scholarly journals Evolution of Embryo Implantation Was Enabled by the Origin of Decidual Stromal Cells in Eutherian Mammals

2020 ◽  
Author(s):  
Arun R Chavan ◽  
Oliver W Griffith ◽  
Daniel J Stadtmauer ◽  
Jamie Maziarz ◽  
Mihaela Pavlicev ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Monodelphis Domestica ◽  
Dasypus Novemcinctus ◽  
Stem Lineage ◽  
Procavia Capensis ◽  
The Common ◽  
Embryo Attachment

Abstract Mammalian pregnancy evolved in the therian stem lineage, that is, before the common ancestor of marsupials and eutherian (placental) mammals. Ancestral therian pregnancy likely involved a brief phase of attachment between the fetal and maternal tissues followed by parturition—similar to the situation in most marsupials including the opossum. In all eutherians, however, embryo attachment is followed by implantation, allowing for a stable fetal–maternal interface and an extended gestation. Embryo attachment induces an attachment reaction in the uterus that is homologous to an inflammatory response. Here, we elucidate the evolutionary mechanism by which the ancestral inflammatory response was transformed into embryo implantation in the eutherian lineage. We performed a comparative uterine transcriptomic and immunohistochemical study of three eutherians, armadillo (Dasypus novemcinctus), hyrax (Procavia capensis), and rabbit (Oryctolagus cuniculus); and one marsupial, opossum (Monodelphis domestica). Our results suggest that in the eutherian lineage, the ancestral inflammatory response was domesticated by suppressing one of its modules detrimental to pregnancy, namely, neutrophil recruitment by cytokine IL17A. Further, we propose that this suppression was mediated by decidual stromal cells, a novel cell type in eutherian mammals. We tested a prediction of this model in vitro and showed that decidual stromal cells can suppress the production of IL17A from helper T cells. Together, these results provide a mechanistic understanding of early stages in the evolution of eutherian pregnancy.

scholarly journals Evolution of embryo implantation was enabled by the origin of decidual cells in eutherian mammals

2018 ◽  
Author(s):  
Arun R. Chavan ◽  
Oliver W. Griffith ◽  
Daniel Stadtmauer ◽  
Jamie Maziarz ◽  
Mihaela Pavlicev ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Neutrophil Infiltration ◽  
Monodelphis Domestica ◽  
Published Data ◽  
Ancestral State ◽  
Decidual Cells ◽  
Remodeling Of Extracellular Matrix

AbstractEmbryo implantation is the first step in the establishment of pregnancy in eutherian (Placental) mammals. Although viviparity evolved prior to the common ancestor of marsupials and eutherian mammals (therian ancestor), implantation is unique to eutherians. The ancestral therian pregnancy likely involved a short phase of attachment between the fetal and maternal tissues followed by parturition rather than implantation, similar to the mode of pregnancy found in marsupials such as the opossum. Embryo implantation in eutherian mammals as well as embryo attachment in opossum, induce a homologous inflammatory response in the uterus. Here, we elucidate the evolutionary mechanism by which the ancestral inflammatory fetal-maternal attachment was transformed into the process of implantation. We performed a comparative transcriptomic and immunohistochemical study of the gravid and non-gravid uteri of two eutherian mammals, armadillo (Dasypus novemcinctus) and hyrax (Procavia capensis); a marsupial outgroup, opossum (Monodelphis domestica); and compared it to previously published data on rabbit (Oryctolagus cuniculus). This taxon sampling allows inference of the eutherian ancestral state. Our results show that in the eutherian lineage, the ancestral inflammatory response was domesticated by suppressing a detrimental componentviz. signaling by the cytokine IL17A, while retaining components that are beneficial to placentation,viz. angiogenesis, vascular permeability, remodeling of extracellular matrix. IL17A mediates recruitment of neutrophils to inflamed mucosal tissues, which, if unchecked, can damage the uterus as well as the embryo and lead to expulsion of the fetus. We hypothesized that the uterine decidual stromal cells, which evolved coincidentally with embryo implantation, evolved, in part, to prevent IL17A-mediated neutrophil infiltration. We tested a prediction of this hypothesisin vitro, and showed that decidual stromal cells can suppress differentiation of human naïve T cells into IL17A-producing Th17 cells. Together, these results provide a mechanistic understanding of early stages of the evolution of the eutherian mode of pregnancy, and also identify a potentially ancestral function of an evolutionary novelty, the decidual stromal cell-type.

