Details of a Researcher - YAMADA Mitsutoshi

Papers - YAMADA Mitsutoshi

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子宮頸管妊娠に対しメトトレキサート(MTX)と子宮動脈塞栓術(UAE)を併用し保存的治療を行った2例

白石慧, 上條慎太郎, 佐久間萌子, 大岡令奈, 松沢優一, 内田志穂, 祝井麻希, 内田明花, 山田満稔, 山上亘, 田中守

東京産科婦人科学会会誌 ((一社)東京産科婦人科学会) 73 ( 4 ) 848 - 853 2024.10

ISSN 2186-0599

子宮頸管妊娠は異所性妊娠の一型であり,止血困難に至る疾患である.現在,治療法は子宮を温存する保存的治療法が主体となっている.メトトレキサート(methotrexate:MTX)の投与,子宮動脈塞栓術(uterine artery embolization:UAE)などによる保存的治療法が行われるが,診断基準・治療方針については未だコンセンサスが確立されていない.今回我々は子宮頸管妊娠に対し保存的治療としてMTXとUAEを併用し,子宮温存しえた2症例を経験した.子宮頸管妊娠は早期診断が重要であることに加え,治療経過中に出血をきたすことも多い.緊急での輸血やUAEなど急変に対応できる体制のもとで診断・治療をすることが重要である.(著者抄録)

Calcium oscillations and mitochondrial enzymes in stem cells

Fukuoka M., Kang W., Horiike S., Yamada M., Miyado K.

Regenerative Therapy 26 811 - 818 2024.06

Calcium oscillations are rhythmic fluctuations of the intracellular concentration of calcium ions (Ca2+). As Ca2+ evokes various cellular processes, its intracellular concentration is tightly regulated. Ca2+ oscillations control biological events, including neuronal differentiation and proliferation of mesenchymal stem cells. The frequency and pattern of Ca2+ oscillations depend on cell type. Researchers have studied Ca2+ oscillations to better understand how cells communicate and regulate physiological processes. Dysregulation of Ca2+ oscillations causes health problems, such as neurodegenerative disorders. This review discusses the potential functions of Ca2+ oscillations in stem cells.

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Overdue Calcium Oscillation Causes Polyspermy but Possibly Permits Normal Development in Mouse Eggs

Fukuoka M., Kang W., Katano D., Horiike S., Miyado M., Tanaka M., Miyado K., Yamada M.

International Journal of Molecular Sciences (International Journal of Molecular Sciences) 25 ( 1 ) 2024.01

ISSN 16616596

In some non-mammalian eggs, the fusion of one egg and multiple sperm (polyspermy) induces a robust rise in intracellular calcium ion (Ca2+) concentration due to a shortage of inducers carried by a single sperm. Instead, one of the sperm nuclei is selected inside the egg for normal embryogenesis. Polyspermy also occurs during the in vitro fertilization of human eggs; however, the fate of such eggs is still under debate. Hence, the relationship between polyspermy and repetitive Ca2+ increases (Ca2+ oscillation) in mammals remains unknown. To address this issue, we used mouse sperm lacking extramitochondrial citrate synthase (eCS), which functions as a Ca2+ oscillation inducer; its lack causes retarded Ca2+ oscillation initiation (eCs-KO sperm). Elevated sperm concentrations normalize Ca2+ oscillation initiation. As expected, eCS deficiency enhanced polyspermy in both zona pellucida (ZP)-free and ZP-intact eggs despite producing the next generation of eCs-KO males. In conclusion, similarly to non-mammalian eggs, mouse eggs may develop normally under polyspermy conditions caused by problematic Ca2+ oscillation.

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Assessment of embryologist sufficiency and associated regional disparities in Japanese assisted reproduction facilities using nationwide survey data (IZANAMI project)

Shirasawa H., Yamada M., Jwa S.C., Kuroda K., Harada M., Osuga Y.

Journal of Obstetrics and Gynaecology Research (Journal of Obstetrics and Gynaecology Research) 2024

ISSN 13418076

Aims: This study aims to comprehensively examine the employment and practices of embryologists in Japan's assisted reproductive technology (ART) laboratories, focusing on the impact of various factors such as ART cycle numbers, add-ons, and regional differences. Additionally, it seeks to assess the extent to which Japanese ART facilities meet international minimum standards set by the American Society for Reproductive Medicine (ASRM). Methods: A survey was conducted from December 2021 to February 2022 among 621 ART facilities in Japan. The study categorized facilities into five ART cycle groups and compared the number of embryologists across these groups. It also examined the correlation between the number of embryologists, ART cycles, add-ons, and regional differences. Data were analyzed using linear regression and multiple linear regression analyses. Results: The study's findings revealed a significant correlation between the total number of embryologists at each facility and the ART cycles. Notably, there were significant differences in the number of embryologists across all ART cycle categories. Of the 435 facilities, only 44.6% met the ASRM minimum embryologist staffing requirement. The regression analysis further highlighted the significance of ART cycles and preimplantation genetic testing for aneuploidies as factors. Moreover, the number of embryologists stationed at urban facilities was significantly higher than at nonurban facilities, indicating a potential regional disparity. Conclusion: In Japan, it was first found that more than 50% of ART facilities do not have sufficient embryologists in place relative to the number of ART cycles. Furthermore, the add-ons and regional differences affect the placement of embryologists.

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Variation in diagnostic methods, criteria, and treatment for chronic endometritis: A nationwide survey in Japan

Jwa S.C., Kuroda K., Shirasawa H., Harada M., Osuga Y., Yamada M.

Journal of Obstetrics and Gynaecology Research 2024

ISSN 13418076

Aim: To investigate variation in the diagnosis and treatment of chronic endometritis (CE) at the national level in Japan. Methods: We performed a nationwide survey targeting all assisted reproductive technology (ART) facilities across Japan between 2021 and 2022. Diagnostic methods, criteria, and first- and second-line treatment protocols for CE were collected via a questionnaire. Results: Among 616 ART facilities, 437 responded to the survey (response rate: 70.9%) of which 339 (77.6%) implemented diagnosis and treatment of CE. In the diagnosis of CE, 214 (63.1%) facilities used CD138 immunohistochemical staining of endometrial tissue, while hysteroscopy was the most frequently used as an adjunct diagnostic method (241 facilities, 71.1%). The most frequent cutoff value of CD138-positive cells for diagnosing CE was 3–5 cells/20 high-power fields (50%), but 7.9% (17 facilities) and 5.1% (11 facilities) used cutoff values of 1 and 2 cells, respectively. The most common first- and second-line treatment methods were doxycycline (210 facilities, 61.9%) and ciprofloxacin + metronidazole (164 facilities, 48.0%), respectively. Conclusions: There is considerable variation in the number of CD138-positive cells used for diagnosing CE. Establishing unified diagnostic criteria and therapeutic methods for CE is essential to provide standardized medicine for CE at the national level.

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Fertility preservation after gonadotoxic treatments for cancer and autoimmune diseases

Saito S., Yamada M., Yano R., Takahashi K., Ebara A., Sakanaka H., Matsumoto M., Ishimaru T., Utsuno H., Matsuzawa Y., Ooka R., Fukuoka M., Akashi K., Kamijo S., Hamatani T., Tanaka M.

