|Year : 2018 | Volume
| Issue : 1 | Page : 1-7
Galectin-9 Promotes Human Trophoblast Cell Invasion through Matrix Metalloproteinase-2 and p38 Signaling Pathway
Feng-Run Sun1, Chun-Qing Chen1, Min Yu2, Song-Cun Wang1, Da-Jin Li1, Mei-Rong Du1
1 Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011; Key Lab of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai 200032; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China
2 IVF-ET Center, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China
|Date of Submission||19-Jan-2018|
|Date of Web Publication||21-May-2018|
Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011
Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011
Source of Support: None, Conflict of Interest: None
Objective: Adequate extravillous trophoblast (EVT) invasion plays a crucial role in the establishment of successful pregnancy. Insufficient trophoblast migration and invasion can result in defective placentation, which is associated with a number of clinical pathological conditions of pregnancy including spontaneous abortion and preeclampsia. Galectin-9 (Gal-9) has a wide variety of regulatory functions in innate and adaptive immunity during infection, tumor growth, and organ transplantation.
Methods: We utilized immortalized human first-trimester EVT cells (HTR8/SVneo) for our functional study. We examined the effects of Gal-9 on viability, proliferation, and invasion of HTR8/SVneo cells, as well as on matrix metalloproteinase-2 (MMP-2) production in HTR8/SVneo cells. Furthermore, we observed the effects of different MAPK-signaling pathway inhibitors on the stimulatory functions of Gal-9 on HTR8/SVneo cells' invasion.
Results: We verified the secretion of Gal-9 by trophoblasts and detected a correlation between low levels of Gal-9 and spontaneous abortion. Gal-9 promoted the invasion of HTR8/SVneo cells through its interaction with Tim-3, not CD44, and subsequently increased MMP-2 production. Blockade of p38 signaling pathway inhibited Gal-9 activities in HTR8/SVneo cells.
Conclusion: Gal-9 promotes human trophoblast cell invasion through MMP-2 and p38 signaling pathway in a Tim-3-dependent manner.
Keywords: Galectin-9; Invasion; Matrix Metalloproteinase-2; p38 Signaling Pathway; Trophoblast Cells
|How to cite this article:|
Sun FR, Chen CQ, Yu M, Wang SC, Li DJ, Du MR. Galectin-9 Promotes Human Trophoblast Cell Invasion through Matrix Metalloproteinase-2 and p38 Signaling Pathway. Reprod Dev Med 2018;2:1-7
|How to cite this URL:|
Sun FR, Chen CQ, Yu M, Wang SC, Li DJ, Du MR. Galectin-9 Promotes Human Trophoblast Cell Invasion through Matrix Metalloproteinase-2 and p38 Signaling Pathway. Reprod Dev Med [serial online] 2018 [cited 2020 Jun 5];2:1-7. Available from: http://www.repdevmed.org/text.asp?2018/2/1/1/232880
| Introduction|| |
The placenta is a highly specialized organ that possesses several important functions essential for a successful pregnancy. Extravillous trophoblasts (EVTs) are the main cell type involved in the placentation process. In the human placenta, cytotrophoblasts undergo an epithelial–mesenchymal transition and differentiate into EVTs, which in turn invade the underlying decidua and migrate into the uterine spiral arteriolar walls, remodeling the uterine vasculature. Trophoblast cells mediate interactions between the conceptus and the maternal environment for exchange of nutrients, gases, and waste products and the regulation of immune tolerance. Inadequate EVT invasion into the decidua and subsequent incomplete remodeling of the spiral arteries are closely associated with several pregnancy-associated diseases including spontaneous abortion, preeclampsia (PE), and intrauterine growth restriction.,
Due to the high proliferation, invasive properties, and the capacity to escape from immune attack, the placenta is regarded as a pseudomalignant type of tissue or a physiological metastasis. Like tumor invasion, matrix metalloproteinases (MMPs) play important roles in dissolving the extracellular matrix (ECM) and the surrounding tissue during EVT invasion. The biggest difference between trophoblast invasion and tumor cell invasion is that trophoblast invasion is temporally and locally controlled by hormones, cytokines, and functional cells at the maternal–fetal interface.