P–322 Addressing progesterone and cAMP signalling pathways for decidualization induction of endometrial stromal cells of patients with endometriosis

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
J Moyer ◽  
D Dunj. Baston-Buest ◽  
G Wennemuth ◽  
A Bielfeld ◽  
R Grümmer
Keyword(s):  
Stromal Cells ◽  
Day Treatment ◽  
Embryo Implantation ◽  
Flow Cytometric Analysis ◽  
Prolactin Secretion ◽  
In Vivo Model ◽  
Endometrial Stromal Cells ◽  
Simultaneous Application

Abstract Study question Which compounds/compound combinations are most effective in decidualization induction of endometrial stromal cells (ESCs) of patients with and without endometriosis? Summary answer Combination of compounds addressing different steps in the signalling cascade of decidualization induce decidualization more effectively than application of the individual compounds alone. What is known already Decidualization is the monthly recurring differentiation process of the ESCs in preparation for embryo implantation in human. Undifferentiated ESCs reveal an increased potential to proliferate and invade after retrograde menstruation. This may lead to the formation of ectopic lesions and the manifestation of the chronic gynaecological disease of endometriosis due to an impairment of the decidualization process. Study design, size, duration Compounds and compound combinations addressing the progesterone receptor- or the cAMP-mediated pathway were evaluated with regard to their own and their synergistic potential to induce decidualization of ESCs from women with (n = 10) and without (n = 10) endometriosis during a 6-day treatment. Participants/materials, setting, methods Human primary ESCs were isolated via enzymatic-mechanic digestion from eutopic endometrium from women with and without endometriosis and treated for 6 days in vitro with different progestins (progesterone, medoxyprogesterone acetate (MPA)), 8-Br-cAMP, forskolin, or phosphodiesterase (PDE)-inhibitor (Rolipram) alone or in combination. The degree of decidualization induction was quantified by morphological, biochemical (prolactin) and molecular (HAND2, FOXO1) parameters by means of ELISA, flow cytometric analysis, Realtime PCR and Western blot analysis. Main results and the role of chance After 6 days of treatment, decidualization was induced by forskolin as well as by 8-Br-cAMP whereas progestins or PDE alone hardly induced prolactin secretion by ESCs as a marker of decidualization. A change of morphology from undifferentiated fibroblast-like cells to rounded cells could be observed in parallel with the secretion of prolactin. Forskolin and 8-Br-cAMP-induced decidualization was significantly enhanced by MPA but not by progesterone. These effects were similar in ESCs from women with and without endometriosis. Moreover, forskolin-induced decidualization was significantly enhanced by simultaneous application of PDE. Interestingly, this effect was higher in cells of patients with endometriosis. An induction of decidualization in ESCs was associated with a parallel increase of the process-associated transcription factors HAND2 and FOXO1. This rise of transcription was markedly increased in combination with MPA but not with progesterone. Limitations, reasons for caution Endometrial tissue was obtained from women undergoing infertility treatment and thus may differ from the endometrium of fertile women. Results obtained from primary cells in vitro may not cover the in vivo situation in all respects. Wider implications of the findings: The results of this study provide baseline data for the development of a possible therapeutical approach to induce decidualization as a treatment option for endometriosis. Further research is required to determine the effectiveness of the in vitro tested compound combinations in an in vivo model. Trial registration number Not applicable

P-322 Addressing progesterone and cAMP signalling pathways for decidualization induction of endometrial stromal cells of patients with endometriosis

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
J Moyer ◽  
D Dunja Baston-Buest ◽  
G Wennemuth ◽  
A Bielfeld ◽  
R Grümmer
Keyword(s):  
Stromal Cells ◽  
Day Treatment ◽  
Embryo Implantation ◽  
Flow Cytometric Analysis ◽  
Prolactin Secretion ◽  
In Vivo Model ◽  
Endometrial Stromal Cells ◽  
Simultaneous Application