Journal of Ovarian Research (Journal of Ovarian Research) 16 ( 1 ) 2023.12

Background: The indications for fertility preservation (FP) have expanded. A few patients who underwent gonadotoxic treatment did not have the opportunity to receive FP, leading to concerns that these patients may develop premature ovarian insufficiency. However, the usefulness of FP in women with reduced ovarian reserve has also been questioned. Progestin-primed ovarian stimulation can improve the controlled ovarian stimulation (COS) protocol, but there is limited data on the efficacy of FP with progestin-primed ovarian stimulation. Methods: We conducted a prospective study of 43 women with cancer or autoimmune diseases before and after gonadotoxic treatment at the reproductive unit of Keio University Hospital, counselled between 1 January 2018 and 31 December 2021. After counselling, informed consent was obtained for FP from 43 patients, with those who underwent gonadotoxic treatment of the primary disease being prioritised. Gonadotropin-releasing hormone analogue or progestin was used to suppress luteinising hormone in COS before or after gonadotoxic treatment. The number of cryopreserved mature oocytes was the primary outcome. Results: Forty-three patients and 67 assisted reproductive technology cycles were included in the analysis. The median age at entry was 32 [inter quartile range (IQR), 29–37] years. All patients in the post-gonadotoxic treatment group had their oocytes frozen. Gonadotoxic treatment resulted in fewer oocytes [median 3 (IQR 1–4); pre-gonadotoxic treatment group: five patients, 13 cycles] vs. median 9 (IQR 5–14; pre-gonadotoxic treatment group: 38 patients, 54 cycles; P < 0.001). Although anti-Müllerian hormone levels were lower in the post-gonadotoxic treatment group (n = 5, 13 cycles, median 0.29 (IQR 0.15–1.04) pg/mL) than in the pre-gonadotoxic treatment group (n = 38, 54 cycles, median 1.89 (IQR 1.15–4.08) pg/mL) (P = 0.004), oocyte maturation rates were higher in the post-gonadotoxic treatment group [median 100 (IQR 77.5–100) %] than in the pre-gonadotoxic group [median 90.3 (IQR 75.0–100) %; P = 0.039]. Five patients in the pre-gonadotoxic treatment group had their cryopreserved embryos thawed, of which three had live births. Conclusions: Oocytes obtained for FP from women with cancer or autoimmune disease for FP are of satisfactory quality, regardless of whether they are obtained post-gonadotoxic treatment or COS protocols.

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Fact-finding survey on assisted reproductive technology in Japan

Harada S., Yamada M., Shirasawa H., Jwa S.C., Kuroda K., Harada M., Osuga Y.

Journal of Obstetrics and Gynaecology Research (Journal of Obstetrics and Gynaecology Research) 49 ( 11 ) 2593 - 2601 2023.11

ISSN 13418076

Aims: In anticipation of the future development of assisted reproductive technology (ART) and to smoothly introduce new technology, it is necessary to understand the current staffing status of the medical system and the current state of treatment, as well as the status of in vitro fertilization add-ons, where the need for insurance coverage is currently a matter of debate. Methods: ART facilities in Japan were surveyed (437 valid responses, response rate: 71%). Current staffing status of the medical system, implementation rates of ART, add-on treatments, and medical supplies were investigated. Results: Despite the abundance of embryologists, nurses, and obstetricians and gynecologists in facilities, the majority of facilities lacked counselors, anesthesiologists, and other essential medical professionals. Conventional ovarian stimulation was widely adopted (median 120 [interquartile range 60–300] cycles), followed by mild ovarian simulation (60 [30–200]). Additionally, freeze–thaw embryo transfer cycles (300 [120–750]) were performed more frequently than fresh embryo transfer cycles (30 [30–60]). Among the add-ons, assisted hatching (85.1%), chronic endometritis examination (77.2%) and treatment (76.9%), artificial oocyte activation (67.3%), endometrial receptivity analysis (64.2%), and endometrial microbiome analysis (58.9%) were relatively widely employed. Conclusions: The implementation of frozen–thawed embryo transfer cycles, freeze-all strategies, and add-on treatments have become popular and widely accepted despite the lack of robust evidence regarding their safety and efficacy.

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保存的に加療し得た卵管間質部妊娠の1例

佐久間萌子, 山田満稔, 松沢優一, 大岡令奈, 福岡美桜, 宮崎康太郎, 木村寛子, 上條慎太郎, 浜谷敏生, 青木大輔, 田中守

東京産科婦人科学会会誌 ((一社)東京産科婦人科学会) 72 ( 4 ) 752 - 757 2023.10

ISSN 2186-0599

卵管間質部妊娠は異所性妊娠の2～4%と稀であり,治療や管理方法に一定の見解が示されていない.今回メトトレキサート(MTX)の全身投与による保存治療が有効であった卵管間質部妊娠の1症例を経験したので報告する.症例は35歳,2妊1産.妊娠6週1日に異所性妊娠疑いにて当院を紹介受診した.妊娠6週6日には血清hCG 2,334.3mIU/mL,画像検査において左卵管角付近に子宮筋層で囲まれた造影効果のある被膜を伴う直径7.2mmの嚢胞を認め,左卵管間質部妊娠と診断した.MTXの全身投与を2回行って奏効を得,MTX治療後142日目に血清hCGは陰転化し,277日目に胎嚢の消失を確認した.502日目に凍結融解胚盤胞移植を行い,正所性妊娠が成立した.MTX療法は卵管間質部妊娠において,次回妊娠時の安全性を考慮した保存治療として有用であると考える.(著者抄録)

Sodium Hexametaphosphate Serves as an Inducer of Calcium Signaling

Katano D., Kang W., Harada Y., Kawano N., Miyado M., Saito T., Fukuoka M., Yamada M., Miyado K.

Biomolecules (Biomolecules) 13 ( 4 ) 2023.04

In bacteria, polymers of inorganic phosphates, particularly linear polyphosphate, are used as alternative phosphate donors for adenosine triphosphate production. A six-chain form of sodium metaphosphate, sodium hexametaphosphate (SHMP), is believed to have no physiological functions in mammalian cells. In this study, we explored the possible effects of SHMP on mammalian cells, using mouse oocytes, which are useful for observing various spatiotemporal intracellular changes. Fertilization-competent oocytes were isolated from the oviducts of superovulated mice and cultured in an SHMP-containing medium. In the absence of co-incubation with sperm, SHMP-treated oocytes frequently formed pronuclei and developed into two-cell embryos owing to the increase in calcium concentration in the cytoplasm. We discovered an intriguing role for SHMP as an initiator of calcium rise in mouse oocytes, presumably in a wide variety of mammalian cells.

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Embryonic β-Catenin Is Required for Priming of the Uterus to Implantation

Takezawa Y., Iwai M., Fujiki Y., Yokomizo R., Kishigami H., Miyado M., Kawano N., Yamada M., Shindo M., Suzuki M., Sato B., Katano D., Kamijo S., Hamatani T., Tanaka M., Umezawa A., Kang W., Miyado K.

Laboratory Investigation (Laboratory Investigation) 103 ( 3 ) 2023.03

ISSN 00236837

Repeated implantation failure is a major cause of infertility among healthy women. Uterine β-catenin (CTNNB1) plays a critical role in implantation. However, the role of embryonic CTNNB1 during implantation remains unclear. We addressed this topic by analyzing mice carrying Ctnnb1-deficient (Ctnnb1Δ/Δ) embryos. Ctnnb1Δ/Δ embryos were produced by intercrossing mice bearing Ctnnb1-deficient eggs and sperms. We found that Ctnnb1Δ/Δ embryos developed to the blastocyst stage; thereafter, they were resorbed, leaving empty decidual capsules. Moreover, leukemia inhibitory factor, a uterine factor essential for implantation, was undetectable in Ctnnb1Δ/Δ blastocysts. Furthermore, CDX2, a transcription factor that determines the fate of trophectoderm cells, was not observed in Ctnnb1Δ/Δ blastocysts. Intrauterine injection with uterine fluids (from control mice) and recombinant mouse leukemia inhibitory factor proteins rescued the uterine response to Ctnnb1Δ/Δ blastocysts. These results suggest that embryonic CTNNB1 is required for the secretion of blastocyst-derived factor(s) that open the implantation window, indicating that the uterine response to implantation can be induced using supplemental materials. Therefore, our results may contribute to the discovery of a similar mechanism in humans, leading to a better understanding of the pathogenesis of repeated implantation failure.

