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State-of-the-Art Molecular Reproduction in Japan

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Reproduction".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 26024

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Special Issue Editors

Prof. Dr. Kazuhiro Tamura

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Guest Editor

Department of Endocrine Pharmacology, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
Interests: endometriosis; endometrium; implantation; decidualization; placenta; cellular senescence; senolysis; prostaglandin; inflammation; hypertensive disorders of pregnancy
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Takeshi Kajihara

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Guest Editor

Department of Obstetrics and Gynecology, Saitama Medical University, Saitama 350-0495, Japan
Interests: reproduction; implantation; endometrium; decidualization; endometriosis; assisted reproductive technology

Special Issue Information

Dear Colleagues,

This Special Issue titled "State-of-the-Art Molecular Reproduction in Japan" is intended to provide an innovative and broad perspective on the research in Japan in the field of molecular reproductive biology and medicine, as well as reproductive and developmental biology. We kindly encourage our colleagues in Japan involved in all fields of molecular reproduction to make contributions to this Special Issue. High-quality review articles, research articles and communications are all welcomed. The potential topics include, but are not limited to:

Reproductive biology;
Reproductive immunology;
Reproductive medicine;
Reproductive endocrinology;
Molecular regulation of reproductive processes;
Embryo development;
New techniques and methods in reproductive biology;
Gametogenesis and fertilization.

Prof. Dr. Kazuhiro Tamura
Prof. Dr. Takeshi Kajihara
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

molecular reproduction
endometriosis
endometrium
implantation
decidualization
placenta
cellular senescence
senolysis
prostaglandin
inflammation
pregnancy
reproduction
implantation
decidualization
endometriosis
assisted reproductive technology
molecular reproductive biology
reproductive biology
reproductive immunology
reproductive medicine
reproductive endocrinology
molecular regulation of reproductive processes
embryo development
reproductive biology
gametogenesis and fertilization

Published Papers (10 papers)

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Research

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12 pages, 2175 KiB

Open AccessArticle

Pivotal Role of Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) in Uterine Leiomyoma

by Tomoo Suzuki, Yidan Dai, Masanori Ono, Junya Kojima, Toru Sasaki, Hiroshi Fujiwara, Naoaki Kuji and Hirotaka Nishi

Biomolecules 2023, 13(2), 193; https://doi.org/10.3390/biom13020193 - 18 Jan 2023

Viewed by 1978

Abstract

Uterine leiomyomas are smooth-muscle tumors originating in the myometrium and are the most common pelvic tumors in women of reproductive age. Symptomatic tumors may result in abnormal uterine bleeding, bladder dysfunction, pelvic discomfort, and reproductive issues, such as infertility and miscarriage. There are currently few non-invasive treatments for leiomyoma, but there are no practical early intervention or preventive methods. In this study, human uterine leiomyoma and myometrial tissues were used to detect the protein and mRNA expression levels of UCHL1. To explore the effects of UCHL1 knockdown and inhibition in leiomyoma and myometrial cells, we determined the mRNA expressions of COL1A1 and COL3A1. Collagen gel contraction and wound-healing assays were performed on myometrial and leiomyoma cells. We found that UCHL1 expression was considerably higher in uterine leiomyomas than in the myometrium. COL1A1 and COL3A1 expression levels were downregulated after inhibition of UCHL1 in human leiomyoma cells. Furthermore, the elimination of UCHL1 significantly decreased the migration and contractility of leiomyoma cells. In conclusion, these results indicate that UCHL1 is involved in the growth of leiomyoma in humans. For the treatment of uterine leiomyoma, targeting UCHL1 activity may be a unique and possible therapeutic strategy. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Reproduction in Japan)

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14 pages, 1025 KiB

Open AccessArticle

Calnexin Is Involved in Forskolin-Induced Syncytialization in Cytotrophoblast Model BeWo Cells

by Hitomi Matsukawa, Midori Ikezaki, Kaho Nishioka, Naoyuki Iwahashi, Masakazu Fujimoto, Kazuchika Nishitsuji, Yoshito Ihara and Kazuhiko Ino

Biomolecules 2022, 12(8), 1050; https://doi.org/10.3390/biom12081050 - 28 Jul 2022