Abstract Study question Which compounds/compound combinations are most effective in decidualization induction of endometrial stromal cells (ESCs) of patients with and without endometriosis? Summary answer Combination of compounds addressing different steps in the signalling cascade of decidualization induce decidualization more effectively than application of the individual compounds alone. What is known already Decidualization is the monthly recurring differentiation process of the ESCs in preparation for embryo implantation in human. Undifferentiated ESCs reveal an increased potential to proliferate and invade after retrograde menstruation. This may lead to the formation of ectopic lesions and the manifestation of the chronic gynaecological disease of endometriosis due to an impairment of the decidualization process. Study design, size, duration Compounds and compound combinations addressing the progesterone receptor- or the cAMP-mediated pathway were evaluated with regard to their own and their synergistic potential to induce decidualization of ESCs from women with (n = 10) and without (n = 10) endometriosis during a 6-day treatment. Participants/materials, setting, methods Human primary ESCs were isolated via enzymatic-mechanic digestion from eutopic endometrium from women with and without endometriosis and treated for 6 days in vitro with different progestins (progesterone, medoxyprogesterone acetate (MPA)), 8-Br-cAMP, forskolin, or phosphodiesterase (PDE)-inhibitor (Rolipram) alone or in combination. The degree of decidualization induction was quantified by morphological, biochemical (prolactin) and molecular (HAND2, FOXO1) parameters by means of ELISA, flow cytometric analysis, Realtime PCR and Western blot analysis. Main results and the role of chance After 6 days of treatment, decidualization was induced by forskolin as well as by 8-Br-cAMP whereas progestins or PDE alone hardly induced prolactin secretion by ESCs as a marker of decidualization. A change of morphology from undifferentiated fibroblast-like cells to rounded cells could be observed in parallel with the secretion of prolactin. Forskolin and 8-Br-cAMP-induced decidualization was significantly enhanced by MPA but not by progesterone. These effects were similar in ESCs from women with and without endometriosis. Moreover, forskolin-induced decidualization was significantly enhanced by simultaneous application of PDE. Interestingly, this effect was higher in cells of patients with endometriosis. An induction of decidualization in ESCs was associated with a parallel increase of the process-associated transcription factors HAND2 and FOXO1. This rise of transcription was markedly increased in combination with MPA but not with progesterone. Limitations, reasons for caution Endometrial tissue was obtained from women undergoing infertility treatment and thus may differ from the endometrium of fertile women. Results obtained from primary cells in vitro may not cover the in vivo situation in all respects. Wider implications of the findings The results of this study provide baseline data for the development of a possible therapeutical approach to induce decidualization as a treatment option for endometriosis. Further research is required to determine the effectiveness of the in vitro tested compound combinations in an in vivo model. Trial registration number not applicable

scholarly journals HB-EGF regulates Prss56 expression during mouse decidualization via EGFR/ERK/EGR2 signaling pathway

2017 ◽  
Vol 234 (3) ◽  
pp. 247-254 ◽  
Author(s):  
Jie Liu ◽  
Fei Gao ◽  
Yue-Fang Liu ◽  
Hai-Ting Dou ◽  
Jia-Qi Yan ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Implantation Site ◽  
Mouse Uterus ◽  
Delayed Implantation ◽  
Initial Stage ◽  
And Function ◽  
Key Steps

Embryo implantation and decidualization are key steps for successful reproduction. Although numerous factors have been identified to be involved in embryo implantation and decidualization, the mechanisms underlying these processes are still unclear. Based on our preliminary data, Prss56, a trypsin-like serine protease, is strongly expressed at implantation site in mouse uterus. However, the expression, regulation and function of Prss56 during early pregnancy are still unknown. In mouse uterus, Prss56 is strongly expressed in the subluminal stromal cells at implantation site on day 5 of pregnancy compared to inter-implantation site. Under delayed implantation, Prss56 expression is undetected. After delayed implantation is activated by estrogen, Prss56 is obviously induced at implantation site. Under artificial decidualization, Prss56 signal is seen at the primary decidual zone at the initial stage of artificial decidualization. When stromal cells are induced for in vitro decidualization, Prss56 expression is significantly elevated. Dtprp expression under in vitro decidualization is suppressed by Prss56 siRNA. In cultured stromal cells, HB-EGF markedly stimulates Prss56 expression through EGFR/ERK pathway. Based on promoter analysis, we also showed that Egr2 is involved in Prss56 regulation by HB-EGF. Collectively, Prss56 expression at implantation site is modulated by HB-EGF/EGFR/ERK signaling pathway and involved in mouse decidualization.