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Morphometric assessment of blastocysts: relationship with the ongoing pregnancy rate

Utsuno H., Ishimaru T., Matsumoto M., Sasamori C., Takahashi H., Kimura H., Kamijo S., Yamada M., Tanaka M., Hamatani T.

F and S Reports (F and S Reports) 4 ( 1 ) 85 - 92 2023.03

Objective: To explore a morphometric grading system for blastocysts that is associated with ongoing pregnancy. Design: Cross-sectional study. Setting: None. Patients(s): All consecutive vitrified blastocysts at our center from July 2018 to November 2021 that were transferred in single blastocyst transfer cycles until January 2022. Intervention(s): None. Main Outcome Measure(s): The ongoing pregnancy rate after a single vitrified-warmed blastocyst transfer. Interobserver agreement on morphometric values among embryologists. Result(s): Three morphometric variables (blastocyst diameter, area of inner cell mass [ICM], and the estimated trophectoderm cell count) were used to evaluate the expansion, ICM, and trophectoderm morphology. During the study period, 585 blastocysts were involved in this study. Of the 3 morphometric variables, ICM area (per 500 μm2, adjusted odds ratio, 1.19; 95% confidence interval, 1.09−1.30) and estimated trophectoderm cell count (per 10 cells, adjusted odds ratio, 1.25; 95% confidence interval, 1.12−1.39) were significantly associated with the ongoing pregnancy rate after adjustment for confounding factors. The ongoing pregnancy rate was 2.0% (1/49) with an ICM area of <2,500 μm2 and the estimated trophectoderm cell count <70. The ongoing pregnancy rate reached 47.8% (22/46) when the ICM area and the estimated trophectoderm cell count were >3,500 μm2 and >110, respectively. Interobserver agreement on the blastocyst diameter, ICM area, and the estimated trophectoderm cell count was excellent-to-good among 5 embryologists (intraclass correlation coefficients: 0.99, 0.87, and 0.91, respectively). Conclusion(s): Morphometric values of ICM and trophectoderm are promising predictors of pregnancy success. The high reproducibility suggests that the morphometric variables will contribute to identifying blastocysts with the highest developmental potential as well as those that will not result in a successful pregnancy.

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Identification of a syncytin gene in a non-rodent laboratory mammal, Suncus murinus

Suzuki M., Nakamura A., Matsumoto Y., Kang W., Ichinose M., Kawano N., Yamada M., Shindo M., Katano D., Saito T., Harada Y., Miyado M., Miyado K.

Journal of Veterinary Medical Science (Journal of Veterinary Medical Science) 85 ( 9 ) 912 - 920 2023

ISSN 09167250

An endogenous retrovirus-derived membrane protein, syncytin (SYN), contributes to placental function via trophoblast fusion. Multinuclear trophoblasts (syncytiotrophoblasts) physically and functionally mediate the interaction between fetal and maternal vessels in various ways. Suncus murinus (suncus) is a small mammalian species with a pregnancy duration of approximately 30 days, 1.5 times longer than mice. However, the molecular basis for the longer pregnancy duration is unknown. In this study, we first isolated two genes that encoded putative SYN proteins expressed in the suncus placenta, which were named syncytin-1-like proteins 1 and 2 (SYN1L1 and SYN1L2). When their expression vectors were introduced into cultured cells, suncus SYN1L2 was found to be active in cell fusion. Moreover, the SYN1L2 protein was homologous to a SYN1-like protein identified in greater mouse-eared bats (bat SYN1L) and was structurally compared with bat SYN1L and other SYN proteins, implying the presence of structural features of the SYN1L2 protein.

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Artificial oocyte activation using Ca<sup>2+</sup> ionophores following intracytoplasmic sperm injection for low fertilization rate

Akashi K., Yamada M., Jwa S.C., Utsuno H., Kamijo S., Hirota Y., Tanaka M., Osuga Y., Kuji N.

Frontiers in Endocrinology (Frontiers in Endocrinology) 14 2023

This large multi-center retrospective study examined whether artificial oocyte activation (AOA) using Ca2+ ionophore following ICSI improves the live birth rate for couples with previous ICSI cycles of unexplained low fertilization rate. In this large-scale multi-center retrospective study conducted in Japan, data were collected from Keio University and 17 collaborating institutions of the Japanese Institution for Standardizing Assisted Reproductive Technology. Between January 2015 and December 2019, 198 couples were included in this study. Oocytes for both the intervention and control groups were procured from the same pool of couples. Oocytes obtained from ICSI cycles with no or low fertilization rate (<50%) with unknown causes were included in the control (conventional ICSI) group while oocytes procured from ICSI cycles followed by performing AOA were assigned to the intervention (ICSI-AOA) group. Those fertilized with surgically retrieved sperm were excluded. ICSI-AOA efficacy and safety were evaluated by comparing these two groups. Live birth rate was the primary outcome. The ICSI-AOA group (2,920 oocytes) showed a significantly higher live birth per embryo transfer rate (18.0% [57/316]) compared to that of the conventional ICSI group with no or low fertilization rate (1,973 oocytes; 4.7% [4/85]) (odds ratio 4.5, 95% confidence interval 1.6–12.6; P<0.05). A higher live birth rate was observed in younger patients without a history of oocyte retrieval. Miscarriage, preterm delivery, and fetal congenital malformation rates were similar between the two groups. ICSI-AOA may reduce fertilization failure without increasing risks during the perinatal period. AOA may be offered to couples with an ICSI fertilization rate < 50%.

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【不妊と薬の知識　患者に寄り添う薬剤師になる!】不妊治療に使用される薬の使い方　凍結融解胚移植におけるホルモン調整周期に用いる薬

山田, 満稔

調剤と情報 28 ( 13 ) 2224 - 2228 2022.10

ISSN 1341-5212

過去10年の間に凍結融解胚移植の実施件数は大幅に増加している。着床をサポートするためには,子宮内膜と胚の発生段階を同期させることが必要である。一般的な子宮内膜の調整方法は,発育中の卵胞から子宮内膜の成熟に必要なエストロゲンとプロゲステロンが順次分泌される自然周期と,これらを順次投与するホルモン調整周期がある。ホルモン調整周期におけるモニタリング方法,およびエストロゲンおよびプロゲステロンの理想的な投与量,投与方法,投与期間を決定するために,さらなる研究が求められている。(著者抄録)

【AYA世代の女性ヘルスケア-対応と実際-】生殖機能維持と保存　生殖補助医療による妊孕性の限界と今後の展望

明石, 一浩, 宇津野, 宏樹 and 山田, 満稔

産婦人科の実際 71 ( 10 ) 1142 - 1149 2022.09

ISSN 0558-4728

＜文献概要＞女性に対する代表的な妊孕性温存療法には,卵子/受精卵(胚)凍結,卵巣組織凍結が挙げられる。卵子/胚凍結は標準治療の位置づけとして確立しつつある一方,卵巣組織凍結は米国臨床腫瘍学会(ASCO)Clinical Practice Guideline 2018年版ではいまだ実験段階の方法としての位置づけとなっており,有効性・安全性に関する科学的エビデンスの蓄積が求められている。妊孕性温存に向けた実験的な試みとして,in vitro maturation(IVM),卵巣組織凍結における卵胞生存率を高める取り組み,人工卵巣,再生医療による卵子作成などの研究が行われている。本稿では,妊孕性温存療法の実態と限界,今後の展望について解説する。

Trehalose Suppresses Lysosomal Anomalies in Supporting Cells of Oocytes and Maintains Female Fertility

Kang W., Ishida E., Amita M., Tatsumi K., Yonezawa H., Yohtsu M., Katano D., Onozawa K., Kaneko E., Iwasaki W., Naito N., Yamada M., Kawano N., Miyado M., Sato B., Saito H., Saito T., Miyado K.