Galectin-9 (Gal-9), a member of the galectin family that is expressed on lymphocytes and other cell types, has a wide variety of regulatory functions in innate and adaptive immunity. Upon interaction with one of its receptors (e.g., Tim-3), Gal-9 terminates T helper 1 and T cytotoxic 1 cell responses by inducing immune cell apoptosis, which plays a critical role in regulating immune activities during infection, tumor growth, and organ transplantation. In contrast to its immunosuppressive activities in promoting tumor escape, Gal-9 is also associated with cancer cell aggregation, apoptosis, and invasion inhibition, and Gal-9 is found to be present in the spongiotrophoblast layer of the hemochorial placenta. However, the function of Gal-9 in placental development is poorly understood.
In the present study, we investigated whether Gal-9 plays a functional role in the biological behaviors of trophoblast related to placental development. We also used immortalized human first-trimester EVT cells (HTR8/SVneo) to perform functional studies. We first examined the effects of Gal-9 on viability and proliferation in HTR8/SVneo cells and then assessed the invasive properties of these cells, as well as on MMP-2 production. Furthermore, we observed the effects of different MAPK-signaling inhibitors on the stimulatory functions of Gal-9 on HTR8/SVneo cell invasion.
| Methods|| |
First-trimester (gestational age 6–12 weeks) human villous and decidual tissues were obtained from clinical miscarriages (diagnosed as recurrent spontaneous abortion, defined as twice or even more times of consecutive miscarriages, excluding genetic, anatomic, or endocrine abnormalities or infection, poor health habits, etc., n = 12) and normal pregnancies (terminated for nonmedical reasons, n = 21). The miscarried villous and decidual tissues were obtained right after they were identified. The use and collection of these samples were approved by the Human Research Ethics Committee of the Obstetrics and Gynecology Hospital of Fudan University (No. Kyy2016-4). All participants provided written informed consents. All the methods were carried out in accordance with the approved guidelines.
Human cell isolation and culture
Trophoblasts were obtained from the villous tissue of normal pregnancies. The villous tissue was cut and digested in Dulbecco Modified Eagle Medium (DMEM) with high glucose and supplemented with trypsin (0.25%) and DNase I (150 U/mL; Applichem, Saxony-Anhalt, Germany) and underwent discontinuous Percoll gradient centrifugation as previously described. This method generates a 95% purity of trophoblast cells (Cytokeratin 7+ HLA-G + Vimentin −).
HTR8/SVneo cells (ATCC, Virginia, USA) were grown in DMEM/Ham F12 medium supplemented with 10% fetal bovine serum (FBS), 100 U/mL penicillin, 100 μg/mL streptomycin, and 1 μg/mL amphotericin B at 37°C in 5% CO2.
HTR8/SVneo cells were cultured overnight in complete medium and further incubated in serum-free medium for 12 h, followed by treatment with a range of concentrations of Gal-9 (R&D Systems, MN, USA, 0, 10, 50, 100, 500, 1,000, and 2,500 ng/mL, as plasma Gal-9 concentration in normal early pregnant women was about 2,000 pg/mL, and the ED50 of Gal-9 to induce apoptosis of Jurkat [human acute T cell leukemia] cells was 1–5 μg/mL ) for 48 h. To some wells, 10 μg/mL anti-Tim-3 mAb (BioLegend, CA, USA), 10 μg/mL anti-Gal-9 mAb (BioLegend, CA, USA), 10 μg/mL anti-CD44 mAb (Thermo Scientific, CA, USA), JNK signaling pathway inhibitor SP600125 (30 μmol/L), p38 signaling pathway inhibitor SB202190 (30 μmol/L), AKT inhibitor GDC0068 (30 μmol/L), PI3K inhibitor LY294002 (50 μmol/L), or MEK1/2 inhibitor U0126 (30 μmol/L) was added.
Sections (5 μm) of paraffin-embedded first-trimester human villus and decidua were rehydrated in Tris-buffered saline and incubated with hydrogen peroxide and 1% bovine serum albumin to block endogenous peroxidase activity. Sections were incubated with rabbit antihuman Gal-9 antibody (0.5 mg/mL; Abcam, Cambridge, UK) overnight in a humidified chamber. After washing, sections were overlaid with poly-HRP anti-rabbit IgG (Golden Bridge International, Beijing, China). The reaction was developed with 3,3-diaminobenzidine, and sections were counterstained with hematoxylin.
