Development of a novel fetal treatment for myelomeningocele using recombinant HGF protein.

• Project/Area Number: 20K08215
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kitasato University (2022); Keio University (2020-2021)
• Principal Investigator: Ochiai Daigo 北里大学, 医学部, 教授 (80348713)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 脊髄髄膜瘤 / 肝細胞成長因子 / 二分脊椎症 / ヒト羊水幹細胞 / 胎児治療 / 間葉系幹細胞 / HGF

Outline of Research at the Start

脊髄髄膜瘤は先天性疾患の１つであり、胎児期に羊水中に露出した脊髄が損傷し神経障害を引き起こし、重篤な後遺症を来す。胎児期に病態が進行するため胎児治療が検討されているが、現在まで確立されていない。
我々はこれまでに、羊水幹細胞が肝細胞増殖因子を分泌し脊髄を保護・再生することを世界で初めて見出した。
そこで、本研究では、脊髄髄膜瘤モデルラットに幹細胞ではなく、HGF蛋白質を投与し治療効果を検討する。

Outline of Final Research Achievements

To develop a novel treatment for a rat model of myelomeningocele, intra-amniotic cavity and local administration of hepatocyte growth factor (HGF), which has a proven track record in adult spinal cord injury, was used. Intra-amniotic administration did not produce a sufficient therapeutic effect, but local administration of HGF in the vicinity of the lesion decreased the expression of inflammatory cytokines in the spinal nerves, suggesting a certain therapeutic effect.
A new technique was also developed to remove only the spinal nerves from a rat model of myelomeningocele. Previously, the nerves was removed from the lesion, which may have been contaminated supporting tissue. However, this method is simpler, as it can be reliably pulled out from the head side and does not require special instruments such as microsurgery.

Academic Significance and Societal Importance of the Research Achievements

脊髄髄膜瘤は確立された治療法がない周産期難治性神経疾患であり、新たな治療法の開発が急務である。脊髄損傷に有効であるHGFを動物モデルに投与したところ、炎症性サイトカインの発現量が低下した。これによりHGFが脊髄髄膜瘤に対して有効である可能性が示唆されたが、他の因子については十分な効果が認められなかったため、至適投与量・投与間隔のさらなる検討が必要である。
そのためには、脊髄髄膜瘤モデルラット胎仔から脊髄神経のみを確実に摘出する手術法が必要であるが、本研究を通じて安定した手技の確立に成功した。

