Etiological and Prognostic Studies of Biliary Atresia by Quantitative Analysis of Maternal Chimeric Cells

• Project/Area Number: 20K17588
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: University of Miyazaki
• Principal Investigator: Masuya Ryuta 宮崎大学, 医学部, 助教 (90448572)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 胆道閉鎖症 / 母親由来キメラ細胞 / 移植片対宿主病 / maternal microchimerism / 肝門部空腸吻合術 / リアルタイムPCR

Outline of Research at the Start

本研究は3年間で末梢静脈血中の母親由来細胞の量および性状、BA 発症との相関の有無を明
らかにする。
1 ) BA 患児および非 BA 患児静脈血中における母親由来キメラ細胞の定量的評価
2 ) BA 患児および非 BA 患児静脈血における母親由来キメラ細胞の性状の評価
3 ) BA 患児および非 BA 患児と母親との免疫学的寛容の評価
4 ) BA 発症の有無とキメラ細胞量、免疫学的寛容の程度との相関の評価

Outline of Final Research Achievements

The etiology of biliary atresia (BA) is unknown, but maternal-fetal immune interactions have been proposed as a possible etiology of BA. However, whether maternal chimeric (MC) cells circulate in the peripheral blood and the role of MC cells in the etiology of BA remain unclear. We have classified postoperative patients with BA into good and poor prognosis groups and quantified the DNA of maternal chimeric cells in the peripheral blood using qPCR.
We found that significantly more MC cells were detected in the peripheral blood mononuclear cells of the poor prognosis group, and the detection of maternal-derived cells in the peripheral blood mononuclear cells was significantly associated with poor prognosis.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果から胎児期に胎盤を介して胎児血液中に流入した母親由来細胞が胆道閉鎖症患者の末梢血に残留し、胆道閉鎖症の予後に影響を与えることが明らかになった。
胆道閉鎖症は成人期までに反芻が肝移植に至る予後不良かつ原因不明の難病で、本邦では1万出生に1人の割合で発症する。
胆道閉鎖症の発症及び病状進行における母親由来細胞の役割を今後更に究明していくことによって、発症や病状進行を予防する治療法を開発することができる。