Trophoblasts (2 × 105/well) were grown in 24-well plates for 24, 48, and 72 h. Supernatants from trophoblast cultures were collected, centrifuged at 2,000 g, and stored at −80°C. Thereafter, the secreted Gal-9 in the supernatants was quantified using a commercially available ELISA kit (R&D Systems, MN, USA) following the manufacturer's instructions.
Cell viability assay
HTR8/SVneo cells (1 × 105/well) were cultured in 96-well plates and treated with Gal-9 for 48 h as described above. Thereafter, 10 μL of CCK-8 (Dojindo, Kumamoto, Japan) was added to each well and incubated at 37°C for 0.5–4 h. The optical density at 450 nm was determined using an enzyme-linked immunosorbent assay reader (Molecular Devices, CA, USA) to measure cell viability.
Alexa Fluor 488-conjugated antihuman MMP-9 (Abcam, Cambridge, UK), phycoerythrin-conjugated antihuman MMP-2 (R&D Systems, MN, USA), and brilliant violet 421-conjugated antihuman Ki67 (BioLegend, CA, USA) were used. Cells were fixed and permeabilized using the Fix/Perm Kit (BioLegend, CA, USA). A minimum of 10,000 events were acquired using a CyAn ADP flow cytometer (Beckman-Coulter, CA, USA) and analyzed using FlowJo software (Tree Star, OR, USA).
Matrigel invasion assay
Cell culture inserts were precoated with Matrigel (Corning, NY, USA) and placed in a 24-well plate. HTR8/SVneo cells (2 × 105 in 200 μL of DMEM/Ham F12 with 10% FBS) were plated in the upper chamber. The lower chamber was filled with 500 μL of DMEM/Ham F12 with 10% FBS. Gla-9, anti-Tim-3 mAb, anti-CD44 mAb, anti-Gal-9 mAb, or signaling pathway inhibitors were added to the lower chamber as previously described, and the cells were incubated at 37°C for 48 h. Thereafter, the Matrigel and noninvading cells were removed from the upper surface of the filter by wiping with a cotton swab. The inserts were fixed and stained with hematoxylin. Cells were observed using an Olympus BX51tDP70 fluorescence microscope (Olympus, Tokyo, Japan). Cells that had migrated to the lower surface were counted at a magnification of 200. Each experiment was carried out in triplicate and repeated three times independently.
The significance of differences between two groups was determined by post hoc Dunnett t-test. Multiple groups were analyzed by one-way or two-way ANOVA with Bonferroni posttests using Prism Version 5 software (GraphPad, CA, USA). For all statistical tests, P < 0.05 was considered statistically significant.
| Results|| |
Gal-9 expression is decreased in tissues from human miscarriage
We first examined the expression of Gal-9 in villus and decidua tissues from human first-trimester pregnancy and determined whether there was a correlation between Gal-9 expression and pregnancy outcome. Compared with the healthy controls, the expression of Gal-9 was decreased in villus and decidual tissues from miscarriage, suggesting a correlation between low levels of Gal-9 and spontaneous abortion [Figure 1]a and [Figure S1].[Additional file 1] As the difference was more obvious in villus tissues, the Gal-9 secreted by trophoblast cells from normal pregnancy showed a time-dependent manner [Figure 1]b. As such, we suspected that Gal-9 is involved in placenta development and further promotes the maintenance of normal pregnancy.