Cited by 1 | Viewed by 1886

Abstract

Calnexin (CNX), a membrane-bound molecular chaperone, is involved in protein folding and quality control of nascent glycoproteins in the endoplasmic reticulum. We previously suggested critical roles of calreticulin, a functional paralogue of CNX, in placentation, including invasion of extravillous trophoblasts and syncytialization of cytotrophoblasts. However, the roles of CNX in placentation are unclear. In human choriocarcinoma BeWo cells, which serve as an experimental model of syncytialization, CNX knockdown suppressed forskolin-induced cell fusion and β-human chorionic gonadotropin (β-hCG) induction. Cell-surface luteinizing hormone/chorionic gonadotropin receptor, a β-hCG receptor, was significantly down-regulated in CNX-knockdown cells, which suggested the presence of a dysfunctional autocrine loop of β-hCG up-regulation. In this study, we also found abundant CNX expression in normal human placentas. Collectively, our results revealed the critical role of CNX in the syncytialization-related signaling in a villous trophoblast model and suggest a link between CNX expression and placenta development. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Reproduction in Japan)

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12 pages, 2883 KiB

Open AccessArticle

PGRMC1 Regulates Cellular Senescence via Modulating FOXO1 Expression in Decidualizing Endometrial Stromal Cells

by Atsuya Tsuru, Mikihiro Yoshie, Junya Kojima, Ryo Yonekawa, Mana Azumi, Kazuya Kusama, Hirotaka Nishi and Kazuhiro Tamura

Biomolecules 2022, 12(8), 1046; https://doi.org/10.3390/biom12081046 - 28 Jul 2022

Cited by 7 | Viewed by 1936

Abstract

The appropriate differentiation of endometrial stromal cells (ESCs) into decidual cells is required for embryo implantation and subsequent placentation into humans. Decidualization is accompanied by the appearance of senescent-like cells. We recently reported the secretory phase-specific downregulation of endometrial progesterone receptor membrane component 1 (PGRMC1) and enhanced decidualization upon PGRMC1 knockdown and inhibition in cultured ESCs. However, it remains unknown whether PGRMC1 is involved in cellular senescence during decidualization. Here, we showed that the small interfering RNA (siRNA)-mediated knockdown of PGRMC1 and the inhibition of PGRMC1 by AG-205 increased the expression of the transcription factor forkhead box protein O1 (FOXO1) and the senescence-associated β-galactosidase activity in cAMP analog- and progesterone-treated ESCs. Furthermore, the knockdown of FOXO1 repressed the decidual senescence induced by siRNA-based PGRMC1 knockdown or AG-205 treatment. Taken together, the decreased PGRMC1 expression in ESCs may accelerate decidualization and cellular senescence via the upregulation of FOXO1 expression for appropriate endometrial remodeling and embryo implantation during the secretory phase. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Reproduction in Japan)

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16 pages, 3158 KiB

Open AccessArticle

Notch Signaling Induced by Endoplasmic Reticulum Stress Regulates Cumulus-Oocyte Complex Expansion in Polycystic Ovary Syndrome

by Hiroshi Koike, Miyuki Harada, Akari Kusamoto, Chisato Kunitomi, Zixin Xu, Tsurugi Tanaka, Yoko Urata, Emi Nose, Nozomi Takahashi, Osamu Wada-Hiraike, Yasushi Hirota, Kaori Koga and Yutaka Osuga

Biomolecules 2022, 12(8), 1037; https://doi.org/10.3390/biom12081037 - 27 Jul 2022

Cited by 10 | Viewed by 2500

Abstract

Endoplasmic reticulum (ER) stress activated in granulosa cells contributes to the pathophysiology of polycystic ovary syndrome (PCOS). In addition, recent studies have demonstrated that Notch signaling plays multiple roles in the ovary via cell-to-cell interactions. We hypothesized that ER stress activated in granulosa cells of antral follicles in PCOS induces Notch signaling in these cells, and that activated Notch signaling induces aberrant cumulus-oocyte complex (COC) expansion. Expression of Notch2 and Notch-target transcription factors was increased in granulosa cells of PCOS patients and model mice. ER stress increased expression of Notch2 and Notch-target transcription factors in cultured human granulosa-lutein cells (GLCs). Inhibition of Notch signaling abrogated ER stress-induced expression of genes associated with COC expansion in cultured human GLCs, as well as ER stress-enhanced expansion of cumulus cells in cultured murine COCs. Furthermore, inhibition of Notch signaling reduced the areas of COCs in PCOS model mice with activated ER stress in the ovary, indicating that Notch signaling regulates COC expansion in vivo. Our findings suggest that Notch2 signaling is activated in granulosa cells in PCOS and regulates COC expansion. It remains to be elucidated whether aberrant COC expansion induced by the ER stress-Notch pathway is associated with ovulatory dysfunction in PCOS patients. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Reproduction in Japan)

