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- Author: Lin Chen x
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Division of Genetics, Institute of Clinical Medicine, Department of Economics, Institute of Molecular Medicine, Department of Obstetrics and Gynecology
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Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and its receptor genes (PROKR1 (PKR1) and PROKR2 (PKR2)) play an important role in human early pregnancy. We have previously shown that PROKR1 and PROKR2 are associated with recurrent miscarriage (RM) using the tag-SNP method. In this study, we aimed to identify PROKR1 and PROKR2 variants in idiopathic RM patients by genotyping of the entire coding regions. Peripheral blood DNA samples of 100 RM women and 100 controls were subjected to sequence the entire exons of PROKR1 and PROKR2. Significant non-synonymous variant genotypes present in the original 200 samples were further confirmed in the extended samples of 144 RM patients and 153 controls. Genetic variants that were over- or under-represented in the patients were ectopically expressed in HEK293 and JAR cells to investigate their effects on intracellular calcium influx, cell proliferation, cell invasion, cell–cell adhesion, and tube organization. We found that the allele and genotype frequencies of PROKR1 (I379V) and PROKR2 (V331M) were significantly increased in the normal control groups compared with idiopathic RM women (P<0.05). PROKR1 (I379V) and PROKR2 (V331M) decreased intracellular calcium influx but increased cell invasiveness (P<0.05), whereas cell proliferation, cell–cell adhesion, and tube organization were not significantly affected. In conclusion, PROKR1 (I379V) and PROKR2 (V331M) variants conferred lower risk for RM and may play protective roles in early pregnancy by altering calcium signaling and facilitating cell invasiveness.
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Recent studies have demonstrated that embryonic stem cells (ESCs) have an underdeveloped innate immune system, but the biological implications of this finding are poorly understood. In this study, we compared the responses of mouse ESCs (mESCs) and mESC differentiated fibroblasts (mESC-FBs) to tumor necrosis factor α (TNFα) and interferons (IFNs). Our data revealed that TNFα, IFNα, IFNβ, or IFNγ alone do not cause apparent effects on mESCs and mESC-FBs, but the combination of TNFα and IFNγ (TNFα/IFNγ) showed toxicity to mESC-FBs as indicated by cell cycle inhibition and reduced cell viability, correlating with the expression of inducible nitric oxide synthase (iNOS). However, none of these effects were observed in mESCs that were treated with TNFα/IFNγ. Furthermore, mESC-FBs, but not mESCs, are vulnerable to cytotoxicity resulting from lipopolysaccharide (LPS)-activated macrophages. The insensitivity of mESCs to cytotoxicity in all cases is correlated with their lack of responses to TNFα and IFNγ. Similar to mESCs, human ESCs (hESCs) and iPSCs (hiPSCs) do not respond to TNFα and are not susceptible to the cytotoxicity of TNFα, IFNβ, or IFNγ alone or in combination that significantly affects human foreskin fibroblast (hFBs) and Hela cells. However, unlike mESCs, hESCs and hiPSCs can respond to IFNγ, but this does not cause significant cytotoxicity in hESCs and hiPSCs. Our findings in both mouse and human PSCs together support the hypothesis that attenuated innate immune responses could be a protective mechanism that limits immunologic cytotoxicity resulting from inflammatory and immune responses.
