The new method for the liver failure using the hybrid transplantation of the liver and Muse cells

• Project/Area Number: 17K10504
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Tohoku University
• Principal Investigator: Shigehito Miyagi 東北大学, 大学病院, 准教授 (00420042)
• Co-Investigator(Kenkyū-buntansha): 後藤 昌史 東北大学, 医学系研究科, 教授 (50400453) ; 戸子台 和哲 東北大学, 大学病院, 助教 (50581641) ; 原 康之 東北大学, 医学系研究科, 非常勤講師 (50636008) ; 中西 渉 東北大学, 大学病院, 助教 (50636024) ; 宮澤 恒持 東北大学, 医学系研究科, 非常勤講師 (80757237)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: Muse細胞 / 心停止ドナーグラフト / 過小グラフト / 酸素化灌流 / 類洞微小循環 / 移植・再生医療

Outline of Final Research Achievements

The treatment for the sinusoidal microcirculatory injury (SMI) induced by excessive shear stress to liver sinusoidal endothelial cells (LSECs) is necessary for the regeneration. Multilineage-differentiating Stress Enduring (Muse) cells selectively home to the injured organ and repair by spontaneously differentiation. We hypothesized that intravenous administration of Muse cells might improve SMI the sinusoid. Then we evaluated the protective effects of Muse cells using an extra-small partial liver transplantation model in rats. The analysis of liver sinusoidal images, indocyanine green test, immunohistochemical stain of LSECs revealed that sinusoidal continuity, volume and surface area were protected significantly by administrated Muse cells. Furthermore, Ki-67 positive ratio of hepatocyte is higher in Muse group. The combination of cell transplantation using Muse cells and organ transplantation of small-for-size grafts is effective as a treatment for end-stage of liver disease.

Academic Significance and Societal Importance of the Research Achievements

肝不全治療における新たな手法、臓器移植と細胞移植のハイブリッド移植という新たな治療の臨床応用へのきっかけを作るこ事ができた。Muse細胞のすぐれた組織修復能力と抗炎症効果が確認でき、今後の再生医療におけるきっかけとなった。過小肝グラフト移植などにおける類洞内皮障害や門脈圧亢進症状（SFSS）の改善というレベルでの効果は、Museの組織修復能力は有効だと確認できた。今後の研究継続が必要である。