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Graphical abstract

10 pages, 904 KiB

Open AccessArticle

Progesterone Suppresses Uterine Contraction by Reducing Odontogenic Porphyromonas gingivalis Induced Chronic Inflammation in Mice

by Yuko Teraoka, Jun Sugimoto, Haruhisa Konishi, Hiroshi Miyoshi, Hisako Furusho, Mutsumi Miyauchi, Shunichi Kajioka, Iemasa Koh and Yoshiki Kudo

Biomolecules 2022, 12(8), 1029; https://doi.org/10.3390/biom12081029 - 26 Jul 2022

Cited by 2 | Viewed by 1832

Abstract

Preterm birth is one of the most significant obstetric complications. Inflammation reportedly promotes uterine contraction and weakening of the fetal membrane, which induces preterm birth. Previous studies using animal models of lipopolysaccharide-induced acute inflammation have shown that progesterone (P4) promotes uterine quiescence. However, this effect is not fully understood in chronic inflammation. This study aimed to investigate the effects of P4 on uterine contractility and inflammation of the fetal membrane in mice infected with Porphyromonas gingivalis (P.g.), a major periodontal pathogen as a model of preterm birth caused by chronic inflammation. Mice were injected with 1 mg of P4 from day 15.5 to 17.5. P4 prolonged the mean gestation period of P.g mice from 18.3 to 20.4 days, and no reduction in the gestation period was observed. P4 treatment suppressed spontaneous uterine contractility and decreased oxytocin sensitivity. In addition, the expression of inflammatory cytokines in the fetal membrane was significantly reduced. Thus, P4 prevented preterm birth by suppressing enhanced uterine contractility induced by chronic inflammation in this model. This result describes the effects of P4 in a chronic inflammation model, which may lead to a better understanding of the efficacy of P4 in preventing preterm birth in humans. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Reproduction in Japan)

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16 pages, 2609 KiB

Open AccessEditor’s ChoiceArticle

Mitochondria Transfer from Adipose Stem Cells Improves the Developmental Potential of Cryopreserved Oocytes

by Udayanga Sanath Kankanam Gamage, Shu Hashimoto, Yuki Miyamoto, Tatsuya Nakano, Masaya Yamanaka, Akiko Koike, Manabu Satoh and Yoshiharu Morimoto

Biomolecules 2022, 12(7), 1008; https://doi.org/10.3390/biom12071008 - 21 Jul 2022

Cited by 4 | Viewed by 2354

Abstract

Although it is not a well-established technology, oocyte cryopreservation is becoming prevalent in assisted reproductive technologies in response to the growing demands of patients’ sociological and pathological conditions. Oocyte cryopreservation can adversely affect the developmental potential of oocytes by causing an increase in intracellular oxidative stresses and damage to the mitochondrial structure. In this study, we studied whether autologous adipose stem cell (ASC) mitochondria supplementation with vitrified and warmed oocytes could restore post-fertilization development that decreased due to mitochondrial damage following cryopreservation. ASC mitochondria showed similar morphology to oocytes’ mitochondria and had a higher ATP production capacity. The vitrified-warmed oocytes from juvenile mice were supplemented with ASC mitochondria at the same time as intracellular sperm injection (ICSI), after which we compared their developmental capacity and the mitochondria quality of 2-cell embryos. We found that, compared to their counterpart, mitochondria supplementation significantly improved development from 2-cell embryos to blastocysts (56.8% vs. 38.2%) and ATP production in 2-cell embryos (905.6 & 561.1 pmol), while reactive oxygen species levels were comparable. With these results, we propose that ASC mitochondria supplementation could restore the quality of cryopreserved oocytes and enhance the embryo developmental capacity, signifying another possible approach for mitochondrial transplantation therapy. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Reproduction in Japan)

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Review

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14 pages, 1619 KiB

Open AccessFeature PaperReview

Sperm and Oocyte Chromosomal Abnormalities

by Osamu Samura, Yoshiharu Nakaoka and Norio Miharu

Biomolecules 2023, 13(6), 1010; https://doi.org/10.3390/biom13061010 - 17 Jun 2023

