Bipotential semen proteins as sperm-protective and immunosuppressive reagents

• Project/Area Number: 17K18164
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Integrative animal science; General medical chemistry
• Research Institution: Meiji University
• Principal Investigator: Kawano Natsuko 明治大学, 農学部, 専任講師 (00451691)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 体内受精 / 精液タンパク質 / 自然免疫 / 補体 / ヒト型精液モデルマウス / 生殖免疫 / 前立腺 / 精嚢腺 / 不妊 / 免疫抑制剤 / 移植・再生医療

Outline of Final Research Achievements

Internal fertilization is a complicated process, including gametes and liquid factors from both female and male. We hypothesized competitive factors in the internal fertilization: spermicide in female uterine fluid and sperm-protectant in male semen. These factors seem to be essential for the internal fertilization, but the precise mechanism was still unclear. In this study, we produced Svs2-6-/- male mice for deleting mouse-type semen and human SemgI/II knockin male mice for introducing human-type semen. We suppose the possibility for the humanized male mice with high fertility, which suggests that the seminal plasma proteins across the two species protect sperm from female immunity and development for human immunosuppressive reagents. In female spermicide, we found that uterine complement C3 kills sperm in the absence of SVS2. C3 covered the surface of the killed sperm with unique formation. Our research about the internal fertilization may shed light on the new innate immune system.

Academic Significance and Societal Importance of the Research Achievements

ヒトの繁殖様式である体内受精には、女性因子と男性因子のバランスで成り立つ複雑さがある。現在の不妊患者のうち、卵や精子には異常が見られない原因不明とされるケースが多数存在する。複雑な体内受精のしくみを少しでも明らかにすることで、不妊原因の究明および、より自然な妊娠を可能にする治療法の開発が可能になると考えている。本研究では、男性の精液タンパク質に異常がある場合は精子形成が正常でも子宮内で精子が死滅すると予想され、女性の免疫力が亢進している場合は過剰に精子が排除されていると予想される。それぞれのしくみを詳細に知ることが、受精率の高い体内受精とはどういう状態のことを意味するのか理解したい。