Department of Physiology, Medical Research Center, Library, Nursing School of Jiujiang University, Medical College of Nanchang University, 461 Bayi Road, Donghu District, Nanchang 330006, People's Republic of China
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Tri-ortho-cresyl phosphate (TOCP) has been widely used as plasticizers, plastic softeners, and flame retardants in industry and reported to have a deleterious effect on the male reproductive system in animals besides delayed neurotoxicity. Our preliminary results found that TOCP could disrupt the seminiferous epithelium in the testis and inhibit spermatogenesis, but the precise mechanism is yet to be elucidated. This study shows that TOCP inhibited viability of rat spermatogonial stem cells in a dose-dependent manner. TOCP could not lead to cell cycle arrest in the cells; the mRNA levels of p21, p27, p53, and cyclin D1 in the cells were also not affected by TOCP. Meanwhile, TOCP did not induce apoptosis of rat spermatogonial stem cells. After treatment with TOCP, however, both LC3-II and the ratio of LC3-II/LC3-I were markedly increased; autophagy proteins ATG5 and beclin 1 were also increased after treatment with TOCP, indicating that TOCP could induce autophagy in the cells. Ultrastructural observation under the transmission electron microscopy indicated that autophagic vesicles in the cytoplasm containing extensively degraded organelles such as mitochondria and endoplasmic reticulum increased significantly after the cells were treated with TOCP. In summary, we have shown that TOCP can inhibit viability of rat spermatogonial stem cells and induce autophagy of the cells, without affecting cell cycle and apoptosis.
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Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, China
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Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
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In brief
The establishment and maintenance of embryo implantation and pregnancy require decidualization of endometrial stromal cells. This paper reveals that SHP2 ensures the correct subcellular localization of progesterone receptor, thereby safeguarding the process of decidualization.
Abstract
Decidualization is the process of conversion of endometrial stromal cells into decidual stromal cells, which is caused by progesterone production that begins during the luteal phase of the menstrual cycle and then increases throughout pregnancy dedicated to support embryonic development. Decidualization deficiency is closely associated with various pregnancy complications, such as recurrent miscarriage (RM). Here, we reported that Src-homology-2-containing phospho-tyrosine phosphatase (SHP2), a key regulator in the signal transduction process downstream of various receptors, plays an indispensable role in decidualization. SHP2 expression was upregulated during decidualization. SHP2 inhibitor RMC-4550 and shRNA-mediated SHP2 reduction resulted in a decreased level of phosphorylation of ERK and aberrant cytoplasmic localization of progesterone receptor (PR), coinciding with reduced expression of IGFBP1 and various other target genes of decidualization. Solely inhibiting ERK activity recapitulated these observations. Administration of RMC-4550 led to decidualization deficiency and embryo absorption in mice. Moreover, reduced expression of SHP2 was detected in the decidua of RM patients. Our results revealed that SHP2 is key to PR's nuclear localization, thereby indispensable for decidualization and that reduced expression of SHP2 might be engaged in the pathogenesis of RM.
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In brief
The impact of HVJ-E employed in mitochondrial replacement techniques (MRTs) on embryonic development remains uncertain. This study has exhibited the influence of HVJ-E utilized in MRTs on embryonic development and has devised a novel HVJ-E-induced fusion approach to curtail the amount of HVJ-E employed in MRTs.
Abstract
Mitochondrial replacement techniques (MRTs) provide a viable option for women carrying pathogenic mitochondrial DNA (mtDNA) variants to conceive disease-free offspring with a genetic connection. In comparison to electrofusion, HVJ-E-induced fusion has been identified as the most promising approach for clinical translation of MRTs due to its absence of electrical interference. However, despite confirmation of the absence of RNA activity in HVJ-E, a reduction in blastocyst quality has been observed in various MRTs studies utilizing the HVJ-E-induced fusion scheme. Recent investigations have revealed a dose-dependent elevation of reactive oxygen species (ROS) levels in various cancer cells incubated with HVJ-E. However, the impact of HVJ-E as a sole determinant on embryonic development in MRTs remains unverified. This investigation establishes that the augmented concentration of HVJ-E utilized in the conventional HVJ-E fusion protocol is an autonomous variable that influences embryonic development in MRTs. This effect may be attributed to amplified DNA damage resulting from heightened levels of ROS in reconstructed embryos. To mitigate the presence of HVJ-E in reconstructed zygotes while maintaining optimal fusion efficiency in MRTs, a novel HVJ-E-induced fusion approach was devised, namely, press-assisted fusion. This technique offers potential advantages in reducing detrimental factors that impede embryo development in MRTs.
