Development of novel human intestinal disease model to elucidate intractable gastrointestinal malabsorption disorders

• Project/Area Number: 16K21668
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General surgery; General medical chemistry
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Sasaki Kengo 国立研究開発法人国立成育医療研究センター, 臓器・運動器病態外科部, レジデント (10740871)
• Research Collaborator: Kasahara Mureo ; Fukuda Akinari ; Uchida Hajime ; Yoshioka Takako ; Nakazawa Atsuko ; Akutsu Hidenori ; Umezawa Akihiro ; Machida Masakazu ; Kawasaki Tomoyuki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 胆汁酸 / オルガノイド / iPS細胞 / SLC10A2 / CYP3A4 / 腸管様構造体 / 遺伝子発現解析 / 難治性腸管吸収不全症 / 移植外科学 / 発生医学 / 疾患モデル / 難治性腸疾患 / ＰＦＩC

Outline of Final Research Achievements

Bile acids are reabsorbed in the lower part of the small intestine, transported to the liver via the portal vein, chemically conjugated, and then secreted back into the small intestine for enterohepatic circulation. Progressive familial intrahepatic cholestasis type 1 (PFIC 1) is a heterozygous mutation of the membrane protein ATP8B1 gene that causes malabsorption by secondarily decreasing the expression of bile acid transporters such as SLC10A2. In this study, we succeeded in producing small intestinal organoids from PFIC1-iPS cells, and characterized them and constructed a model for visualizing bile acid absorption. Quantitative PCR analysis revealed decreased expression of SLC10A2, a bile acid transporter, and decreased bile acid absorption compared with controls.

Academic Significance and Societal Importance of the Research Achievements

これまでPFIC1患者の肝臓における病態については数多く研究されてきているが、小腸についての研究は殆ど成されていない。小腸吸収不良の原因と関連するSLC10A2の低下と胆汁酸吸収を可視化できるシステムを構築することが出来た。これにより、SLC10A2の発現が増強する薬剤を探索・評価することが可能となりPFIC1型の創薬開発へ貢献することが出来た。