Research Products

• [Journal Article] Circulating maternal chimeric cells have an impact on the outcome of biliary atresia (2022)
  • Author(s): Masuya Ryuta、Muraji Toshihiro、Kanaan Sami B.、Harumatsu Toshio、Muto Mitsuru、Toma Miki、Yanai Toshihiro、Stevens Anne M.、Nelson J. Lee、Nakame Kazuhiko、Nanashima Atsushi、Ieiri Satoshi
  • Journal Title: Frontiers in Pediatrics Volume: 10 Pages: 1007927-1007927
  • DOI: 10.3389/fped.2022.1007927
  • Peer Reviewed / Open Access
• [Journal Article] New insights in understanding biliary atresia from the perspectives on maternal microchimerism (2022)
  • Author(s): Muraji Toshihiro、Masuya Ryuta、Harumatsu Toshio、Kawano Takafumi、Muto Mitsuru、Ieiri Satoshi
  • Journal Title: Frontiers in Pediatrics Volume: 10 Pages: 1007987-1007987
  • DOI: 10.3389/fped.2022.1007987
  • Peer Reviewed / Open Access
• [Journal Article] Biliary atresia: Graft-versus-host disease with maternal microchimerism as an etiopathogenesis (2022)
  • Author(s): Masuya Ryuta、Muraji Toshihiro、Harumatsu Toshio、Muto Mitsuru、Nakame Kazuhiko、Nanashima Atsushi、Ieiri Satoshi
  • Journal Title: Transfusion and Apheresis Science Volume: - Issue: 2 Pages: 103410-103410
  • DOI: 10.1016/j.transci.2022.103410
  • Peer Reviewed / Open Access
• [Journal Article] Using indocyanine green fluorescence in laparoscopic surgery to identify and preserve rare branching of the right hepatic artery in pediatric congenital biliary dilatation (2022)
  • Author(s): Masuya Ryuta、Matsukubo Makoto、Nakame Kazuhiko、Kai Kengo、Hamada Takeomi、Yano Koichi、Imamura Naoya、Hiyoshi Masahide、Nanashima Atsushi、Ieiri Satoshi
  • Journal Title: Surgery Today Volume: 52 Issue: 10 Pages: 1510-1513
  • DOI: 10.1007/s00595-022-02516-5
  • Peer Reviewed / Open Access
• [Journal Article] Impact of the Number of Board-Certified Pediatric Surgeons per Pediatric Population on the Outcomes of Laparoscopic Fundoplication for Neurologically Impaired Patients (2022)
  • Author(s): Masuya Ryuta、Muto Mitsuru、Nakame Kazuhiko、Murakami Masakazu、Sugita Koshiro、Yano Keisuke、Onishi Shun、Harumatsu Toshio、Yamada Koji、Yamada Waka、Matsukubo Makoto、Kaji Tatsuru、Nanashima Atsushi、Ieiri Satoshi
  • Journal Title: Journal of Laparoendoscopic & Advanced Surgical Techniques Volume: 32 Issue: 5 Pages: 571-575
  • DOI: 10.1089/lap.2021.0713
  • Peer Reviewed
• [Journal Article] Laparoscopic dome resection for pediatric nonparasitic huge splenic cyst safely performed using indocyanine green fluorescence and percutaneous needle grasper (2022)
  • Author(s): Masuya Ryuta、Nakame Kazuhiko、Tahira Kosei、Kai Kengo、Hamada Takeomi、Yano Koichi、Imamura Naoya、Hiyoshi Masahide、Nanashima Atsushi、Ieiri Satoshi
  • Journal Title: Asian Journal of Endoscopic Surgery Volume: 15 Issue: 3 Pages: 693-696
  • DOI: 10.1111/ases.13052
  • Peer Reviewed
• [Presentation] CIRCULATING MATERNAL CHIMERIC CELLS HAVE AN IMPACT ON THE OUTCOME OF BILIARY ATRESIA (2022)
  • Author(s): Ryuta Masuya, Toshihiro Muraji, Sami Kanaan, Toshio Harumatsu, Mitsuru Mutoh, Miki Toma, Toshihiro Yanai, Anne Stevens, J Nelson, Atsushi Nanashima, Saoshi Ieiri
  • Organizer: 35th International Symposium on Pediatric Surgical Research.
  • Int'l Joint Research
• [Presentation] CLINICAL OUTCOME AND NEUROLOGICAL DEVELOPMENT OF PATIENTS WITH BILIARY ATRESIA ASSOCIATED WITH BLEEDING TENDENCY: A SINGLE INSTITUTION EXPERIENCE (2022)
  • Author(s): Ryuta Masuya, Toshihiro Muraji, Toshio Harumatsu, Seiro Machigashira, Masakazu Murakami, Koshiro Sugita, Keisuke Yano, Shun Onishi, Koji Yamada, Waka Yamada, Takafumi Kawano, Mitsuru Muto, Kazuhiko Nakame, Tatsuru Kaji, Atsushi Nanashima, Satoshi Ieiri
  • Organizer: The 26th Congress Of The Asian Association Of Pediatric Surgeons.
  • Int'l Joint Research
• [Presentation] 胆道閉鎖症術後患児における末梢血中の母親由来キメラ細胞検出と予後との相関の検討 (2022)
  • Author(s): 桝屋 隆太, 連 利博, Sami B. Kanaan, 春松 敏夫, 武藤 充, 東間 未来, 矢内 俊裕, Anne M Stevens, J Lee Nelson, 中目 和彦, 七島 篤志, 家入 里志
  • Organizer: 第49回日本胆道閉鎖症研究会
• [Presentation] 術前に判明した右肝動脈の破格を伴う先天性胆道拡張症に対する腹腔鏡手術の工夫 (2022)
  • Author(s): 桝屋 隆太,中目 和彦, 三好 きな, 松久保 眞, 七島 篤志, 家入 里志
  • Organizer: 第59回日本小児外科学会学術集会
• [Presentation] 術前に判明した右肝動脈の破格を伴う先天性胆道拡張症に対する腹腔鏡手術の工夫 (2022)
  • Author(s): 桝屋 隆太, 中目 和彦, 三好 きな, 松久保 眞, 土持 有貴, 濱田 剛臣, 今村 直哉, 旭吉 雅秀, 七島 篤志, 家入 里志
  • Organizer: 第45回日本膵・胆管合流異常研究会
• [Presentation] 胆道閉鎖症の病因論としての母親キメリズム関連GvHD仮説―臍帯血および胎盤病理に関する共同研究の提案― (2021)
  • Author(s): 桝屋隆太、連利博、春松敏夫、中目和彦、家入里志
  • Organizer: 第57回日本周産期・新生児医学会