Research Products

• [Journal Article] Membrane protein CD9 is repositioned and released to enhance uterine function. (2019)
  • Author(s): 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.
  • Journal Title: Laboratory Investigation Volume: 99 Issue: 2 Pages: 200-209
  • DOI: 10.1038/s41374-018-0145-1
  • Peer Reviewed / Open Access
• [Journal Article] Chemotactic behavior of egg mitochondria in response to sperm fusion in mice (2018)
  • Author(s): Iwai Maki、Harada Yuichirou、Miyabayashi Rinako、Kang Woojin、Nakamura Akihiro、Kawano Natsuko、Miyamoto Yoshitaka、Yamada Mitsutoshi、Hamatani Toshio、Miyado Mami、Yoshida Keiichi、Saito Hidekazu、Tanaka Mamoru、Umezawa Akihiro、Miyado Kenji
  • Journal Title: Heliyon Volume: 4 Issue: 11 Pages: e00944-e00944
  • DOI: 10.1016/j.heliyon.2018.e00944
  • Peer Reviewed / Open Access
• [Journal Article] Autophagy-disrupted LC3 abundance leads to death of supporting cells of human oocytes. (2018)
  • Author(s): Kang W, Ishida E, Yamatoya K, Nakamura A, Miyado M, Miyamoto Y, Iwai M, Tatsumi K, Saito T, Saito K, Kawano N, Hamatani T, Umezawa A, Miyado K, Saito H.
  • Journal Title: Biochem Biophys Rep. Volume: 21(15) Pages: 107-114
  • DOI: 10.1016/j.bbrep.2018.08.002
  • Peer Reviewed / Open Access
• [Journal Article] Degradation of phosphate polymer polyP enhances lactic fermentation in mice. (2018)
  • Author(s): 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.
  • Journal Title: Genes Cells. Volume: 23(10) Issue: 10 Pages: 904-914
  • DOI: 10.1111/gtc.12639
  • Peer Reviewed / Open Access
• [Journal Article] Ubiquitin-activating enzyme E1 inhibitor PYR-41 retards sperm enlargement after fusion to the egg. (2018)
  • Author(s): Yoshida K, Kang W, Nakamura A, Kawano N, Hanai M, Miyado M, Miyamoto Y, Iwai M, Hamatani T, Saito H, Miyado K and Umezawa A.
  • Journal Title: Reprod Toxicol. Volume: 76 Pages: 71-77
  • DOI: 10.1016/j.reprotox.2018.01.001
  • Peer Reviewed
• [Journal Article] Exosomes versus microexosomes: Shared components but distinct functions (2017)
  • Author(s): Miyado K, Kang W, Yamatoya K, Hanai M, Nakamura A, Mori T, Miyado M, Kawano N
  • Journal Title: J Plant Res Volume: 130 Issue: 3 Pages: 479-483
  • DOI: 10.1007/s10265-017-0907-7
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Birth weights and Down syndrome in neonates delivered after frozen-thawed embryo transfer: Six-year study (2007-2012) on the national assisted reproduction registry data in Japan (2017)
  • Author(s): Yamatoya K, Saito K, Saito T, Kang W, Nakamura A, Miyado M, Kawano N, Miyamoto Y, Umezawa A, Miyado K, Saito H
  • Journal Title: Reproductive Medicine and Biology Volume: 16 Issue: 2 Pages: 228-234
  • DOI: 10.1002/rmb2.12033
  • Peer Reviewed / Open Access
• [Presentation] 精子-卵膜融合に関わるマイクロエクソソームと CD9 の相互作用について (2018)
  • Author(s): 花井 慎弦，吉田 学，吉田 薫，大和屋 健二，康 宇鎭，河野 菜摘子，宮戸 健二
  • Organizer: 日本動物学会第89回札幌大会
• [Presentation] 特殊な生殖様式 sperm drinking を行うナマズ目コリドラスの精子核塩基性タンパク質の解析 (2018)
  • Author(s): 紙谷 惇樹，日比野 拓，河野 菜摘子
  • Organizer: 日本動物学会第89回札幌大会
• [Presentation] 松下 稜，日比野 拓，宮戸 健二，河野 菜摘子 (2018)
  • Author(s): シリアンハムスター卵の解析―種認識する融合因子の同定
  • Organizer: 日本動物学会第89回札幌大会
• [Presentation] 新規クエン酸合成酵素eCSによる卵活性化メカニズム (2018)
  • Author(s): 康宇鎭, 原田裕一郎, 河野菜摘子, 齊藤英和, 宮戸健二
  • Organizer: 第36回日本受精着床学会総会/学術講演会
• [Presentation] 精液研究からわかってきた子宮の免疫機構 (2017)
  • Author(s): 河野菜摘子、今泉明音、吉田 薫、吉田 学、齊藤英和、宮戸健二
  • Organizer: 第58回 日本卵子学会
  • Invited
• [Presentation] ラクトフェリンと女性機能 (2017)
  • Author(s): 河野 菜摘子、坂口 大樹、金井 誠也、出雲 信夫
  • Organizer: 第19回 応用薬理シンポジウム
• [Presentation] Antibacterial activities of seminal vesicle secretions in SVS2-6 KO mice (2017)
  • Author(s): Takeo Yamazaki, Natsuko Kawano and Kenji Miyado
  • Organizer: 12Th TOIN Internationa Symposium on Biomedical Engineering
• [Presentation] Analysis of Syrian hamster eggs - Identification of fusogenic factors (2017)
  • Author(s): Ryo Matsushita, Kenji Miyado, Natsuko Kawano
  • Organizer: 12Th TOIN Internationa Symposium on Biomedical Engineering
• [Presentation] Protective effects of seminal plasma proteins on uterine sperm (2017)
  • Author(s): Daiki Sakaguchi, Kaoru Yoshida, Kazuma Hayashi, Natsuko Kawano
  • Organizer: 12Th TOIN Internationa Symposium on Biomedical Engineering
• [Presentation] Functional analysis of CD9 and micro-exosome facilitating sperm-egg membrane fusion (2017)
  • Author(s): Maito Hanai, Kenji Yamatoya, Woojin Kang, Natsuko Kawano, Kenji Miyado
  • Organizer: 12Th TOIN Internationa Symposium on Biomedical Engineering
• [Presentation] 母性の自然免疫が妊孕性に及ぼす影響 (2017)
  • Author(s): 河野 菜摘子、吉田 薫、岩本 晃明、吉田 学、宮戸 健二
  • Organizer: 第40回日本分子生物学会
  • Invited
• [Book] 卵子・精子形成 (特集 周産期再生医療の現状と未来 : 周産期医療はどこに向かうのか ; 産婦人科領域) (2018)
  • Author(s): 祝井 麻希, 河野 菜摘子, 宮戸 健二
  • Total Pages: 5
  • Publisher: 東京医学社
• [Book] Regulation of Sperm-Egg Fusion at the Plasma Membrane (2018)
  • Author(s): Miyado K, Yamatoya K, Kang W, Kawano N
  • Total Pages: 10
  • Publisher: Reproductive and Developmental Strategies
• [Book] Seminal Vesicle-Structure (2018)
  • Author(s): Yoshida M, Kawano N, Iwamoto T, Yoshida K
  • Total Pages: 5
  • Publisher: in “Encycropedia of Reproduction 2nd. Edition Vol. 1: Male Reproduction” (Eds. by Skinner, M. and Jegou, B.)
• [Book] Encycropedia of Reproduction 2nd. Edition Vol. 1: Male Reproduction (2018)
  • Author(s): Yoshida, M., Kawano, N., Iwamoto, T., and Yoshida, K.
  • Total Pages: 3864
  • Publisher: Elsevier
  • ISBN: 9780128118993
• [Patent(Industrial Property Rights)] 妊娠中の母子の健康状態改善剤 (2018)
  • Inventor(s): 河野菜摘子、加賀谷伸治
  • Industrial Property Rights Holder: 河野菜摘子、加賀谷伸治
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-013395
  • Filing Date: 2018