|Figure 1: Gla-9 decrease is correlated with human miscarriage. (a) Immunohistochemical localization of Gal-9 in villous and decidual tissues from normal pregnancy (n = 15) and miscarriage. (n = 12). (b) The secretion of Gal-9 by trophoblasts at different culture times. Data represent the mean ± standard error of the mean of one representative experiment among three to five separate experiments. n = 9 trophoblasts in the first trimester of normal pregnancy. *P ≥ 0.05, P ≥ 0.01.|
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Gal-9 promotes the invasion of HTR8/SVneo cells
To investigate the potential role of Gal-9 in placenta development, we studied the effect of Gal-9 on the biological behaviors of HTR8/SVneo cells including viability (through CCK-8 assay), proliferation (assessed by the expression of Ki-67), and invasion (using Matrigel invasion assays). As shown in [Figure 2]a and [Figure 2]b, with a concentration range of 10–2,500 ng/mL, Gal-9 had no effect on the viability or proliferation of HTR8/SVneo cells. The number of cells penetrating through the polycarbonate membranes coated with Matrigel appeared to increase in a concentration-dependent manner with the Gal-9 dose [Figure 2]c and [Figure 2]d. However, administration of anti-Gal-9 mAb reversed the induction of HTR8/SVneo cell invasion by Gal-9 [Figure 2]e and [Figure 2]f.
|Figure 2: Gal-9 promotes invasion of HTR8/SVneo cells in a Tim-3-dependent manner. (a) HTR8/SVneo cells were seeded at 1 × 105 cells/100 μL in 96-well plates and treated with a range of concentrations of Gal-9 (0, 10, 50, 100, 500, 1,000, and 2,500 ng/mL) for 48 h. A commercial cell enumeration kit was used to analyze HTR8/SVneo cell viability. (b) Flow cytometric analysis assessing the expression of Ki67 by HTR8/SVneo cells treated with or without (Ctrl) Gal-9. (c and d) Matrigel invasion assays of HTR8/SVneo cells treated with different concentrations of Gal-9. The invasion index was calculated using the following formula: Invasion index = Mtest/Ntest ÷ Mcon/Ncon × 100, where Mtest represents the number of migrated cells under different Gal-9 treatments; Ntest represents the total number of cells subjected to the respective Gal-9 treatments; Mcon represents the number of migrated cells under the control treatment, and Ncon represents the number of total cells under the corresponding control treatment. Images are representative of six individual experiments. Data represent the mean ± standard error of the mean. *P ≥ 0.05, †P ≥ 0.01, ‡P ≥ 0.001. (e and f) Matrigel invasion assays of HTR8/SVneo cells treated with Gal-9 (1,000 ng/mL) in the presence or absence of anti-Gal-9, anti-CD44, or anti-Tim–3 mAbs. Images are representative of three individual experiments. Data represent the mean ± standard error of the mean. *P ≥ 0.001, compared with the control group. †P < 0.001, compared with the Gal-9 group.|
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Previous studies have indicated that the immunoregulatory effect of Gal-9 depends on its interaction with its receptor Tim-3 or CD44; therefore, we used anti-Tim-3 and anti-CD44 neutralizing antibodies to directly analyze the Gal-9 interaction with these receptors in HTR8/SVneo cells. We found that pretreatment with anti-Tim-3 mAb notably reversed the induction of HTR8/SVneo cells' invasion by Gal-9, whereas the anti-CD44 mAb had no effect on Gal-9-mediated invasion [Figure 2]e and [Figure 2]f. These observations indicted that this activity of Gal-9 was dependent on Tim-3, rather than CD44, in HTR8/SVneo cells.
Gal-9 increases MMP-2 production in HTR8/SVneo cells
MMP-2 and MMP-9 are two important gelatinases involved in the remodeling of the ECM during trophoblast invasion. The effects of Gal-9 on MMP-2 and MMP-9 expression were examined by flow cytometry. As shown in [Figure 3]a, [Figure 3]c, and [Figure 3]d, 1,000 ng/mL of Gal-9 increased the production of MMP-2 by HTR8/SVneo cells, which was reversed by the administration of the anti-Gal-9 mAb. However, Gal-9 had no effect on the expression of MMP-9 [Figure 3]b. We also observed that the increase of MMP-2 mediated by Gal-9 was dependent on Tim-3 [Figure 3]c and [Figure 3]d. Combined with the data presented in [Figure 2], these findings suggested that Gal-9-stimulated invasion of HTR8/SVneo cells was mediated by MMP-2 production in a Tim-3-dependent manner.