Nutrients (Nutrients) 14 ( 10 ) 2022.05

Supporting cells of oocytes, i.e., cumulus cells, control oocyte quality, which determines fertilization success. Therefore, the transformation of mature and immature cumulus cells (MCCs and ICCs, respectively) into dysmature cumulus cells (DCCs) with dead characteristics deteriorates oocyte quality. However, the molecular basis for this transformation remains unclear. Here, we explored the link between autophagic decline and cumulus transformation using cumulus cells from patients with infertility, female mice, and human granulosa cell-derived KGN cell lines. When human cumulus cells were labeled with LysoTracker probes, fluorescence corresponding to lysosomes was enhanced in DCCs compared to that in MCCs and ICCs. Similarly, treatment with the autophagy inhibitor chloroquine elevated LysoTracker fluorescence in both mouse cumulus cells and KGN cells, subsequently suppressing ovulation in female mice. Electron microscopy analysis revealed the proliferation of abnormal lysosomes in chloroquine-treated KGN cells. Conversely, the addition of an autophagy inducer, trehalose, suppressed chloroquine-driven problematic lysosomal anomalies and ameliorated ovulation problems. Our results suggest that autophagy maintains the healthy state of the supporting cells of human oocytes by suppressing the formation of lysosomes. Thus, our results provide insights into the therapeutic effects of trehalose on female fertility.

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治療法の再整理とアップデートのために専門家による私の治療　機能性子宮出血

明石, 一浩 and 山田, 満稔

日本医事新報 ( 5114 ) 48 - 49 2022.04

ISSN 0385-9215

福岡, 美桜, 山田, 満稔, 宇津野, 宏樹, 上條, 慎太郎, 浜谷, 敏生 and 田中, 守

臨床婦人科産科 76 ( 4 ) 239 - 243 2022.04

ISSN 0386-9865

The possible effects of the Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 on the practice of fertility preservation in female cancer patients in Japan

Kunitomi C., Harada M., Sanada Y., Kusamoto A., Takai Y., Furui T., Kitagawa Y., Yamada M., Watanabe C., Tsugawa K., Nishiyama H., Hosoi H., Miyachi M., Sugiyama K., Maeda Y., Kawai A., Hamatani T., Fujio K., Suzuki N., Osuga Y.

Reproductive Medicine and Biology (Reproductive Medicine and Biology) 21 ( 1 ) 2022.01

ISSN 14455781

Purpose: In 2017, the first guidelines for fertility preservation in cancer patients were published in Japan. However, the impact of the guidelines remains unknown. Therefore, the authors conducted a nationwide survey on cryopreservation procedures in the period from shortly before to after publication of the guidelines (2016–2019) and compared the results with our previous survey (2011–2015). The authors also surveyed reproductive specialists’ awareness of the guidelines and implementation problems. Methods: The authors sent a questionnaire to 618 assisted reproductive technology facilities certified by the Japanese Society of Obstetrics and Gynecology. Results: The authors received responses from 395 institutions (63.8%). Among them, 144 institutions conducted cryopreservation for cancer patients (vs. 126 in 2011–2015) and performed 2537 embryo or oocyte and 178 ovarian tissue cryopreservation procedures (vs. 1085 and 122, respectively). Compared with the previous period, indications were more varied and protocols for controlled ovarian stimulation were more standardized. Reproductive specialists’ interest in oncofertility was high, but many reported three main difficulties: selecting a treatment method, storing samples in the long term, and securing the necessary human resources. Conclusions: The practice of fertility preservation in cancer patients in Japan has been considerably affected by the first Japanese guidelines.

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Identification of an antibacterial polypeptide in mouse seminal vesicle secretions

Morohoshi K., Yamazaki T., Kito K., Sato B., Kang W., Hibino T., Yoshida M., Yoshida K., Iwamoto T., Yamada M., Miyado K., Kawano N.

Journal of Reproductive Immunology (Journal of Reproductive Immunology) 148 2021.11

ISSN 01650378

In both men and women, pathogenic bacteria enter the reproductive tract and cause harmful symptoms. Intrauterine and oviductal inflammation after copulation may have severe effects, such as infertility, implantation failure, oviduct obstruction, and robust life-threatening bacterial infection. Human seminal plasma is considered to be protective against bacterial infection. Among its components, Semenogelin-I/-II proteins are digested to function as bactericidal factors; however, their sequences are not conserved in mammals. Therefore, alternative antibacterial (bactericidal and/or bacteriostatic) systems may exist across mammals. In this study, we examined the antibacterial activity in the seminal plasma of mice lacking a gene cluster encoding Semenogelin-I/-II counterparts. Even in the absence of the majority of seminal proteins, antibacterial activity remained in the seminal plasma. Moreover, a combination of gel chromatography and liquid chromatography coupled with tandem mass spectrometry revealed that the prostate and testis expressed 4 protein as a novel antibacterial (specifically, bacteriostatic) protein, the sequence of which is broadly conserved across mammals. Our results provide the first evidence of a bacteriostatic protein that is widely present in the mammalian seminal plasma.

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高齢不妊治療患者に対する治療戦略　卵子の加齢と救済法に関する基礎的知見

山田, 満稔

日本産科婦人科学会雑誌 73 ( 11 ) 1580 - 1585 2021.11

ISSN 0300-9165

Using piggyBac transposon gene expression vectors to transfect Zscan5b gene into mouse pluripotent stem cells

Yamada M., Sugawara T., Usami S., Nakanishi R., Akustu H.

STAR Protocols (STAR Protocols) 2 ( 3 ) 2021.09

We recently demonstrated that the zygotic gene Zscan5b is involved in maintaining the genomic integrity of pluripotent stem cells (PSCs) during mitosis and that Zscan5b gene expression can prevent chromosomal abnormalities. Here, we provide a detailed protocol for the transfection of mouse embryonic stem cells (mESCs) and mouse-induced PSCs (miPSCs) with a Zscan5b constitutive expression plasmid, using the piggyBac transposon gene expression vector system. For complete details on the use and execution of this protocol, please refer to Ogawa et al. (2019).