Viewed by 2773

Abstract

Gametogenesis, the process of producing gametes, differs significantly between oocytes and sperm. Most oocytes have chromosomal aneuploidies, indicating that chromosomal aberrations in miscarried and newborn infants are of oocyte origin. Conversely, most structural anomalies are of sperm origin. A prolonged meiotic period caused by increasing female age is responsible for an increased number of chromosomal aberrations. Sperm chromosomes are difficult to analyze because they cannot be evaluated using somatic cell chromosome analysis methods. Nevertheless, researchers have developed methods for chromosome analysis of sperm using the fluorescence in situ hybridization method, hamster eggs, and mouse eggs, allowing for the cytogenetic evaluation of individual sperm. Reproductive medicine has allowed men with severe spermatogenic defects or chromosomal abnormalities to have children. However, using these techniques to achieve successful pregnancies results in higher rates of miscarriages and embryos with chromosomal abnormalities. This raises questions regarding which cases should undergo sperm chromosome analysis and how the results should be interpreted. Here, we reviewed clinical trials that have been reported on oocyte and sperm chromosome analyses. Examination of chromosomal abnormalities in gametes is critical in assisted reproductive technology. Therefore, it is necessary to continue to study the mechanism underlying gametic chromosomal abnormalities. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Reproduction in Japan)

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16 pages, 1380 KiB

Open AccessReview

Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development

by Atsushi Hattori and Maki Fukami

Biomolecules 2023, 13(4), 691; https://doi.org/10.3390/biom13040691 - 19 Apr 2023

Cited by 1 | Viewed by 1295

Abstract

Gonadal development is the first step in human reproduction. Aberrant gonadal development during the fetal period is a major cause of disorders/differences of sex development (DSD). To date, pathogenic variants of three nuclear receptor genes (NR5A1, NR0B1, and NR2F2) have been reported to cause DSD via atypical testicular development. In this review article, we describe the clinical significance of the NR5A1 variants as the cause of DSD and introduce novel findings from recent studies. NR5A1 variants are associated with 46,XY DSD and 46,XX testicular/ovotesticular DSD. Notably, both 46,XX DSD and 46,XY DSD caused by the NR5A1 variants show remarkable phenotypic variability, to which digenic/oligogenic inheritances potentially contribute. Additionally, we discuss the roles of NR0B1 and NR2F2 in the etiology of DSD. NR0B1 acts as an anti-testicular gene. Duplications containing NR0B1 result in 46,XY DSD, whereas deletions encompassing NR0B1 can underlie 46,XX testicular/ovotesticular DSD. NR2F2 has recently been reported as a causative gene for 46,XX testicular/ovotesticular DSD and possibly for 46,XY DSD, although the role of NR2F2 in gonadal development is unclear. The knowledge about these three nuclear receptors provides novel insights into the molecular networks involved in the gonadal development in human fetuses. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Reproduction in Japan)

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13 pages, 1594 KiB

Open AccessReview

An In Vivo Screening Model for Investigation of Pathophysiology of Human Implantation Failure

by Hitomi Nakamura and Tadashi Kimura

Biomolecules 2023, 13(1), 79; https://doi.org/10.3390/biom13010079 - 30 Dec 2022

Cited by 3 | Viewed by 1519

Abstract

To improve current infertility treatments, it is important to understand the pathophysiology of implantation failure. However, many molecules are involved in the normal biological process of implantation and the roles of each molecule and the molecular mechanism are not fully understood. This review highlights the hemagglutinating virus of Japan (HVJ; Sendai virus) envelope (HVJ-E) vector, which uses inactivated viral particles as a local and transient gene transfer system to the murine uterus during the implantation period in order to investigate the molecular mechanism of implantation. In vivo screening in mice using the HVJ-E vector system suggests that signal transducer and activator of transcription-3 (Stat-3) could be a diagnostic and therapeutic target for women with a history of implantation failure. The HVJ-E vector system hardly induces complete defects in genes; however, it not only suppresses but also transiently overexpresses some genes in the murine uterus. These features may be useful in investigating the pathophysiology of implantation failure in women. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Reproduction in Japan)

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16 pages, 1471 KiB

Open AccessReview

The Regulators of Human Endometrial Stromal Cell Decidualization

by Hiromi Murata, Susumu Tanaka and Hidetaka Okada

Biomolecules 2022, 12(9), 1275; https://doi.org/10.3390/biom12091275 - 10 Sep 2022

Cited by 7 | Viewed by 6703

Abstract

Several factors are important for implantation and subsequent placentation in the endometrium, including immunity, angiogenesis, extracellular matrix, glucose metabolism, reactive oxidative stress, and hormones. The involvement or abnormality of these factors can impair canonical decidualization. Unusual decidualization can lead to perinatal complications, such as disruption of trophoblast invasion. Drastic changes in the morphology and function of human endometrial stromal cells (hESCs) are important for decidualization of the human endometrium; hESCs are used to induce optimal morphological and functional decidualization in vitro because they contain estrogen and progesterone receptors. In this review, we will focus on the studies that have been conducted on hESC decidualization, including the results from our laboratory. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Reproduction in Japan)

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