266. Supressor of cytokine signalling 3 regulates IL-11 induced human endometrial stromal cell decidualization

2005 ◽  
Vol 17 (9) ◽  
pp. 109
Author(s):  
E. Dimitriadis ◽  
C. Stoikos ◽  
L. A. Salamonsen
Keyword(s):  
Stromal Cells ◽  
Embryo Implantation ◽  
Cellular Protein ◽  
Pcr Analysis ◽  
Cytokine Signaling ◽  
Pituitary Cells ◽  
Human Pituitary ◽  
Endometrial Stromal Cells ◽  
Socs3 Protein

Decidualization of endometrial stromal cells is critical for embryo implantation and establishment of pregnancy. Locally produced cytokines such as interleukin (IL)-11 enhance decidualization of human endometrial stromal cells (HESC). IL-11 signaling is negatively regulated by suppressor of cytokine signaling (SOCS) proteins. IL-11 stimulates SOCS3 in human pituitary cells. The aim of this study was to examine the role of SOCS3 on IL-11 induced HESC decidualization. Decidualization of HESC was assessed using an in vitro model in which estrogen (E)+progesterone (P) or cAMP was administered for 8 days to cells. Medium was collected for prolactin (PRL) assay (a decidual marker). Cellular protein was extracted for Western analysis and cellular RNA for real-time RT-PCR analysis. SOCS3 was overexpressed in HESC cells and the effect on decidualization assessed. HESC treated with E+P or cAMP secreted PRL from day 6. Treatment of HESC with E+P or cAMP increased the abundance of SOCS3 protein, coinciding with an increase in PRL secretion. cAMP maximally stimulated SOCS3 protein and mRNA during decidualization. Antiprogestin (onapristone) added to E+P or cAMP treated cells at day 6 reduced PRL secretion but had no influence on SOCS3 abundance suggesting that SOCS3 protein was not regulated via the P-receptor pathway. Addition of IL-11 to HESC increased SOCS3 abundance from 1 h. SOCS3 abundance returned to control levels following treatment of cells with IL-11 and IL-11 neutralising antibody. SOCS3 overexpression in HESC treated with cAMP reduced PRL secretion compared to mock- or non-transfected HESC. Furthermore, IL-11 mediated decidualization was diminished by SOCS3 overexpression. We have demonstrated for the first time that SOCS3 regulates IL-11 induced decidualization and that SOCS3 overexpression in HESC disrupts decidualization. This knowledge is important in understanding the mechanisms by which IL-11 promotes decidualization of HESC and thus the formation of decidua, an essential component of a functional placenta.

scholarly journals Decidual Differentiation of Stromal Cells Promotes Proprotein Convertase 5/6 Expression and Lefty Processing

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5313-5320 ◽  
Author(s):  
Meiyi Tang ◽  
Anatoly Mikhailik ◽  
Ilse Pauli ◽  
Linda C. Giudice ◽  
Asgerally T. Fazelabas ◽  
...  
Keyword(s):  
Estrous Cycle ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Fold Increase ◽  
Uterine Horn ◽  
Proprotein Convertase ◽  
Endometrial Stroma ◽  
Long Form

Lefty/Ebaf polypeptides, novel members of the TGF-β superfamily, are involved in endometrial differentiation and embryo implantation. Recently, we showed that, during undisturbed estrous cycle, lefty is present in mouse uterine horn primarily in a precursor form. Here, we show that decidual differentiation of endometrial stroma leads to increased lefty (∼3.1- to 3.6-fold in vivo and 5- to 8-fold in vitro) and processing of its precursor primarily to its long form. This event occurs on d 5 of pregnancy, and is paralleled by proprotein convertase (PC)5/6 up-regulation (∼6-fold increase for PC5A and 3-fold increase for PC5B) in decidualized uterine horn, independent of embryo implantation. Among the known convertases, only PC5/6A processes lefty to its long form. Taken together, the findings show that decidualized differentiation of stroma, which is a prerequisite for embryo implantation, leads to processing of lefty by PC5/6A.