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副腎皮質過形成とAZFcの部分欠失を合併した男性不妊症に対して精巣内精子採取術を実施し妊娠に至った1例

高畑, 海音子, 佐藤, 卓, 末岡, 浩, 水口, 雄貴, 上條, 慎太郎, 山田, 満稔, 浜谷, 敏生, 田中, 守 and 青木, 大輔

東京産科婦人科学会会誌 ((一社)東京産科婦人科学会) 70 ( 2 ) 210 - 215 2021.04

ISSN 2186-0599

副腎皮質過形成(congenital adrenal hyperplasia:CAH)およびAZF遺伝子の欠失は、いずれも非閉塞性無精子症(NOA)の原因となりうる遺伝子異常である。今回我々は、CAHとAZFc部分欠失を合併した男性不妊症の事例に対して、精巣内精子採取術(TESE)および顕微授精(ICSI)により妊娠に至った事例を経験したので報告する。症例は、41歳男性と38歳女性の夫婦である。夫はCAHと診断されステロイド補充療法が実施されたものの、射出精液中に運動精子が認められず、NOAが疑われた。染色体検査およびAZF遺伝子検査がなされた結果、AZFcの部分欠失を認めた。以上を踏まえてTESEおよびICSIにより妊娠が成立したが、児は子宮内胎児死亡に至った。CAHとAZF遺伝子欠失とを原因とするNOAの事例においてもTESEが有用であることが示唆された。(著者抄録)

【骨・軟部腫瘍のマネジメント(その1)】治療総論　AYA世代への対応　小児および思春期・若年成人(AYA)世代悪性骨・軟部腫瘍患者に対する妊孕性温存療法

中山, ロバート, 山口, さやか and 山田, 満稔

別冊整形外科 ( 79 ) 163 - 167 2021.04

ISSN 0287-1645

＜文献概要＞はじめに　悪性骨・軟部腫瘍は運動器に発生する希少な悪性腫瘍であり,「肉腫」と総称される.骨肉腫,Ewing肉腫などが代表的な疾患であり,若年発症[小児および思春期・若年成人(AYA)世代]が多い.化学療法を含む集学的治療の確立により,高悪性度肉腫の治療成績は改善したが,同時に長期サバイバーの生活の質(QOL)が課題となっている.中でも重要なものが妊孕性の温存である.本稿では,小児・AYA世代の悪性骨・軟部腫瘍患者に対するがん生殖医療について,日本癌治療学会より刊行された『小児,思春期・若年がん患者の妊孕性温存に関する診療ガイドライン2017年版』(本邦妊孕性温存GL)に沿って解説する.

【COVID-19に対する産婦人科医療の対策】生殖医療におけるCOVID-19への日本生殖医学会の対応

山田, 満稔, 西村, 綾乃, 吉野, 修, 湯村, 寧, 辻村, 晃 and 大須賀, 穣

産婦人科の実際 70 ( 2 ) 151 - 157 2021.02

ISSN 0558-4728

＜文献概要＞新型コロナウイルス感染症(COVID-19)のパンデミックは,SARS-CoV-2と命名されたコロナウイルスにより引き起こされる。COVID-19パンデミック下においても,女性と男性が子どもを産み,家庭を築く権利をはじめとしたreproductive rightsが尊重され,COVID-19の拡大を防ぐ社会のニーズと調和させるための努力が求められる。本稿では,COVID-19パンデミックにおける日本生殖医学会の取り組みについてまとめる。

Mitochondrial replacement by genome transfer in human oocytes: Efficacy, concerns, and legality

Yamada M., Sato S., Ooka R., Akashi K., Nakamura A., Miyado K., Akutsu H., Tanaka M.

Reproductive Medicine and Biology (Reproductive Medicine and Biology) 20 ( 1 ) 53 - 61 2021.01

ISSN 14455781

Background: Pathogenic mitochondrial (mt)DNA mutations, which often cause life-threatening disorders, are maternally inherited via the cytoplasm of oocytes. Mitochondrial replacement therapy (MRT) is expected to prevent second-generation transmission of mtDNA mutations. However, MRT may affect the function of respiratory chain complexes comprised of both nuclear and mitochondrial proteins. Methods: Based on the literature and current regulatory guidelines (especially in Japan), we analyzed and reviewed the recent developments in human models of MRT. Main findings: MRT does not compromise pre-implantation development or stem cell isolation. Mitochondrial function in stem cells after MRT is also normal. Although mtDNA carryover is usually less than 0.5%, even low levels of heteroplasmy can affect the stability of the mtDNA genotype, and directional or stochastic mtDNA drift occurs in a subset of stem cell lines (mtDNA genetic drift). MRT could prevent serious genetic disorders from being passed on to the offspring. However, it should be noted that this technique currently poses significant risks for use in embryos designed for implantation. Conclusion: The maternal genome is fundamentally compatible with different mitochondrial genotypes, and vertical inheritance is not required for normal mitochondrial function. Unresolved questions regarding mtDNA genetic drift can be addressed by basic research using MRT.

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【着床環境の改善はどこまで可能か?-エキスパートに聞く最新研究と具体的対処法】子宮内感染　子宮内細菌叢と生殖補助医療との関係

齋藤, 早貴 and 山田, 満稔

臨床婦人科産科 74 ( 12 ) 1236 - 1240 2020.12

ISSN 0386-9865

Suppression of Non-Random Fertilization by MHC Class I Antigens

Kamiya, J., Kang, W., Yoshida, K., Takagi, R., Kanai, S., Hanai, M., Nakamura, A., Yamada, M., Miyamoto, Y., Miyado, M., Kuroki, Y., Hayashi, Y., Umezawa, A., Kawano, N. and Miyado, K.

Int J Mol Sci 21 ( 22 ) 2020.11

ISSN 1422-0067

Hermaphroditic invertebrates and plants have a self-recognition system on the cell surface of sperm and eggs, which prevents their self-fusion and enhances non-self-fusion, thereby contributing to genetic variation. However, the system of sperm-egg recognition in mammals is under debate. To address this issue, we explored the role of major histocompatibility complex class I (MHC class I, also known as histocompatibility 2-K(b) or H2-K(b) and H2-D(b) in mice) antigens by analyzing H2-K(b-/-)H2-D(b-/-)β2-microglobulin (β2M)(-/-) triple-knockout (T-KO) male mice with full fertility. T-KO sperm exhibited an increased sperm number in the perivitelline space of wild-type (WT) eggs in vitro. Moreover, T-KO sperm showed multiple fusion with zona pellucida (ZP)-free WT eggs, implying that the ability of polyspermy block for sperm from T-KO males was weakened in WT eggs. When T-KO male mice were intercrossed with WT female mice, the percentage of females in progeny increased. We speculate that WT eggs prefer fusion with T-KO sperm, more specifically X-chromosome-bearing sperm (X sperm), suggesting the presence of preferential (non-random) fertilization in mammals, including humans.

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ゲノム編集　ヒト受精卵のゲノム編集研究の現状と課題『ゲノム編集』の技術的側面と臨床的に期待される可能性

山田, 満稔

医事法学 35 37 - 41 2020.10

ISSN 0912-7194

治療法の再整理とアップデートのために　専門家による私の治療　卵巣過剰刺激症候群

山田, 満稔

日本医事新報 ( 5011 ) 62 - 63 2020.05

ISSN 0385-9215

子宮鏡検査が子宮角部妊娠の診断に有用であった1例

岡, 愛実子, 山田, 満稔, 佐藤, 健二, 升田, 博隆, 上條, 慎太郎, 浜谷, 敏生, 田中, 守 and 青木, 大輔

東京産科婦人科学会会誌 68 ( 4 ) 710 - 713 2019.10

ISSN 2186-0599

子宮角部妊娠は全異所性妊娠の0.6%と稀な疾患であり、いまだ確立された治療法はない。今回子宮鏡検査により子宮角部妊娠を補助診断し、良好な経過を得た症例を経験したので報告する。症例は35歳、1妊0産。無月経5週3日の血中hCG 9930mIU/mL、経腟超音波断層検査で胎嚢を認めず、異所性妊娠疑いにて当院紹介受診。血中hCGの上昇率は緩徐のため異常妊娠と診断した。MRI検査で右子宮角部に胎嚢様構造を認めた。着床部位をより正確に確認し、安全に治療を行うため施行した子宮鏡検査にて右子宮角部に腫瘤性病変を確認した。経腹超音波断層検査併用下に子宮内容除去術を行い、摘出検体の病理組織検査で絨毛組織を認めた。血中hCGは術後すみやかに低下し、術後44日目に陰転化した。子宮鏡検査は着床部位が困難な症例における補助診断および安全な治療遂行に有用であると考える。(著者抄録)

Zscan5b Deficiency Impairs DNA Damage Response and Causes Chromosomal Aberrations during Mitosis

Ogawa S., Yamada M*(corresponding author)., Nakamura A., Sugawara T., Nakamura A., Miyajima S., Harada Y., Ooka R., Okawa R., Miyauchi J., Tsumura H., Yoshimura Y., Miyado K., Akutsu H., Tanaka M., Umezawa A., Hamatani T.

