Reproduction depends on many factors, from gamete quality to placenta formation, to fetal development. The mTOR pathway is emerging as a major player that integrates several cellular processes in response to a variety of environmental cues that are relevant in many aspects of reproduction. This review provides a general overview, summarizing the involvement of the two mTOR complexes (mTORC1 and mTORC2) in integrating signaling pathways, sensing environmental status, and managing physiological processes inherent to successful reproductive outcomes and pluripotent stem cell function. As a well-known governor of multiple cellular functions, it is not surprising that mTOR has a key regulatory role in determining cell quiescence or differentiation. In the gonads mTOR helps maintain spermatogonial stem cell and follicle identity and tightly regulates differentiation in both systems to ensure proper gamete production. The mTOR pathway is also known to prevent premature follicle exhaustion, while also controlling the blood-testis barrier in the male gonad. In stem cells mTOR again seems to have a role in controlling both pluripotency and differentiation, mirrored by its in vivo roles in the embryo, notably in regulating diapause. Finally, although there are clearly more complex systems intertwined in placental function, mTOR seems to serve as an early checkpoint for development progression and successful implantation.
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Bibiana Correia, Maria Inês Sousa and Joao Ramalho-Santos
Guangdong Li, Xiuzhi Tian, Dongying Lv, Lu Zhang, Zhenzhen Zhang, Jing Wang, Minghui Yang, Jingli Tao, Teng Ma, Hao Wu, Pengyun Ji, Yingjie Wu, Zhengxing Lian, Wei Cui and Guoshi Liu
NLRP (NACHT, LRR and PYD domain-containing proteins) family plays pivotal roles in mammalian reproduction. Mutation of NLRP7 is often associated with human recurrent hydatidiform moles. Few studies regarding the functions of NLRP7 have been performed in other mammalian species rather than humans. In the current study, for the first time, the function of NLRP7 has been explored in ovine ovary. NLRP7 protein was mainly located in ovarian follicles and in in vitro pre-implantation embryos. To identify its origin, 763 bp partial CDS of NLRP7 deriving from sheep cumulus oocyte complexes (COCs) was cloned, it showed a great homology with Homo sapiens. The high levels of mRNA and protein of NLRP7 were steadily expressed in oocytes, parthenogenetic embryos or IVF embryos. NLRP7 knockdown by the combination of siRNA and shRNA jeopardized both the parthenogenetic and IVF embryo development. These results strongly suggest that NLRP7 plays an important role in ovine reproduction. The potential mechanisms of NLRP7 will be fully investigated in the future.
Jérôme Artus, Isabelle Hue and Herve Acloque
In ungulates, early embryonic development differs dramatically from that of mice and humans and is characterized by an extended period of pre- and peri-implantation development in utero. After hatching from the zona pellucida, the ungulate blastocyst will stay free in the uterus for many days before implanting within the uterine wall. During this protracted peri-implantation period, an intimate dialogue between the embryo and the uterus is established through a complex series of paracrine signals. The blastocyst elongates, leading to extreme growth of extra-embryonic tissues, and at the same time, the inner cell mass moves up into the trophoblast and evolves into the embryonic disc, which is directly exposed to molecules present in the uterine fluids.
In the peri-implantation period, uterine glands secrete a wide range of molecules, including enzymes, growth factors, adhesion proteins, cytokines, hormones, and nutrients like amino and fatty acids, which are collectively referred to as histotroph. The identification, role, and effects of these secretions on the biology of the conceptus are still being described; however, the studies that have been conducted to date have demonstrated that histotroph is essential for embryonic development and serves a critical function during the pre- and peri implantation periods.
Here, we present an overview of current knowledge on the molecular dialogue among embryonic, extraembryonic, and maternal tissues prior to implantation. Taken together, the body of work described here demonstrates the extent to which this dialogue enables the coordination of the development of the conceptus with respect to the establishment of embryonic and extra-embryonic tissues as well as in preparation for implantation.