scholarly journals Immunoregulation of the decidualization program: focus on the endoplasmic reticulum stress

Reproduction ◽  
2020 ◽  
Vol 159 (4) ◽  
pp. R203-R211 ◽  
Author(s):  
Elizabeth Soczewski ◽  
Esteban Grasso ◽  
Lucila Gallino ◽  
Vanesa Hauk ◽  
Laura Fernández ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Inflammatory Response ◽  
Er Stress ◽  
Stromal Cells ◽  
Pregnancy Loss ◽  
Recurrent Pregnancy Loss ◽  
Embryo Implantation ◽  
Endometrial Stromal Cells ◽  
Unfolded Protein ◽  
Protein Response

Decidualization denotes the reprogramming of endometrial stromal cells that includes the secretion of different mediators like cytokines, chemokines, and the selective recruitment of immune cells. This physiological process involves changes in the secretome of the endometrial stromal cells leading to the production of immunomodulatory factors. The increased amount of protein secretion is associated with a physiological endoplasmic reticulum (ER) stress and the resulting unfolded protein response (UPR), allowing the expansion of ER and the machinery to assist the protein folding. Notably, the signaling pathways involved in the ER stress and the UPR are interconnected with the onset of a sterile inflammatory response, as well as with angiogenesis. Both of these processes have a key role in decidualization and placentation, therefore, alterations in them could lead to pregnancy complications. In this review, we will discuss how the induction of ER stress and the UPR processes that accompanies the decidualization are associated with embryo implantation and whether they might condition pregnancy outcome. The ER stress activates/triggers sensing proteins which, among others, induces kinase/RNAse-TXNIP expression, activating the NLRP3 inflammasome. This multiprotein system allows caspase-1 activation, which catalyzes the cleavage of the inactive IL-1β proform toward the mature secretory form, with pro-implantatory effects. However, the sterile inflammatory response should be later controlled in favor of a tolerogenic microenvironment to sustain pregnancy. In accordance, alterations of the ER stress and UPR processes can be reflected in recurrent implantation failures (RIF), recurrent pregnancy loss (RPL), or complications associated with deficient placentation, such as preeclampsia (PE).

scholarly journals Cyclin G1 inhibits the proliferation of mouse endometrial stromal cell in decidualization

2017 ◽  
Vol 69 (1) ◽  
pp. 71-81
Author(s):  
Qian Xu ◽  
Dong-zhi Yuan ◽  
Sheng Zhang ◽  
Ting Qu ◽  
Shi-mao Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Embryo Implantation ◽  
Negative Regulator ◽  
Cell Cycle Regulators ◽  
Cyclin G1 ◽  
Decidual Cells

Uterine stromal cell decidualization is a dynamic physiological process in which cell proliferation, differentiation and apoptosis are orchestrated and occur in a temporal and cell-specific manner. This process is important for successful embryo implantation. Many cell-cycle regulators are involved in decidualization. The protein cyclin G1 is a unique regulator of the cell cycle with dual functions in cell proliferation. It was reported that cyclin G1 is expressed in mouse uterine stromal cells during the period of peri-implantation. To prove the function of cyclin G1 in mouse uterine stromal cells during this period, immunohistochemistry was used to stain mouse uterine tissues on days 4-8 of pregnancy. The results showed obvious spatial and temporal expression of cyclin G1 in uterine stromal cells, and that it is expressed in the cells of the primary decidual zone (PDZ) on day 5 and secondary decidual zone (SDZ) on days 6 and 7, when the stromal cells experienced active proliferation and differentiation was initiated. Applying the decidualization model of cultured primary stromal cells in vitro, we further revealed that the expression of cyclin G1 is associated with decidualization of stromal cells induced by medroxyprogesterone acetate (MPA) and estradiol-17? (E2). RNA interference was used for the knockdown of cyclin G1 in the induced decidual cells. Flow cytometry analysis indicated that the proportion of cells in the S stage was increased, and decreased in the G2/M phase. Our study indicates that cyclin G1, as a negative regulator of the cell cycle, plays an important role in the process of decidualization in mouse uterine stromal cells by inhibiting cell-cycle progression.