Stem Cell Reports (Stem Cell Reports) 12 ( 6 ) 1366 - 1379 2019.06

ISSN 22136711

© 2019 The Authors Zygotic genome activation (ZGA) begins after fertilization and is essential for establishing pluripotency and genome stability. However, it is unclear how ZGA genes prevent mitotic errors. Here we show that knockout of the ZGA gene Zscan5b, which encodes a SCAN domain with C2H2 zinc fingers, causes a high incidence of chromosomal abnormalities in embryonic stem cells (ESCs), and leads to the development of early-stage cancers. After irradiation, Zscan5b-deficient ESCs displayed significantly increased levels of γ-H2AX despite increased expression of the DNA repair genes Rad51l3 and Bard. Re-expression of Zscan5b reduced γ-H2AX content, implying a role for Zscan5b in DNA damage repair processes. A co-immunoprecipitation analysis showed that Zscan5b bound to the linker histone H1, suggesting that Zscan5b may protect chromosomal architecture. Our report demonstrates that the ZGA gene Zscan5b is involved in genomic integrity and acts to promote DNA damage repair and regulate chromatin dynamics during mitosis. In this article, Yamada and colleagues show that Zscan5b deficiency increases DNA stress, compromises chromosomal structure during mitosis, and leads to the development of early-stage cancers. Zscan5b deficiency may offer a murine model of human chromosomal breakage syndromes.

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【生殖医学のcutting edge】ミトコンドリア病における核移植

山田, 満稔

HORMONE FRONTIER IN GYNECOLOGY 26 ( 2 ) 103 - 106 2019.06

ISSN 1340-220X

ミトコンドリアはエネルギーを産生する細胞内小器官の1つであり、固有のDNA(ミトコンドリアDNA;mtDNA)をもつ。mtDNAの病的変異によりミトコンドリア機能に異常をきたすと、ミトコンドリア脳筋症、心筋症、難聴、糖尿病、腎障害といったさまざまな疾患を呈しうる(ミトコンドリア病)。ミトコンドリア病は、卵子の細胞質を介して母親から子どもへと遺伝される遺伝性疾患(母系遺伝)であり、根本的な治療法が存在しない。核移植は変異mtDNAを正常mtDNAと置換することで、次世代へのミトコンドリア病の伝播を防ぐ有効な治療法となると期待されており、2015年には英国で合法化された。しかしながら核移植においては、核側卵子ドナーから持ち込まれる少量のmtDNA(mtDNA carryover)が存在し、その後の発生過程において健常なミトコンドリアを駆逐してしまい、ミトコンドリア置換法で防がれるはずだった疾患を発症する恐れがある。本稿では、これまでのミトコンドリア病の遺伝の予防を目的とした核移植について得られている知見を紹介する。(著者抄録)

【新時代に入ったがん・生殖医療】小児、思春期・若年がん患者の妊孕性温存に関する診療ガイドラインに沿った臨床の展開　骨・軟部腫瘍

中山, ロバート and 山田, 満稔

産科と婦人科 86 ( 4 ) 481 - 485 2019.04

ISSN 0386-9792

悪性骨・軟部腫瘍は運動器に発生する希少な悪性腫瘍の総称で『肉腫』とよばれる。骨肉腫、ユーイング肉腫などが代表的な疾患であるが、若年発症(小児・AYA世代がん)が多く、化学療法を含んだ集学的治療の確立により治療成績が改善したため、長期サバイバーのQOLが課題となっている。本稿では、悪性骨・軟部腫瘍の長期サバイバーに対するがん・生殖医療について、「小児、思春期・若年がん患者の妊孕性温存に関する診療ガイドライン」に沿って解説する。(著者抄録)

Membrane protein CD9 is repositioned and released to enhance uterine function

Iwai M., Hamatani T., Nakamura A., Kawano N., Kanai S., Kang W., Yoshii N., Odawara Y., Yamada M., Miyamoto Y., Saito T., Saito H., Miyado M., Umezawa A., Miyado K., Tanaka M.

Laboratory Investigation (Laboratory Investigation) 99 ( 2 ) 200 - 209 2019.02

ISSN 00236837

© 2018, United States & Canadian Academy of Pathology. Tetraspanin CD9 is essential for sperm–egg fusion and also contributes to uterine repair through microexosome formation. Microexosomes share CD9 with exosomes and are released from eggs and uterine epithelial cells. However, the mechanism for the formation of microexosomes remains unknown. To address this issue, we examined membrane localization and extracellular release of CD9 proteins using uterine epithelial cells and secretions in mice and humans. In mice, CD9 localized predominantly on the basal region of the plasma membrane and relocated to the apical region upon embryo implantation. Furthermore, extracellular CD9 proteins were detected in uterine secretions of mice and women undergoing infertility treatment, but were below detectable levels in supernatants of pluripotent stem cells. Ultrastructural analysis demonstrated that membrane projections were shortened and the number of mitochondria was reduced in uterine epithelial cells lacking Cd9 genes. Our results suggest that CD9 repositioning and release affect both membrane structures and mitochondrial state in the uterus, and contribute to female fertility.

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Chemotactic behavior of egg mitochondria in response to sperm fusion in mice

Iwai M., Harada Y., Miyabayashi R., Kang W., Nakamura A., Kawano N., Miyamoto Y., Yamada M., Hamatani T., Miyado M., Yoshida K., Saito H., Tanaka M., Umezawa A., Miyado K.

Heliyon (Heliyon) 4 ( 11 ) 2018.11

ISSN 24058440

© 2018 The Authors Mitochondria are the powerhouses of eukaryotic cells and their positioning contributes to fertilization and early developmental processes. We report that sperm fusion triggers Ca 2+ oscillations and mitochondrial movement toward fused sperm (mitochondrial chemotaxis) in mouse eggs. Mitochondria functioned in Ca 2+ storage and were colocalized with endoplasmic reticulum (ER) during Ca 2+ oscillations. Mitochondria then moved toward the fused sperm. Sperm extracts lacking nuclei induced Ca 2+ oscillations, but did not promote mitochondrial chemotaxis. Our results suggest that sperm fusion motivates Ca 2+ oscillation-independent mitochondrial chemotaxis. This phenomenon indicates that egg mitochondria interact with sperm materials, presumably nuclear substances, and their network tethers egg and sperm nuclei at the early stage of zygote formation.

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【精子・卵子保存法の現在-「産む」選択肢をあきらめないために】配偶子保存の必要性と課題　化学療法・放射線療法の妊孕性への影響

小川, 誠司, 山田, 満稔 and 浜谷, 敏生

臨床婦人科産科 72 ( 5 ) 410 - 416 2018.05

ISSN 0386-9865

＜文献概要＞●がんと診断されてから治療が開始されるまでの限られた時間内に,妊孕性に対するリスクと,適切な妊孕能温存の選択肢について,患者が十分に理解し,医療者とともに協働的意思決定ができるように努めなければならない.●シクロホスファミドを代表とするアルキル化薬剤は卵巣および精巣機能を著しく低下させるリスクがある.●放射線照射は卵巣および精巣機能を低下させるリスクを有し,患者年齢,線量,投与期間などによりリスクの程度は変化する.

Degradation of phosphate polymer polyP enhances lactic fermentation in mice.