Jiangxi Provincial Key Laboratory of Reproductive Physiology and Pathology, Nanchang, People’s Republic of China
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Nursing school of Jiujiang University, Jiujiang, People’s Republic of China
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Jiangxi Provincial Key Laboratory of Reproductive Physiology and Pathology, Nanchang, People’s Republic of China
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Tri-ortho-cresyl phosphate (TOCP) has been widely used as plasticizers, plastic softeners and flame-retardants in industry and reported to have male reproductive toxicology. However, it is still unknown whether TOCP affects the female reproductive system and its underlying mechanism. In the present study, we found that TOCP exposure significantly decreased ovarian coefficient, caused disintegration and depletion of the granulosa cells in the ovary tissue and significantly inhibited the level of serum estradiol (E2). TOCP markedly increased both LC3-II and the ratio of LC3-II/LC3-I as well as autophagy proteins ATG5 and Beclin1 in the ovary tissue, implying that TOCP could induce autophagy in the ovary tissue. To further investigate the potential mechanism, primary ovarian granulosa cells were isolated in vitro and treated with 0–0.5 mM TOCP for 48 h. We showed that TOCP decreased the number of viable mouse granulosa cells without affecting cell cycle and apoptosis of the cells. Intriguingly, TOCP treatment markedly increased both LC3-II and the ratio of LC3-II/LC3-I as well as ATG5 and Beclin1. Furthermore, transmission electron microscopy (TEM) showed that autophagic vesicles in the cytoplasm increased significantly in the TOCP-treated cells, indicating that TOCP could induce autophagy in the cells. Taken together, TOCP reduces the number of viable cells and induces autophagy in mouse ovarian granulosa cells without affecting cell cycle and apoptosis.
Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
Shanghai Municipal Key Clinical Specialty Project, Shanghai, China
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Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
Shanghai Municipal Key Clinical Specialty Project, Shanghai, China
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Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
Shanghai Municipal Key Clinical Specialty Project, Shanghai, China
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Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
Shanghai Municipal Key Clinical Specialty Project, Shanghai, China
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Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
Shanghai Municipal Key Clinical Specialty Project, Shanghai, China
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Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China
Shanghai Municipal Key Clinical Specialty Project, Shanghai, China
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Abnormal growth and migration of trophoblast cells is one of the main causes of spontaneous abortion. Eukaryotic translation initiation factor 5A (eIF5A) plays an important role in trophoblast cell growth and migration; however, its underlying mechanism remains largely unknown. Here, we first confirmed that eIF5A knockdown reduced human chorionic trophoblast HTR8 cells viability, proliferation, and migration. Next, we sought to systematically identify the genes regulated by eIF5A and observed changes in the transcriptome profile of eIF5A-knockdown HTR8 cells by RNA-seq analysis. Especially, we found that inhibition of eIF5A reduced both the mRNA and protein levels of methyltransferase-like protein 14 (METTL14). Furthermore, inhibition of METTL14 expression resulted in the reduction of viability, proliferation, and migration of HTR8 cells. In addition, we showed that overexpression of METTL14 rescued the effects of eIF5A knockdown in HTR8 cells. Finally, we revealed that eIF5A and METTL14 expression was decreased in spontaneous abortion samples compared to that in elective-induced abortion samples. Collectively, our study demonstrated that eIF5A plays a crucial role in HTR8 cells via modulation of METTL14 expression and may serve as a novel potential target for spontaneous abortion diagnosis and treatment.
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In brief
The regulatory role of BMP15 on porcine ovarian follicular development still remains unclear. This study reveals that biallelic editing of BMP15 impairs SMAD signaling and inhibits granulosa cell proliferation, resulting in porcine follicular development arrest and ovarian hypoplasia.