Research Products

• [Journal Article] Mild to Moderate Intrapulmonary Shunting in Pediatric Liver Transplantation: Is Screening Necessary? (2018)
  • Author(s): Mali V.P.、Fukuda A.、Shigeta T.、Uchida H.、Kanazawa H.、Hirata Y.、Rahayatri T.、Chiaki B.、Sasaki K.、Kitamura M.、Sakamoto S.、Kasahara M.
  • Journal Title: Transplantation Proceedings Volume: 50 Issue: 10 Pages: 3496-3500
  • DOI: 10.1016/j.transproceed.2018.05.025
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ABO-incompatible liver transplantation for children under 2?years of age: A case report and a single-center review (2018)
  • Author(s): Narumoto Soichi、Sakamoto Seisuke、Sasaki Kengo、Hirata Yoshihiro、Fukuda Akinari、Uchiyama Toru、Irie Rie、Yoshioka Takako、Kasahara Mureo
  • Journal Title: Pediatric Transplantation Volume: 23 Issue: 1
  • DOI: 10.1111/petr.13308
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel technique for pediatric living donor liver transplantation in patients with portal vein obstruction: The “pullout technique” (2018)
  • Author(s): Kasahara Mureo、Sasaki Kengo、Uchida Hajime、Hirata Yoshihiro、Takeda Masahiro、Fukuda Akinari、Sakamoto Seisuke
  • Journal Title: Pediatric Transplantation Volume: 22 Issue: 8
  • DOI: 10.1111/petr.13297
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Surgical treatment strategy for advanced hepatoblastoma: Resection versus transplantation (2018)
  • Author(s): Uchida Hajime、Sakamoto Seisuke、Sasaki Kengo、Takeda Masahiro、Hirata Yoshihiro、Fukuda Akinari、Hishiki Tomoro、Irie Rie、Nakazawa Atsuko、Miyazaki Osamu、Nosaka Shunsuke、Kasahara Mureo
  • Journal Title: Pediatric Blood & Cancer Volume: 65 Issue: 12
  • DOI: 10.1002/pbc.27383
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Histologiccal changes of the intestinal mucosa in complications following a living donor liver transplantation for progressive familial intrahepatic cholestasis type1 (2018)
  • Author(s): Stephanie M, Irie R, Sasaki K, Hirata Y, Narumoto S, Fukuda A, Sakamoto S, Arai K, Yoshioka T, Kasahara M
  • Journal Title: Pathology International Volume: 68 Issue: 9 Pages: 536-537
  • DOI: 10.1111/pin.12686
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impact of graft thickness reduction of left lateral segment on outcomes following pediatric living donor liver transplantation (2018)
  • Author(s): Kitajima Toshihiro、Sakamoto Seisuke、Sasaki Kengo、Narumoto Soichi、Kazemi Kourosh、Hirata Yoshihiro、Fukuda Akinari、Imai Rumi、Miyazaki Osamu、Irie Rie、Teramukai Satoshi、Uemoto Shinji、Kasahara Mureo
  • Journal Title: American Journal of Transplantation Volume: 18 Issue: 9 Pages: 2208-2219
  • DOI: 10.1111/ajt.14875
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Modified triangular hepatic vein reconstruction for preventing hepatic venous outflow obstruction in pediatric living donor liver transplantation using left lateral segment grafts (2018)
  • Author(s): Fukuda Akinari、Sakamoto Seisuke、Sasaki Kengo、Narumoto Soichi、Kitajima Toshihiro、Hirata Yoshihiro、Hishiki Tomoro、Kasahara Mureo
  • Journal Title: Pediatric Transplantation Volume: 22 Issue: 3
  • DOI: 10.1111/petr.13167
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel technique for collateral interruption to maximize portal venous flow in pediatric liver transplantation (2018)
  • Author(s): Sakamoto Seisuke、Sasaki Kengo、Kitajima Toshihiro、Hirata Yoshihiro、Narumoto Soichi、Kazemi Kourosh、Fukuda Akinari、Miyazaki Osamu、Nosaka Shunsuke、Kasahara Mureo
  • Journal Title: Liver Transplantation Volume: 24 Issue: 7 Pages: 969-973
  • DOI: 10.1002/lt.25016
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Living donor liver transplantation during the first three months of life (2017)
  • Author(s): Kasahara M, Sakamoto S, Sasaki K, Uchida H, Kitajima T, Shigeta T, Narumoto S, Hirata Y, Fukuda A
  • Journal Title: Liver Transpl Volume: Feb 21 Issue: 8 Pages: 1051-1057
  • DOI: 10.1002/lt.24743
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hyperammonemia in ornithine transcarbamylase-deficient recipients following living donor liver transplantation from heterozygous carrier donors (2017)
  • Author(s): Rahayatri TH, Uchida H, Sasaki K, Shigeta T, Hirata Y, Kanazawa H, Mali V, Fukuda A, Sakamoto S, Kasahara M
  • Journal Title: Pediatr Transplant Volume: 21 Issue: 1
  • DOI: 10.1111/petr.12848
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A xenogeneic-free system generating functional human gut organoids from pluripotent stem cells (2017)
  • Author(s): 2.Uchida H, Machida M, Miura T, Kawasaki T, Okazaki T, Sasaki K, Sakamoto S, Ohuchi N, Kasahara M, Umezawa A, Akutsu H.
  • Journal Title: Journal of Clinical Investigation Insight Volume: 2 Issue: 1
  • DOI: 10.1172/jci.insight.86492
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Chemotherapy-induced B-cell depletion in hepatoblastoma patients undergoing ABO-incompatible living donor liver transplantation (2016)
  • Author(s): Kanazawa H, Fukuda A, Mali VP, Rahayatri TH, Hirata Y, Sasaki K, Uchida H, Shigeta T, Sakamoto S, Matsumoto K, Kasahara M
  • Journal Title: Pediatr Transplant Volume: 20 Issue: 3 Pages: 401-407
  • DOI: 10.1111/petr.12675
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Benefit of early inflow exclusion during living donor liver transplantation for unresectable hepatoblastoma. (2016)
  • Author(s): Uchida H, Fukuda A, Sasaki K, Hirata Y, Shigeta T, Kanazawa H, Nakazawa A, Miyazaki O, Nosaka S, Mali VP, Sakamoto S, Kasahara M
  • Journal Title: J Pediatr Surg Volume: 51 Issue: 11 Pages: 1807-1811
  • DOI: 10.1016/j.jpedsurg.2016.04.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sequential analysis of variable markers for predicting outcomes in pediatric patients with acute liver failure. (2016)
  • Author(s): Uchida H, Sakamoto S, Fukuda A, Sasaki K, Shigeta T, Nosaka S, Kubota M, Nakazawa A, Nakagawa S, Kasahara M
  • Journal Title: Hepatol Res Volume: dec 29 Issue: 12 Pages: 1241-1251
  • DOI: 10.1111/hepr.12859
  • Peer Reviewed / Open Access / Int'l Joint Research