Nakamura A, Kawano N, Motomura K, Kuroda A, Sekiguchi K, Miyado M, Woojin K, Miyamoto Y, Hanai M, Iwai M, Yamada M, Hamatani T, Saito T, Saito H, Tanaka M, Umezawa A, Miyado K.

Genes Cells (Genes to Cells) 23 ( 10 ) 904 - 914 2018

Joint Work, ISSN 13569597

© 2018 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd In bacteria, a polymer of inorganic phosphate (Pi) (inorganic polyphosphate; polyP) is enzymatically produced and consumed as an alternative phosphate donor for adenosine triphosphate (ATP) production to protect against nutrient starvation. In vertebrates, polyP has been dismissed as a “molecular fossil” due to the lack of any known physiological function. Here, we have explored its possible role by producing transgenic (TG) mice widely expressing Saccharomyces cerevisiae exopolyphosphatase 1 (ScPPX1), which catalyzes hydrolytic polyP degradation. TG mice were produced and displayed reduced mitochondrial respiration in muscles. In female TG mice, the blood concentration of lactic acid was enhanced, whereas ATP storage in liver and brain tissues was reduced significantly. Thus, we suggested that the elongation of polyP reduces the intracellular Pi concentration, suppresses anaerobic lactic acid production, and sustains mitochondrial respiration. Our results provide an insight into the physiological role of polyP in mammals, particularly in females.

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生殖医学の最先端　不妊症治療におけるブレイクスルーを目指して　初期胚発生の新規分子メカニズムに基づいた次世代ARTと再生医療の開発

山田, 満稔

日本産科婦人科学会雑誌 69 ( 11 ) 2252 - 2261 2017.11

ISSN 0300-9165

【産婦人科診療で用いられるバイオマーカー】抗ミュラー管ホルモン(anti-Muellerian hormone;AMH)と不妊

浜谷, 敏生, 中川, 亮, 祝井, 麻希, 佐々木, 拓幸, 上條, 慎太郎, 小川, 誠司, 山田, 満稔 and 田中, 守

産婦人科の実際 66 ( 10 ) 1189 - 1196 2017.10

ISSN 0558-4728

【産婦人科におけるリスクマネジメント】生殖医療におけるリスク

浜谷, 敏生, 祝井, 麻希, 佐々木, 拓幸, 小川, 誠司, 山田, 満稔 and 田中, 守

産婦人科の実際 66 ( 6 ) 781 - 786 2017.06

ISSN 0558-4728

【万能幹細胞・幹細胞とゲノム編集-再生医療の進歩が医療を変える】産婦人科領域における再生医療とゲノム編集　ヒト初期胚のゲノム編集と再生医療

山田, 満稔 and 田中, 守

臨床婦人科産科 71 ( 5 ) 445 - 449 2017.05

ISSN 0386-9865

中国の2つのグループから2015,2016年に,ヒト異常受精胚を用いて,CRISPR/Cas9による標的遺伝子のゲノム編集の結果が報告された.CRISPR/Cas9による初期胚のゲノム編集は3つの問題(高いoff-target効果,mosaicism,次世代への変異の伝播)が指摘されている.本邦を含め国際的にヒト受精卵に対するゲノム編集技術の可否が議論され,英国は胚移植をしないことを条件に限定付きで正常な受精卵を用いた遺伝子編集研究を認めた.(著者抄録)

【Non-ARTの不妊症診療-体外受精なしでここまでできる】人工授精のコツ

祝井, 麻希, 山田, 満稔 and 浜谷, 敏生

産科と婦人科 84 ( 3 ) 309 - 313 2017.03

ISSN 0386-9792

配偶者間人工授精(artificial insemination with husband's semen:AIH)は、身体的侵襲や経済的負担が比較的少ないため、不妊症に対する治療法として広く行われている。AIHを数周期(卵巣刺激法の併用も含めて)施行しても妊娠成立に至らない場合は、AIHの際の精液所見や患者の年齢・卵巣予備能などの背景を鑑み、体外受精へステップアップすることを考慮する。(著者抄録)

Genome Transfer Prevents Fragmentation and Restores Developmental Potential of Developmentally Compromised Postovulatory Aged Mouse Oocytes.

YAMADA MitsutoshiDieter Egli

Stem Cell Rep 8 ( 3 ) 576 - 588 2017

Research paper (scientific journal), Joint Work

Genetic Drift Can Compromise Mitochondrial Replacement by Nuclear Transfer in Human Oocytes.

YAMADA Mitsutoshi,mmanuelemmanuele V, Sanchez-Quintero M, Sun B, Lallos G, Paull D, Zimmer M, Pagett S, Prosser R, Sauer M, Hirano M, Egli D

Cell Stem Cell 18 ( 6 ) 749 - 754 2016.06

Joint Work, Accepted

【オミックスが拓く生殖医学の未来】メタボロミクス　メタボロミクスを用いた胚発生の解析

若松, 修平, 山田, 満稔 and 浜谷, 敏生

HORMONE FRONTIER IN GYNECOLOGY 22 ( 1 ) 25 - 30 2015.03

ISSN 1340-220X

メタボロミクスにより、胚発生における胚の代謝機構を解析することが可能となっており、そこから得られた結果から既存の培養液のさらなる改善と、胚の発生段階における新規バイオマーカーの開発が期待される。われわれはメタボロミクスのひとつの解析方法であるCE-TOF-MSを用いて、オクタン酸が胚発生において重要なエネルギー源となっていることを見出した。本稿では培養液の歴史的な変遷について触れるとともに、われわれが実際に行ったメタボロミクスを用いた胚発生の解析方法について紹介する。(著者抄録)

提供卵子を用いたART、当院の現状と問題点

塩谷雅英, 松本由紀子, 岡本恵理, 水澤友利, 滝口修司, 伊原由幸, 城綾乃, 江夏, 宜シェン, 十倉陽子, 安昌恵, 緒方誠司, 山田聡, 片山和明, 野田洋一 and 苔口昭次

日本IVF学会雑誌 18 ( 1 ) 29 - 33 2015

Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells

Mitsutoshi Yamada, Johannesson B, Sagi I, Burnett LC, Kort DH, Prosser RW, Paull D, Nestor MW, Freeby M, Greenberg E, Goland RS, Leibel RL, Solomon SL, Benvenisty N, Sauer MV, Egli D

Nature (NPG) 510 ( 7506 ) 533 - 536 2014.06

Research paper (scientific journal), Joint Work, Accepted

Access to Document (DOI)

【生殖再生医学】ヒトクローンES細胞の樹立

山田, 満稔, 浜谷, 敏生, 阿久津, 英憲, 山田, 朝子 and 吉村, 泰典

HORMONE FRONTIER IN GYNECOLOGY 21 ( 2 ) 117 - 120 2014.06

ISSN 1340-220X

体細胞核移植により体細胞核をリプログラミング(reprogramming)した核移植再構築卵(クローン胚)を胚盤胞まで発生させたあとにES細胞を樹立することは、免疫拒絶されることのない、患者自身に適合する幹細胞の作成につながる。しかしこれまでヒトクローンES細胞の樹立の試みは、いずれも卵割期に発生停止し不可能であった。2011年にEgliらのグループはゲノム除去操作をせずに体細胞核移植を行うことでヒト3倍体ES細胞の樹立に成功した。さらに2013年にTachibanaらのグループは、ヒト2倍体ES細胞の樹立を報告するに至った。以上の知見から、ヒト卵子には分化した体細胞のエピジェネティックメモリーを消去し、reprogrammingする能力があることが示された。(著者抄録)

【生殖医療の進歩と課題-安全性の検証から革新的知見まで】ARTの安全性評価　ART児の発達・長期予後

久慈, 直昭, 竹本, 崇史, 上條, 慎太郎, 戸田, 里実, 若松, 修平, 菅原, かな, 小川, 誠司, 山田, 満稔, 浜谷, 敏生 and 吉村, 泰典

臨床婦人科産科 68 ( 1 ) 107 - 113 2014.01

ISSN 0386-9865

ART由来出生児は自然妊娠に比べ,早産・低出生体重・先天性異常・小児/青年期の癌の発生率,脳性麻痺の罹患率が有意に高いが,その病因は両親の不妊形質によるものと考えられる.出生児の精神運動発達に関しては,これまでの報告では自然妊娠と差がない.インプリント異常疾患はART児で多くなる可能性が懸念されているが,現時点ではその発生率に有意差は認められない.(著者抄録)

Derivation of human decidua-like cells from amnion and menstrual blood

Sugawara K, Hamatani T, Yamada M, Ogawa S, Kamijo S, Kuji N, Akutsu H, Miyado K, Yoshimura Y, Umezawa A.