Research Products

• [Journal Article] Development of a new treatment for preterm birth complications using amniotic fluid stem cell therapy (2023)
  • Author(s): Yushi Abe, Yu Sato, Mamoru Tanaka, Daigo Ochiai
  • Journal Title: HISTOLOGY AND HISTOPATHOLOGY Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Immunosuppressive therapy before and during pregnancy may improve obstetric outcomes in pregnancy complicated by dermatomyositis with anti-MDA-5 antibody positivity: A case report (2023)
  • Author(s): Goto Hiroyuki、Kawahata Kimito、Shida Akiko、Nakagane Saeko、Isohata Hitoshi、Yamazaki Yu、Yoshimura Yoshihiro、Hattori Kyoko、Sekiguchi Kazuki、Ishikawa Ryuzo、Onishi Yoko、Kanai Yuji、Unno Nobuya、Ochiai Daigo
  • Journal Title: Case Reports in Women's Health Volume: 37 Pages: e00479-e00479
  • DOI: 10.1016/j.crwh.2023.e00479
• [Journal Article] Prophylactic administration of human amniotic fluid stem cells suppresses inflammation-induced preterm birth via macrophage polarization (2022)
  • Author(s): Abe Yushi、Ochiai Daigo、Kanzaki Seiji、Sato Yu、Otani Toshimitsu、Ikenoue Satoru、Kasuga Yoshifumi、Tanaka Mamoru
  • Journal Title: Molecular and Cellular Biochemistry Volume: 478 Issue: 2 Pages: 363-374
  • DOI: 10.1007/s11010-022-04512-2
• [Journal Article] Human Amniotic Fluid Stem Cells Ameliorate Thioglycollate-Induced Peritonitis by Increasing Tregs in Mice (2022)
  • Author(s): Abe Yushi、Ochiai Daigo、Taguchi Masako、Kanzaki Seiji、Ikenoue Satoru、Kasuga Yoshifumi、Tanaka Mamoru
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 12 Pages: 6433-6433
  • DOI: 10.3390/ijms23126433
• [Journal Article] Clinical Results of a Massive Blood Transfusion Protocol for Postpartum Hemorrhage in a University Hospital in Japan: A Retrospective Study (2021)
  • Author(s): Ochiai Daigo、Abe Yushi、Yamazaki Rie、Uemura Tomoe、Toriumi Ayako、Matsuhashi Hiroko、Tanaka Yuya、Ikenoue Satoru、Kasuga Yoshifumi、Tanosaki Ryuji、Tanaka Mamoru
  • Journal Title: Medicina Volume: 57 Issue: 9 Pages: 983-983
  • DOI: 10.3390/medicina57090983
  • Peer Reviewed / Open Access
• [Journal Article] The Efficacy of Transarterial Embolization for Postpartum Hemorrhage Complicated with Disseminated Intravascular Coagulation: A Single-Center Experience (2021)
  • Author(s): Ochiai Daigo、Nakatsuka Seishi、Abe Yushi、Ikenoue Satoru、Kasuga Yoshifumi、Inoue Masanori、Jinzaki Masahiro、Tanaka Mamoru
  • Journal Title: Journal of Clinical Medicine Volume: 10 Issue: 18 Pages: 4082-4082
  • DOI: 10.3390/jcm10184082
  • Peer Reviewed / Open Access
• [Journal Article] Deep neural network-based classification of cardiotocograms outperformed conventional algorithms (2021)
  • Author(s): Ogasawara Jun、Ikenoue Satoru、Yamamoto Hiroko、Sato Motoshige、Kasuga Yoshifumi、Mitsukura Yasue、Ikegaya Yuji、Yasui Masato、Tanaka Mamoru、Ochiai Daigo
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 13367-13367
  • DOI: 10.1038/s41598-021-92805-9
  • Peer Reviewed / Open Access
• [Journal Article] Amniotic fluid stem cells as a novel strategy for the treatment of fetal and neonatal neurological diseases (2021)
  • Author(s): Abe Yushi、Ochiai Daigo、Sato Yu、Otani Toshimitsu、Fukutake Marie、Ikenoue Satoru、Kasuga Yoshifumi、Tanaka Mamoru
  • Journal Title: Placenta Volume: 104 Pages: 247-252
  • DOI: 10.1016/j.placenta.2021.01.009
  • Peer Reviewed
• [Journal Article] Cell sheets using human amniotic fluid stem cells reduce tissue fibrosis in murine full-thickness skin wounds (2021)