Abstract
Bone morphogenetic protein 15 (BMP15) is a member of the transforming growth factor beta (TGF-β) superfamily, which is critical for facilitating ovarian folliculogenesis in mono-ovulatory mammalian species but is not essential in polyovulatory mice. Our previously established BMP15-edited pigs presented varied female reproductive phenotypes, suggesting the important role of BMP15 in ovarian folliculogenesis in polyovulatory pigs. To understand the regulatory mechanism underlying the effect of BMP15 on porcine ovarian follicular development, we molecularly characterized infertile biallelic-BMP15-edited gilts with ovarian hypoplasia. We found that an absence of BMP15 proteins in biallelic-BMP15-edited gilts can lead to premature activation of primordial follicles, possibly through the upregulation of KITLG-KIT-PI3K-AKT signaling pathways. However, this absence severely impaired SMAD (Sma and Mad proteins from Caenorhabditis elegans and Drosophila, respectively) signaling, causing severely reduced granulosa cell proliferation, leading to the arrest of follicular development during the preantral stage and ovarian hypoplasia, resulting in complete infertility. Our study expands the understanding of the molecular functions of BMP15 in nonrodent polyovulatory mammals.
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NHC Key Laboratory of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, People’s Republic of China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China
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Department of Obstetrics, Hospital of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai, People’s Republic of China
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In brief
Autophagy is important for trophoblast cells at the maternal–fetal interface during early pregnancy. This study suggests that trophoblast cells can promote the autophagy under a regulation of the LPA/LPAR 1–NHE1 axis.
Abstract
The autophagy of trophoblasts is necessary for developing and maintaining a healthy pregnancy. Autophagy dysfunction in trophoblast cells is linked to recurrent spontaneous abortion (RSA). However, the mechanism underlying trophoblast autophagy is unknown. In this study, we investigated the expression of autophagy-related genes in both normal and RSA villi. We also examined the production of LPA and LPAR1 in trophoblast cells during early pregnancy. We found that the activation of the LPA–LPAR1 axis triggered the autophagy of trophoblast cells and increased the expression of NHE1. Inhibition of NHE1 suppressed the autophagy in trophoblast cells and we confirmed that NHE1 regulates LPA production in trophoblast cells. Additionally, we found decreased expression of autophagy-related genes and LPAR1 in villi from RSA patients. These observations indicate that the LPA/LPAR1–NHE1 axis regulates the autophagy of trophoblast cells during pregnancy. Insufficient autophagy and poor expression of LPAR1 in trophoblast cells may result in the dysfunction of the trophoblasts and an increased risk of spontaneous abortion. Overall, our research elucidated that a positive LPA/LPAR1–NHE1 axis can promote the autophagy of trophoblast cells and the abnormal axis leads to the autophagy deficiency of trophoblast cells in recurrent spontaneous abortion.
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MicroRNAs (miRNAs) are 18–24 nucleotides non-coding RNAs that regulate gene expression by post-transcriptional suppression of mRNA. The Chinese giant salamander (CGS, Andrias davidianus), which is an endangered species, has become one of the important models of animal evolution; however, no miRNA studies on this species have been conducted. In this study, two small RNA libraries of CGS ovary and testis were constructed using deep sequencing technology. A bioinformatics pipeline was developed to distinguish miRNA sequences from other classes of small RNAs represented in the sequencing data. We found that many miRNAs and other small RNAs such as piRNA and tsRNA were abundant in CGS tissue. A total of 757 and 756 unique miRNAs were annotated as miRNA candidates in the ovary and testis respectively. We identified 145 miRNAs in CGS ovary and 155 miRNAs in CGS testis that were homologous to those in Xenopus laevis ovary and testis respectively. Forty-five miRNAs were more highly expressed in ovary than in testis and 21 miRNAs were more highly expressed in testis than in ovary. The expression profiles of the selected miRNAs (miR-451, miR-10c, miR-101, miR-202, miR-7a and miR-499) had their own different roles in other eight tissues and different development stages of testis and ovary, suggesting that these miRNAs play vital regulatory roles in sexual differentiation, gametogenesis and development in CGS. To our knowledge, this is the first study to reveal miRNA profiles that are related to male and female CGS gonads and provide insights into sex differences in miRNA expression in CGS.
