihood of such outcomes, then this process could be referred to as preimplantation prenatal screening (PPS). Pregnancyassociated plasma protein A (PAPP-A), predominantly produced by placental trophoblastic cells [1] and measured in maternal serum during the first trimester for clinical purposes, has been shown to be a potential predictor of adverse obstetric outcomes [2][3][4][5][6] such as spontaneous miscarriage, small for gestational age (SGA)/intrauterine growth restriction (IUGR), pre-eclampsia, and intrauterine fetal demise (IUFD) [1,7]. Furthermore, it has been suggested that a first trimester screening result of PAPP-A less than 0.4 multiples of the median (MoM) in chromosomally and morphologically healthy fetuses may correlate with placental-mediated pregnancy complications [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…PAPP-A is a 4 kilodalton dimeric metalloproteinase that regulates insulin-like growth factor (IGF)-I and IGF-II activity [10] and cleaves IGF-binding protein-4. Since the time that it was first detected in the serum plasma of pregnant women [11], maternal serum PAPP-A has been the subject of many publications, and investigators have studied the secretion of PAPP-A by trophoblastic cells as well [1,12]. Recent data suggest that low levels of PAPP-A in maternal serum is associated with abnormal placentation which may explain potential downstream maternal and fetal complications [13].…”

Section: Introductionmentioning

confidence: 99%

“…PAPP-A expressed in human villi tissues promotes the proliferation of trophoblast cells and cell adhesion in an autocrine manner in vitro [1,26]. Furthermore, in vivo, PAPP-A blockade via PAPP-A antibody injection into the uterine cavity suppressed the embryo implantation rate compared with an injection control group in a pregnant murine model [1]. The question has arisen as to whether PAPP-A is expressed at the blastocyst stage of embryonic development.…”

Section: Introductionmentioning

confidence: 99%

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The expression of pregnancy-associated plasma protein-A (PAPP-A) in human blastocoel fluid–conditioned media: a proof of concept study

Kavoussi

Chen

Wininger

et al. 2022

J Assist Reprod Genet

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Purpose The aim of this study was to determine if pregnancy-associated plasma protein-A (PAPP-A), typically measured in maternal serum and a potential predictor of adverse maternal and fetal outcomes such as spontaneous miscarriage, pre-eclampsia, and stillbirth, is expressed in blastocoel fluid–conditioned media (BFCM) at the embryonic blastocyst stage. Design This is an in vitro study. Methods BFCM samples from trophectoderm-tested euploid blastocysts (n = 80) from in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) patients were analyzed for PAPP-A mRNA. BFCM was obtained from blastocyst stage embryos in 20 uL drops. Blastocysts underwent trophectoderm biopsy for preimplantation genetic testing for aneuploidy prior to blastocyst vitrification and BFCM collection for snap freezing. cfDNA was synthesized using BFCM collected from 80 individual euploid blastocysts. Next, real-time qPCR was performed to detect expression of PAPP-A with GAPDH for normalization of expression in each sample. Results PAPP-A mRNA was detected in 45 of 80 BFCM samples (56.3%), with varying levels of expression across samples. Conclusion Our study demonstrates the expression of PAPP-A in BFCM. To our knowledge, this is the first study to report detection of PAPP-A mRNA in BFCM. Further studies are required and underway to investigate a greater number of BFCM samples as well as the possible correlation of PAPP-A expression with pregnancy outcomes of transferred euploid blastocysts. If found to predict IVF and obstetric outcomes, PAPP-A may provide additional information along with embryonic euploidy for the selection of the optimal blastocyst for embryo transfer.

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Novel function of pregnancy-associated plasma protein A: promotes endometrium receptivity by up-regulating N-fucosylation

Cited by 16 publications

References 53 publications

CBS and MAT2A improve methionine‐mediated DNA synthesis through SAMTOR/mTORC1/S6K1/CAD pathway during embryo implantation

CBS and MAT2A improve methionine‐mediated DNA synthesis through SAMTOR/mTORC1/S6K1/CAD pathway during embryo implantation

poFUT1 promotes endometrial decidualization by enhancing the O-fucosylation of Notch1

The expression of pregnancy-associated plasma protein-A (PAPP-A) in human blastocoel fluid–conditioned media: a proof of concept study

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