  • Author(s): Ochiai Daigo、Abe Yushi、Fukutake Marie、Sato Yu、Ikenoue Satoru、Kasuga Yoshifumi、Masuda Hirotaka、Tanaka Mamoru
  • Journal Title: Tissue and Cell Volume: 68 Pages: 101472-101472
  • DOI: 10.1016/j.tice.2020.101472
  • Peer Reviewed
• [Journal Article] A safe delivery system to prevent COVID-19 transmission without negative-pressure isolation delivery rooms: Experience from a hospital with nosocomial outbreak (2021)
  • Author(s): Kasuga Y, Ochiai D, Tamagawa M, Oishi M, Endo T, Sato Y, Iida M, Ikenoue S, Tanaka M.
  • Journal Title: Taiwan J Obstet Gynecol Volume: 60 Issue: 1 Pages: 183-184
  • DOI: 10.1016/j.tjog.2020.12.001
  • Peer Reviewed / Open Access
• [Journal Article] Case Report: Prenatal Genetic Counseling to Parents of Fetuses Suspected of Having Ambiguous Genitalia (2021)
  • Author(s): Sato T, Ishii T, Yamaguchi Y, Ichihashi Y, Ochiai D, Asanuma H, Kuroda T, Hasegawa T.
  • Journal Title: Front Pediatr Volume: 13
  • DOI: 10.3389/fped.2020.569548
  • Peer Reviewed / Open Access
• [Journal Article] Defining the Normal Growth Curve of Fetal Fractional Limb Volume in a Japanese Population (2021)
  • Author(s): Ikenoue S, Akiba Y, Endo T, Kasuga Y, Yakubo K, Ishii R, Tanaka M, Ochiai D.
  • Journal Title: J Clin Med Volume: 10 Issue: 3 Pages: 485-485
  • DOI: 10.3390/jcm10030485
  • Peer Reviewed / Open Access
• [Journal Article] 【助産力アップ!周産期のガイドライン 深掘りドリル200問『産婦人科診療ガイドライン:産科編2020』に準拠 難易度別助産ケア&最新エビデンスが満載!】(第1章)妊娠期 妊婦健診『産婦人科診療ガイドライン:産科編2020』より出題 (2021)
  • Author(s): 玉川 真澄, 落合 大吾, 田中 守
  • Journal Title: ペリネイタルケア Volume: 0 Pages: 10-19
  • Peer Reviewed
• [Journal Article] Right aortic arch with an aberrant left subclavian artery: sonographic features by HDlive Flow imaging (2020)
  • Author(s): Endo T, Ochiai D, Tanaka M.
  • Journal Title: Cardiol Young Volume: 30 Issue: 6 Pages: 892-893
  • DOI: 10.1017/s1047951120001079
  • Peer Reviewed / Open Access
• [Journal Article] A new diagnostic strategy for gestational diabetes during the COVID-19 pandemic for the Japanese population (2020)
  • Author(s): Kasuga Y, Saisho Y, Ikenoue S, Ochiai D, Tanaka M.
  • Journal Title: Diabetes Metab Res Rev Volume: 36 Issue: 8
  • DOI: 10.1002/dmrr.3351
  • Peer Reviewed / Open Access
• [Journal Article] Universal screening for SARS-CoV-2 in asymptomatic obstetric patients in Tokyo, Japan (2020)
  • Author(s): Ochiai D, Kasuga Y, Iida M, Ikenoue S, Tanaka M.
  • Journal Title: Int J Gynaecol Obstet Volume: 150 Issue: 2 Pages: 268-269
  • DOI: 10.1002/ijgo.13252
  • Peer Reviewed / Open Access
• [Journal Article] Impaired early phase insulin secretion associated with gestational diabetes mellitus in underweight women (2020)
  • Author(s): Kasuga Y, Miyakoshi K, Saisho Y, Ikenoue S, Ochiai D, Tanaka M.
  • Journal Title: J Matern Fetal Neonatal Med Volume: 18 Issue: 12 Pages: 1-3
  • DOI: 10.1080/14767058.2020.1779692
  • Peer Reviewed / Open Access
• [Journal Article] Prophylactic therapy with human amniotic fluid stem cells improved survival in a rat model of lipopolysaccharide-induced neonatal sepsis through immunomodulation via aggregates with peritoneal macrophages (2020)
  • Author(s): Sato Y, Ochiai D, Abe Y, Masuda H, Fukutake M, Ikenoue S, Kasuga Y, Shimoda M, Kanai Y, Tanaka M.
  • Journal Title: Stem Cell Res Ther Volume: 11 Issue: 1
  • DOI: 10.1186/s13287-020-01809-1
  • Peer Reviewed / Open Access
• [Journal Article] Sonographic findings of cervical laceration caused by vaginal delivery in pregnancy after radical trachelectomy (2020)