|Figure 3: Gal-9 increases the expression of MMP-2 by HTR8/SVneo cells. (a and b) Flow cytometric analysis (right) and quantitation (left) of MMP-2 (a) and MMP-2 production (b) by HTR8/SVneo cells after stimulation with or without Gal-9 (1,000 ng/mL) for 48 h. Flow cytometry plot is from one representative experiment. Data represent mean ± standard error of the mean. *P ≥ 0.001. (c and d) Flow cytometric analysis (d) and quantitation (c) of MMP-2 production by HTR8/SVneo cells after stimulation with or without Gal-9 (1,000 ng/mL) in the presence or absence of anti-Gal-9, anti-CD44, or anti-Tim–3 mAbs for 48 h. Flow cytometry plot is from one representative experiment. Data represent the mean ± standard error of the mean. *P ≥ 0.01, †P ≥ 0.001, compared with the control group. ‡P ≥ 0.01, compared with the Gal-9 group.|
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Blocking p38 signaling pathway inhibits Gal-9-stimulated invasion of HTR8/SVneo cells
To further investigate the signaling pathways involved in Gal-9-stimulated invasion of HTR8/SVneo cells, the effect of specific signal transduction inhibitors on HTR8/SVneo cell invasion was examined. The results showed that most signaling pathway inhibitors including U0126 (inhibitor of ERK1/2), LY294002 (inhibitor of PI3K), SP600125 (inhibitor of JNK), and GDC0068 (inhibitor of AKT) had no effect on Gal-9 mediated invasion. However, SB202190 (inhibitor of p38 mitogen-activated protein kinase) markedly reversed this effect [Figure 4]a and [Figure 4]b. In addition, treatment with SB202190 alone did not inhibit HTR8/SVneo cell invasion (data not shown), suggesting the inhibition of invasion caused by SB202190 was not due to its cytotoxic effect, but that it resulted in a reverse of the Gal-9-mediated activity.
|Figure 4: Blockade of p38 signaling inhibits Gal-9-stimulated invasion of HTR8/SVneo cells. (a and b) Matrigel invasion assays of HTR8/SVneo cells treated with Gal-9 (1,000 ng/mL) in the presence or absence of the specific signaling pathway inhibitors. Images are representative of three individual experiments. (c and d) Flow cytometric analysis (d) and quantitation (c) of MMP-2 production by HTR8/SVneo cells after stimulation with or without Gal-9 (1,000 ng/mL) in the presence or absence of the specific signaling pathway inhibitors for 48 h. The flow cytometry plot is from one representative experiment. Data represent the mean ± standard error of the mean. *P ≥ 0.01, †P ≥ 0.001, compared with the control group. ‡P < 0.001, compared with the Gal-9 group.|
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As Gal-9 promoted HTR8/SVneo cells' invasion through MMP-2 [Figure 3], we next analyzed whether interference with the p38 MAPK pathway also affected MMP-2 production by HTR8/SVneo cells. As shown in [Figure 4]c and [Figure 4]d, SB202190 suppressed the increase in MMP-2 induced by Gal-9, whereas U0126, LY294002, SP600125, and GDC0068 had no effect. These data indicated that Gal-9-stimulated invasion of HTR8/SVneo cells likely involved the p38 MAPK signaling pathway.
| Discussion|| |
Successful pregnancy relies on sufficient placental formation besides the maternal immune system tolerating the semi-allogeneic fetus. Adequate EVT invasion is a vital step in placental development, and inadequate EVT invasion is closely related to miscarriage and PE. As miscarriage is the most common complication of pregnancy, and PE is a leading cause of maternal and fetal morbidity and mortality, improving the biological function of trophoblasts is highly important and has raised the concerns of many scientists.