scholarly journals Endometrial pyruvate kinase M2 is essential for decidualization during early pregnancy

2020 ◽  
Vol 245 (3) ◽  
pp. 357-368 ◽  
Author(s):  
Yan Su ◽  
Sujuan Guo ◽  
Chunyan Liu ◽  
Na Li ◽  
Shuang Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pyruvate Kinase ◽  
Early Pregnancy ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Pyruvate Kinase M2 ◽  
Ishikawa Cells ◽  
Implantation Sites

Embryo implantation is essential for normal pregnancy. Decidualization is known to facilitate embryo implantation and maintain pregnancy. Uterine stromal cells undergo transformation into decidual cells after embryo attachment to the endometrium. Pyruvate kinase M2 (PKM2) is a rate limiting enzyme in the glycolysis process which catalyzes phosphoenolpyruvic acid into pyruvate. However, little is known regarding the role of PKM2 during endometrial decidualization. In this study, PKM2 was found to be mainly located in the uterine glandular epithelium and luminal epithelium on day 1 and day 4 of pregnancy and strongly expressed in the decidual zone after embryo implantation. PKM2 was dramatically increased with the onset of decidualization. Upon further exploration, PKM2 was found to be more highly expressed at the implantation sites than at the inter-implantation sites on days 5 to 7 of pregnancy. PKM2 expression was also significantly increased after artificial decidualization both in vivo and in vitro. After PKM2 expression was knocked down by siRNA, the number of embryo implantation sites in mice on day 7 of pregnancy was significantly reduced, and the decidualization markers BMP2 and Hoxa10 were also obviously downregulated in vivo and in vitro. Downregulated PKM2 could also compromise cell proliferation in primary endometrial stromal cells and in Ishikawa cells. The migration rate of Ishikawa cells was also obviously suppressed by si-PKM2 according to the wound healing assay. In conclusion, PKM2 might play an important role in decidualization during early pregnancy, and cell proliferation might be one pathway for PKM2 regulated decidualization.

scholarly journals Immunosuppressive Factor MNSFβ Regulates Cytokine Secretion by Mouse Lymphocytes and Is Involved in Interactions between the Mouse Embryo and Endometrial Cells In Vitro

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Yaping He ◽  
Zhaogui Sun ◽  
Yan Shi ◽  
Yahong Jiang ◽  
Zhefu Jia ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Embryo Implantation ◽  
Cytokine Secretion ◽  
Embryonic Cells ◽  
Suppressor Factor ◽  
Endometrial Stromal Cells ◽  
Endometrial Cells ◽  
Coculture Model ◽  
Mouse Lymphocytes

Immune tolerance at the fetomaternal interface must be established during the processes of implantation and pregnancy. Monoclonal nonspecific suppressor factor beta (MNSFβ) is a secreted protein that possesses antigen-nonspecific immune-suppressive function. It was previously reported that intrauterine immunoneutralization of MNSFβ significantly inhibited embryo implantation in mice. In the present study, MNSFβ protein expression was up- or downregulated by overexpression or RNA interference, respectively, in HCC-94 cells and the culture supernatants used to determine effects of MNSFβ on the secretion of IL-4 and TNFα from mouse lymphocytes as detected by ELISA. A coculture model of mouse embryos and endometrial stromal cells was also utilized to determine the effects of a specific anti-MNSFβ antibody on hatching and growth of embryos in vitro. The results show that MNSFβ induced secretion of IL-4 and inhibited secretion of TNFα from mouse lymphocytes. Following immunoneutralization of MNSFβ protein in the HCC-94 supernatant, the stimulatory effect of MNSFβ on IL-4 secretion from mouse lymphocytes was reduced, while the inhibitory effect on secretion of TNFα was abrogated. Expression of MNSFβ was detected in both embryonic and endometrial stromal cells, and its immunoneutralization inhibited the hatching and spreading of embryos in an in vitro coculture model. These results indicated that MNSFβ may play critical roles during the peri-implantation process by regulating cytokine secretion of lymphocytes and by mediating the crosstalk between embryonic cells and endometrial stromal cells.

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