H A Otun, B A Innes, G E Lash, B Schiessl, E Ball, R F Searle, S C Robson and J N Bulmer
Uterine spiral arteries undergo remodelling in normal pregnancy, with replacement of the musculoelastic arterial media by fibrinoid containing extravillous trophoblast cells. Deficient spiral artery remodelling is associated with several adverse pregnancy outcomes. Although there are distinct components of spiral artery remodelling, assessment is subjective and often based on an overall impression of morphology. We aimed to develop a quantitative approach for assessment of uterine spiral artery remodelling. Placental bed biopsies were immunostained using smooth muscle markers, digital images of spiral arteries were captured and Adobe Photoshop was used to analyse positive immunostaining. The method was then used to investigate variation in the same vessel at different levels within a paraffin block, and the effect of parity, pre-eclampsia or miscarriage on vascular smooth muscle cell content. Results were also compared with a more subjective morphology-based assessment system. There was good intra- and interobserver agreement and the method correlated well with the more subjective assessment system. There was an overall reduction in vascular smooth muscle, as detected by caldesmon 1 (h-caldesmon) immunopositivity, with increasing gestational age from 8 weeks to term. A previous pregnancy did not affect the amount of spiral artery smooth muscle. Comparison of pre-eclampsia and late miscarriage samples with controls of the appropriate gestational age demonstrated increased medial smooth muscle in pathological samples. This technique provides a simple, rapid, reproducible and inexpensive approach to quantitative assessment of spiral artery remodelling in normal and pathological human pregnancy, a process which although fundamental for successful pregnancy, is still incompletely understood.
Ekaterina A Malolina and Andrey Yu Kulibin
Sertoli cells (SCs) are supporting cells in the mammalian testis that proliferate throughout fetal and postnatal development but exit the cell cycle and differentiate at puberty. In our previous study, we isolated a population of highly proliferative Sertoli-like cells (SLCs) from the region of the adult mouse testis containing the rete testis and adjacent seminiferous tubules. Here RNA-seq of the adult SLC culture as well as qPCR analysis and immunofluorescence of the adult and immature (6 dpp) SLC cultures were performed that allowed us to identify SLC-specific genes, including Pax8, Cdh1, and Krt8. Using these, we found that SLCs are mostly localized in the rete testis epithelium; however, some contribution of transitional zones of seminiferous tubules could not be excluded. The main feature of SLCs indicating their relationship to SCs is DMRT1 expression. More than 40% of both adult and immature SLCs expressed DMRT1 at different levels in culture. Only rare DMRT1+ cells were detected in the adult rete testis, whereas more than 40% of cells were positively stained for DMRT1 in the immature rete testis. One more SC protein, AMH, was found in some rete cells of the immature testis. It was also demonstrated that SLCs expressed such SC genes as Nr5a1, Dhh, Gdnf, and Kitl and interacted with germ cells in 3D co-culture with immature testicular cells. All these similarities between SLCs and rete cells on one the hand and SCs on the other, suggest that rete cells could share a common origin with SCs.
Yingying Han, Shuhao Zhang, Haotong Zhuang, Sijie Fan, Jiayi Yang, Liwei Zhao, Weidong Bao, Fuli Gao, Haolin Zhang, Zhengrong Yuan and Qiang Weng
Adiponectin (ADIPOQ, encoded by Adipoq) is an important white adipose-derived adipokine linked to energy homeostasis and reproductive function. This study aims to reveal the expression and role of the adiponectin system in the ovaries under acute malnutrition. In this study, 48-h food deprivation significantly inhibited ovarian growth by suppressing cell proliferation and inducing cell apoptosis in the ovaries of gonadotrophin-primed immature mice. It was also accompanied by significantly decelerated basic metabolism (glucose, triacylglycerol and cholesterol), varied steroid hormones (follicle-stimulating hormone, luteinizing hormone and estradiol) and vanishment of the peri-ovarian fat. It is noteworthy that after acute fasting, the adiponectin levels in ovaries rather than in blood were significantly elevated. Immunohistochemical study demonstrated that adiponectin and its receptors (ADIPOR1 and ADIPOR2) primarily appeared in ovarian somatic and/or germ cells, and their protein expressions were upregulated in the ovaries from fasted mice. Further in vitro study verified that ADIPOR1/2 agonist obviously inhibited follicle-stimulating hormone-induced oocyte meiotic resumption, while the antagonist significantly enhanced the percentage of oocyte maturation in the absence of follicle-stimulating hormone. Furthermore, the build up of peri-ovarian fat under physiological status in mice showed a positive correlation with both the hypertrophy of adipocytes and growth of ovaries. Taken together, these findings indicate that the upregulation of the adiponectin system disturbs the normal female reproductive function under the malnutrition status, and it may be associated with the loss of peri-ovarian fat depots.