Our previous studies confirmed that Tim-3, a receptor of Gal-9, forms a negative feedback loop to inhibit TLR-triggered inflammatory responses in decidual stromal cells. Furthermore, co-expression of Tim-3 and PD-1 on decidual T cells results in a Th2-dominant milieu at the maternal–fetal interface.,, The Tim-3 pathway helps to maintain normal pregnancy; however, the function of Gal-9, the ligand of Tim-3, is poorly understood. Gal-9 was found to be present in the hemochorial placenta, and higher expression of Gal-9 was able to facilitate the Th1 and Th17 responses during pregnancy.,, Furthermore, another study revealed that Gal-9-expressing regulatory T cells play an important role in the maintenance of a healthy pregnancy. Thus, Gal-9 may serve various and possibly opposing roles. It has been reported that the expression of Gal-9 was abnormal from intrauterine growth-restriction trophoblast cells. In the present study, we found that the expression of Gal-9 was decreased in villus and decidual tissues from miscarriage. As such, we suspected that the high expression of Gal-9 might be important for the maintenance of a healthy pregnancy, as there was a correlation between low levels of Gal-9 and spontaneous abortion. In addition, given that targeting certain immune checkpoints is vital to the treatment of some tumors, it is important to consider their potential effects on reproduction.
As expected, though Gal-9 had no effect on the viability and proliferation of immortalized human first-trimester EVTs (HTR8/SVneo cells), it did promote the invasion of these cells, which is vital for placental formation. We further confirmed that the activity of Gal-9 in HTR8/SVneo cells was dependent on Tim-3, similar to most immune cells.
The MMP family is known to degrade nearly all components of the ECM. MMP-2 and MMP-9 mainly degrade collagen IV and a number of other ECM proteins, and their roles in placental invasion have been extensively studied. MMP-2 expression is directly linked to the invasion by EVTs, and dysfunction of MMP-2 is associated with hypertension, a failure to remodel spiral vessels, compromised trophoblast invasion, and PE. MMP-2 is the main gelatinase involved in the function of early first-trimester trophoblasts (6–8 weeks); thereafter, in late first-trimester trophoblasts (8–12 weeks), both MMP-2 and MMP-9 participate in trophoblast invasion. We found that Gal-9 could increase the production of MMP-2, but not MMP-9, by HTR8/SVneo cells. As such, low Gal-9 could be an early warning sign of adverse pregnancy outcome.
The p38 protein, a kinase belonging to the MAPK superfamily, modulates diverse cellular events and is of great importance for placental organogenesis, trophoblast proliferation, and invasion., ERK1/2, p38, and JNK are three key MAPK intermediaries, which function in parallel to one another. Blockade of p38 signaling inhibited Gal-9-mediated invasion and increased levels of MMP-2 in HTR8/SVneo cells. A similar phenomenon has been observed showing that an inhibitor of p38 signaling can block the effects of Gal-9 on dendritic cells,, suggesting that Gal-9 promotes the invasion of HTR8/SVneo cells through MMP-2 in a p38-dependent manner. Since Gal-9 has a critical regulatory role in immune cell function during pregnancy  and decidual immune cells are vital for the immune regulation of trophoblast invasion and remodeling of uterine spiral arteries, it is possible that the Gal-9 produced by trophoblasts also regulates placenta development by affecting the function of decidual immune cells.
In summary, we observed lower expression of Gal-9 in villus tissues from miscarriage. In addition, higher expression of Gal-9 during normal pregnancy promoted the invasion of HTR8/SVneo cells through MMP-2 in a p38-dependent manner [Figure 5]. However, the effects of Gal-9 on primary cells during pregnancy still require further study. Our data have expanded the regulatory function of the Tim-3/Gal-9 signaling pathway during maternal–fetal crosstalk and have provided a potential biomarker and/or therapeutic target for pregnancy-related diseases.
|Figure 5: Schematic diagram of Gal-9-mediated promotion of human trophoblast cell invasiveness. Trophoblast cells secrete Gal-9, which in turn interacts with its receptor Tim-3 in trophoblast cells. Interaction of Gal-9/Tim-3 activates the p38 signaling pathway, which stimulates the expression of MMP-2 and promotes the invasion of human trophoblast cells.|
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Supplementary information is linked to the online version of the paper on the Reproductive and Developmental Medicine website.
Financial support and sponsorship
We are grateful to all the members of our laboratory for their valuable support and hard work. This work was supported by the National Basic Research Program of China (2015CB943300 2017YFC1001400), the National Nature Science Foundation of China (81630036, 91542116, 31570920, 31700799), the Program of Shanghai Academic/Technology Research Leader (17XD1400900), Innovation-oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation (No. CX2017-0X), and the Shanghai Sailing Program (17YF1411600).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
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