  • Author(s): Kasuga Y, Miyakoshi K, Endo T, Takeda T, Nakamura M, Ochiai D, Tanaka M.
  • Journal Title: J Med Ultrason (2001) Volume: 47 Issue: 4 Pages: 655-657
  • DOI: 10.1007/s10396-020-01055-1
  • Peer Reviewed / Open Access
• [Journal Article] Preterm delivery and hypertensive disorder of pregnancy were reduced during the COVID-19 pandemic: A single hospital-based study (2020)
  • Author(s): Kasuga Y, Tanaka M, Ochiai D.
  • Journal Title: J Obstet Gynaecol Res Volume: 0 Issue: 12 Pages: 2703-2704
  • DOI: 10.1111/jog.14518
  • Peer Reviewed / Open Access
• [Journal Article] Prophylactic Therapy with Human Amniotic Fluid Stem Cells Improves Long-Term Cognitive Impairment in Rat Neonatal Sepsis Survivors (2020)
  • Author(s): Abe Y, Ochiai D, Sato Y, Kanzaki S, Ikenoue S, Kasuga Y, Tanaka M.
  • Journal Title: Int J Mol Sci Volume: 21 Issue: 24 Pages: 9590-9590
  • DOI: 10.3390/ijms21249590
  • Peer Reviewed / Open Access
• [Journal Article] 前置血管との鑑別を要した子宮頸管内静脈瘤合併妊娠の1例 (2020)
  • Author(s): 遠藤 豊英, 宮越 敬, 玉川 真澄, 長谷川 慶太, 大石 真希, 大谷 利光, 池ノ上 学, 春日 義史, 落合 大吾, 田中 守
  • Journal Title: 超音波医学 Volume: 47
  • Peer Reviewed
• [Journal Article] Placenta accreta indexによる前置癒着胎盤発症予測に関する検討 (2020)
  • Author(s): 長谷川 慶太, 池ノ上 学, 玉川 真澄, 大石 真希, 遠藤 豊英, 大谷 利光, 春日 義史, 落合 大吾, 宮越 敬, 田中 守
  • Journal Title: 超音波医学 Volume: 47
  • Peer Reviewed
• [Journal Article] 妊娠糖尿病と正常耐糖能例における胎児Fractional limb volumeの発育の比較 (2020)
  • Author(s): 池ノ上 学, 秋葉 洋平, 遠藤 豊英, 春日 義史, 落合 大吾, 宮越 敬, 矢久保 和美, 田中 守
  • Journal Title: 超音波医学 Volume: 47
  • Peer Reviewed
• [Journal Article] 疾患を抱えたAYA世代の出産 胆道閉鎖症術後妊娠の周産期管理 プレコンセプションケアの重要性 (2020)
  • Author(s): 落合 大吾
  • Journal Title: 日本周産期・新生児医学会雑誌 Volume: 56
  • Peer Reviewed
• [Journal Article] インタクトサバイバルを目指す新しい診断・治療のアプローチ 周産期難治性神経疾患に対する自己羊水由来の間葉系幹細胞を用いた新規治療法の提案 (2020)
  • Author(s): 落合 大吾
  • Journal Title: 日本産科婦人科学会雑誌 Volume: 72 Pages: 1520-1532
  • Peer Reviewed
• [Journal Article] 臨床的羊水塞栓症を契機に発症した腹部コンパートメント症候群の1例 (2020)
  • Author(s): 平田 桃, 長谷川 慶太, 春日 義史, 秋田 啓介, 大石 真希, 遠藤 豊英, 大谷 利光, 池ノ上 学, 落合 大吾, 宮越 敬, 田中 守, 青木 大輔
  • Journal Title: 関東連合産科婦人科学会誌 Volume: 57
  • Peer Reviewed
• [Journal Article] 妊娠中に発症した特発性中枢性尿崩症の1例 (2020)
  • Author(s): 島田 紗也葵, 春日 義史, 吉村 拓馬, 山下 博, 長谷川 慶太, 大石 真希, 遠藤 豊英, 池ノ上 学, 落合 大吾, 宮越 敬, 田中 守, 青木 大輔
  • Journal Title: 関東連合産科婦人科学会誌 Volume: 57
  • Peer Reviewed
• [Journal Article] 【もう胎児付属物とはいわせない!-胎盤、臍帯、羊水-】羊水幹細胞治療 (2020)
  • Author(s): 阿部 雄志, 落合 大吾, 田中 守
  • Journal Title: 産科と婦人科 Volume: 87 Pages: 2073-2078
  • Peer Reviewed
• [Presentation] 生殖・周産期免疫~認識と寛容 羊水幹細胞による胎児期からの多面的な脳性麻痺の発症制御 (2021)
  • Author(s): 落合 大吾
  • Organizer: 第36回日本生殖免疫学会シンポジウム
  • Invited
• [Presentation] ヒト羊水幹細胞の腹腔内投与は腹腔内凝集体による炎症制御を介して早産を抑制する (2021)
  • Author(s): 阿部 雄志, 落合 大吾, 升田 博隆, 佐藤 佑, 池ノ上 学, 春日 義史, 田中 守, 青木 大輔
  • Organizer: 第73回日本産科婦人科学会学術集会
• [Presentation] 周産期難治性神経疾患に対する自己羊水由来の間葉系幹細胞を用いた新規治療法の提案 (2020)
  • Author(s): 落合大吾
  • Organizer: 第72回日本産科婦人科学会学術講演会
  • Invited
• [Presentation] 胎児心臓超音波スクリーニング ISUOGガイドライン解説 (2020)
  • Author(s): 落合大吾
  • Organizer: 日本産婦人科超音波研究会
  • Invited
• [Presentation] The therapeutic potentials of human amniotic fluid stem cells on neonatal sepsis model (2020)
  • Author(s): Yu Sato, Daigo Ochiai, Hirotaka Masuda, Yushi Abe, Maki Ooishi, Toshimitsu Otani, Marie Fukutake, Satoru Ikenoue, Yoshifumi Kasuga, Kei Miyakoshi, Mamoru Tanaka, Daisuke Aoki
  • Organizer: 第72回日本産科婦人科学会学術講演会
• [Presentation] 早産児敗血症モデルラットの海馬におけるアストロサイトに関する検討 (2020)
  • Author(s): 阿部雄志，落合大吾，升田博隆，玉川真澄，長谷川慶太，遠藤豊英，大石真希，佐藤佑，大谷利光，池ノ上学，春日義史，宮越敬，田中守，青木大輔
  • Organizer: 第72回日本産科婦人科学会学術講演会