Roger G Gosden
Renjie Wang, Wei Pan, Lei Jin, Yuehan Li, Yudi Geng, Chun Gao, Gang Chen, Hui Wang, Ding Ma and Shujie Liao
Artificial intelligence (AI) has experienced rapid growth over the past few years, moving from the experimental to the implementation phase in various fields, including medicine. Advances in learning algorithms and theories, the availability of large datasets and improvements in computing power have contributed to breakthroughs in current AI applications. Machine learning (ML), a subset of AI, allows computers to detect patterns from large complex datasets automatically and uses these patterns to make predictions. AI is proving to be increasingly applicable to healthcare, and multiple machine learning techniques have been used to improve the performance of assisted reproductive technology (ART). Despite various challenges, the integration of AI and reproductive medicine is bound to give an essential direction to medical development in the future. In this review, we discuss the basic aspects of AI and machine learning, and we address the applications, potential limitations and challenges of AI. We also highlight the prospects and future directions in the context of reproductive medicine.
Huitao Li, Shiwen Liu, Siwen Wu, Linxi Li, Renshan Ge and C Yan Cheng
Recent studies have shown that the testis is producing several biologically active peptides, namely the F5- and the NC1-peptides from laminin-γ3 and collagen α3 (IV) chain, respectively, that promotes blood-testis barrier (BTB) remodeling and also elongated spermatid release at spermiation. Also the LG3/4/5-peptide from laminin-α2 chain also promotes BTB integrity which is likely being used for the assembly of a “new” BTB behind preleptotene spermatocytes under transport at the immunological barrier. These findings thus provides a new opportunity for investigators to better understand the biology of spermatogenesis. Herein, we briefly summarize these recent findings and provide a critique update and a hypothetical model which can serve as the framework for studies in the years to come.
Rebekka Einenkel, Katrin Regina Helene Packhäuser, Jens Ehrhardt, Anne Tüngler, Marek Zygmunt and Damián Oscar Muzzio
Alterations in the immunologic balance during pregnancy have been associated with poor pregnancy outcomes. The underlying mechanisms are complex and mouse models delivered valuable information on inflammatory imbalance in disturbed pregnancies and served as model to test potential anti-inflammatory therapies. CD83 is a transmembrane protein (mCD83) with a soluble form (sCD83) which possesses strong anti-inflammatory properties. During murine pregnancy, upregulated mCD83 expression induces sCD83 release after in vitro stimulation with LPS, phorbol myristate acetate (PMA) and ionomycin. The release mechanism of sCD83 and its control are yet to be elucidated. In this study, the expression of mCD83 and sCD83 has been extensively studied in the CBA/J × DBA/2J mouse model of pro-inflammatory-mediated pregnancy disturbances. mCD83 was higher expressed on splenic B cells, uterus-draining lymph nodes T cells and dendritic cells from mice with poor pregnancy outcome (PPOM) compared to mice with good pregnancy outcome (GPOM). PPOM, however, was accompanied by lower sCD83 serum levels. In vitro treatment of splenic B cells with progesterone led to a reduction of TIMP1 expression, mCD83 expression and sCD83 release, while TIMP1 treatment had a positive effect on sCD83 availability. These results suggest that tissue and matrix components are involved in the regulation of CD83 in murine pro-inflammatory pregnancies.