Sci Rep 4 4599 2014

Accepted

マウス加齢卵におけるテロメア長の解析

山田, 朝子, 浜谷, 敏生, 山田, 満稔, 久慈, 直昭 and 吉村, 泰典

日本生殖内分泌学会雑誌 18 5 - 10 2013.08

ISSN 1348-8031

母体加齢と排卵後加齢というふたつのマウスモデルを用いて、卵子の加齢変化に関してテロメラーゼ活性とテロメア長、ミトコンドリアと酸化ストレスに焦点を置き検討した。母体加齢卵におけるTertのmRNA発現は若齢マウス卵に比較して有意に減少し、マイクロアレイの結果とほぼ一致した。排卵後加齢卵におけるTertのmRNA発現は、新鮮卵と比較して有意に減少した。テロメラーゼ酵素活性は若齢卵と比較して母体加齢卵では有意に低下した。酸化ストレスは、若齢卵では、蛍光色素を示さなかったが、母体加齢卵、排卵後加齢卵では有意に増加した。加齢マウス卵のテロメア長は若齢卵に比べて有意に短縮したが、排卵後加齢卵のテロメア長は、若齢卵に比較して有意な変化を認めなかった。

【産婦人科性感染症とその対策】HIV患者男性に対する生殖医療

久慈, 直昭, 上條, 慎太郎, 井上, 治, 福永, 朝子, 小川, 誠司, 菅原, かな, 奥村, 典子, 山田, 満稔, 浜谷, 敏生 and 吉村, 泰典

産婦人科の実際 62 ( 4 ) 499 - 506 2013.04

ISSN 0558-4728

子宮動脈塞栓術により救命しえた子宮摘出困難な分娩後大量出血の2例

安達, 将隆, 山田, 満稔, 峰岸, 一宏, 浅田, 弘法, 田中, 守, 青木, 大輔 and 吉村, 泰典

関東連合産科婦人科学会誌 50 ( 1 ) 63 - 68 2013.03

ISSN 2186-0610

止血制御としての子宮摘出が困難であった帝王切開時の大量出血に対し,子宮動脈塞栓術(Uterine Artery Embolization;以下UAE)が有効であった2例を経験したので,文献的考察も含めて報告する.症例1は44歳,0経妊0経産.子宮内膜症性嚢胞・子宮筋腫合併.体外受精にて妊娠成立し,妊娠23週に超音波断層検査で全前置胎盤と診断.妊娠37週2日,帝王切開術を施行した.術中出血量は約3,000ml.閉創後,弛緩出血によりショック状態となった.内膜症性癒着によるダグラス窩完全閉鎖のため,子宮摘出は困難と判断.UAEを施行し,出血量は減少した.症例2は42歳,4経妊2経産.子宮筋腫核出術.帝王切開術の既往あり.子宮筋腫・子宮腺筋症合併.MRI検査で,胎盤は子宮前壁の子宮腺筋症部位に接して付着.38週2日,帝王切開術を施行.子宮収縮不良により出血が持続し,出血量は約10,000ml.子宮筋腫や子宮腺筋症,強固な腹腔内癒着のため子宮摘出は困難と考え,UAEを施行し,出血量は減少した.子宮摘出困難な分娩後大量出血における緊急UAE施行は,止血制御に有用かつ,母体救命戦略の一助となることが示された.(著者抄録)

β-Catenin Functions Pleiotropically in Differentiation and Tumorigenesis in Mouse Embryo-Derived Stem Cells

Okumura N, Akutsu H, Sugawara T, Miura T, Takezawa Y, Hosoda A, Yoshida K, Ichida JK, Yamada M, Hamatani T, Kuji N, Miyado K, Yoshimura Y, Umezawa A.

PLoS One 14 ( 8 ) e63265 2013

Joint Work

Age-associated telomere shortening in mouse oocytes

Yamada-Fukunaga T, Yamada M, Hamatani T, Chikazawa N, Ogawa S, Akutsu H, Miura T, Miyado K, Tarín JJ, Kuji N, Umezawa A, Yoshimura Y.

Reprod Biol Endocrinol 11 108 2013

Joint Work

Successful implantation after reducing matrix metalloproteinase activity in the uterine cavity

Yoshii N, Hamatani T, Inagaki N, Hosaka T, Inoue O, Yamada M, Machiya R, Yoshimura Y, Odawara Y.

Reprod Biol Endocrinol 11 37 2013

Joint Work

【不妊症治療-現状の課題と将来への展望-】生殖医療の将来と展望　ARTから再生医療へ

山田, 満稔, 浜谷, 敏生, 福永, 朝子 and 吉村, 泰典

母子保健情報 ( 66 ) 85 - 90 2012.12

ISSN 0389-8997

【不妊と周産期医療】ART妊娠児の長期予後研究

久慈, 直昭, 山田, 満稔, 井上, 治, 福永, 朝子, 小川, 誠司, 菅原, かな, 奥村, 典子, 浜谷, 敏生 and 吉村, 泰典

周産期医学 42 ( 8 ) 991 - 1000 2012.08

ISSN 0386-9881

Yamada M, Takanashi K, Hamatani T, Hirayama A, Akutsu H, Fukunaga T, Ogawa S, Sugawara K, Shinoda K, Soga T, Umezawa A, Kuji N, Yoshimura Y, Tomita M. A medium-chain fatty acid as an alternative energy source in mouse preimplantation development

YAMADA Mitsutoshi

Sci Rep 2 ( 930 ) 1 - 9 2012

Joint Work

Involvement of a novel preimplantation-speciﬁc gene encoding the high mobility group box protein Hmgpi in early embryonic development

YAMADA Mitsutoshi, Hamatani T, Akutsu H, Chikazawa N, Kuji N, Yoshimura Y, Umezawa A.

Hum Mol Genet 19 ( 3 ) 480 - 493 2010

Joint Work, Accepted

Maintenance of pluripotency and self-renewal ability of mouse embryonic stem cells in the absence of tetraspanin CD9

Akutsu H, Miura T, Machida M, Birumachi J, Hamada A, Yamada M, Sullivan S, Miyado K, Umezawa A.

Differentiation 78 137 - 142 2009

Joint Work

卵子提供•代理懐胎の海外での動向

久慈直昭, 持丸佳之, 高野光子, 篠崎佳栄, 山田満稔, 浜谷敏生 and 吉村泰典

PharmaMedica 27 ( 5 ) 35 - 8 2009

Hamatani T, Ko MSh, Yamada M, Kuji N, Mizusawa Y, Shoji M, Hada T, Asada H, Maruyama T, Yoshimura Y. Global gene expression profiling of preimplantation embryos

YAMADA Mitsutoshi

Hum Cell 19 ( 3 ) 98 - 117 2006

Joint Work, Accepted

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