Research Products

• [Journal Article] Strategy towards tailored donor tissue-specific pancreatic islet isolation (2019)
  • Author(s): Miyazaki Yuki、Murayama Kazutaka、Fathi Ibrahim、Imura Takehiro、Yamagata Youhei、Watanabe Kimiko、Maeda Hiroshi、Inagaki Akiko、Igarashi Yasuhiro、Miyagi Shigehito、Shima Hiroki、Igarashi Kazuhiko、Kamei Takashi、Unno Michiaki、Goto Masafumi
  • Journal Title: PLOS ONE Volume: 14 Issue: 5 Pages: e0216136-e0216136
  • DOI: 10.1371/journal.pone.0216136
  • Peer Reviewed / Open Access
• [Journal Article] A simple and useful predictive assay for evaluating the quality of isolated hepatocytes for hepatocyte transplantation (2019)
  • Author(s): Matsumura M, Imura T, Inagaki A, Ogasawara H, Fukuoka K , Fathi I, Miyagi S, Ohashi K, Unno M, Kamei T, Satomi S, Goto M
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 6166-6166
  • DOI: 10.1038/s41598-019-42720-x
  • Peer Reviewed / Open Access
• [Journal Article] Pediatric Living-Donor Liver Transplant Recipients without Transition After Reaching Adulthood (2019)
  • Author(s): Nakanishi C1, Miyagi S1, Tokodai K1, Nakanishi W1, Nishimura R1, Goto M2, Unno M1, Kamei T1.
  • Journal Title: Ann Transplant. 2019 Jan 8;24:18-24 Volume: 24 Pages: 18-24
  • DOI: 10.12659/aot.911544
  • Peer Reviewed
• [Journal Article] Cytoprotective Effects of Mesenchymal Stem Cells During Liver Transplantation from Donors After Cardiac Death in Rats. (2018)
  • Author(s): Sasajima H, Miyagi S, Kakizaki Y, Kamei T, Unno M, Satomi S, Goto M.
  • Journal Title: Transplant Proc. 2018 Nov;50(9):2815-2820. Volume: 50(9) Issue: 9 Pages: 2815-2820
  • DOI: 10.1016/j.transproceed.2018.02.180
  • Peer Reviewed
• [Journal Article] Arterial Complication After Simultaneous Pancreas-Kidney Transplantation From an Abdominal Aortic Aneurysm Donor: A Case Report. (2018)
  • Author(s): Shimizu K, Miyagi S, Maida K, Nakanishi W, Hara Y, Tokodai K, Nakanishi C, Umeda Y, Satomi S, Goto M, Unno M, Kamei T.
  • Journal Title: Transplant Proc. 2018 Nov;50(9):2891-2894. Volume: 50(9) Issue: 9 Pages: 2891-2894
  • DOI: 10.1016/j.transproceed.2018.02.188
  • Peer Reviewed
• [Journal Article] Correlation Between Splenectomy and Portal Vein Complications in Living Donor Liver Transplantation. (2018)
  • Author(s): Miyagi S, Nakanishi C, Hara Y, Nakanishi W, Tokodai K, Shimizu K, Uematsu S, Kumata H, Kakizaki Y, Goto M, Kamei T, Unno M, Satomi S.
  • Journal Title: Transplant Proc. 2018 Nov;50(9):2611-2613. Volume: 50(9) Issue: 9 Pages: 2611-2613
  • DOI: 10.1016/j.transproceed.2018.03.104
  • Peer Reviewed
• [Journal Article] Effect of Middle Hepatic Vein Tributaries Preserving Technique Until Just Before Graft Retrieval on Donors' Surgical Outcomes in Living Donor Liver Transplantation. (2018)
  • Author(s): Miyazawa K, Miyagi S, Nakanishi C, Hara Y, Tokodai K, Nakanishi W, Uematsu S, Shimizu K, Goto M, Kamei T, Unno M.
  • Journal Title: Transplant Proc. 2018 Jun;50(5):1538-1543. Volume: 50(5) Issue: 5 Pages: 1538-1543
  • DOI: 10.1016/j.transproceed.2018.02.061
  • Peer Reviewed
• [Journal Article] The effects of short-term subnormothermic perfusion after cold preservation on liver grafts from donors after cardiac death: An ex vivo rat model (2018)
  • Author(s): Kakizaki Y, Miyagi S, Shimizu K, Miyazawa K, Nakanishi W, Tokodai K, Hara Y, Nakanishi C, Unno M, Kamei T, Goto M, Satomi S
  • Journal Title: Transplantation Volume: 102 Issue: 4 Pages: e147-e154
  • DOI: 10.1097/tp.0000000000002080
  • Peer Reviewed / Open Access
• [Journal Article] The Optimization of the Prevascularization Procedures for Improving Subcutaneous Islet Engraftment. (2018)
  • Author(s): Uematsu SS, Inagaki A, Nakamura Y, Imura T, Igarashi Y, Fathi I, Miyagi S, Ohuchi N, Satomi S, Goto M.
  • Journal Title: Transplantation. 2018 Mar;102(3):387-395 Volume: 102(3) Issue: 3 Pages: 387-395
  • DOI: 10.1097/tp.0000000000001970
  • Peer Reviewed / Open Access
• [Journal Article] Arterial and biliary complications after living donor liver transplantation: a single-center retrospective study and literature review. (2018)
  • Author(s): Miyagi S, Kakizaki Y, Shimizu K, Miyazawa K, Nakanishi W, Hara Y, Tokodai K, Nakanishi C, Kamei T, Ohuchi N, Satomi S.
  • Journal Title: Surg Today Volume: 48(2) Issue: 2 Pages: 131-139
  • DOI: 10.1007/s00595-017-1515-9
  • Peer Reviewed / Open Access
• [Journal Article] The Optimization of Short-Term Hepatocyte Preservation Before Transplantation. (2017)
  • Author(s): Fukuoka K, Inagaki A, Nakamura Y, Matsumura M, Yoshida S, Imura T, Igarashi Y, Miyagi S, Ohashi K, Enosawa S, Kamei T, Unno M, Ohuchi N, Satomi S, Goto M.
  • Journal Title: Transplant Direct. Volume: 19;3(7) Issue: 7 Pages: e176-e176
  • DOI: 10.1097/txd.0000000000000687
  • Peer Reviewed / Open Access
• [Journal Article] Impact of the Trough Level of Calcineurin Inhibitor on the Prevalence of Donor-Specific Human Leukocyte Antigen Antibodies During Long-Term Follow-Up After Pediatric Liver Transplantation: Antibody Strength and Complement-Binding Ability. (2017)
  • Author(s): Tokodai K, Miyagi S, Nakanishi C, Goto M, et al(total8, Second).
  • Journal Title: Transplant Direct. 2017 Jul 11;3(8):e196. Volume: 3(8) Issue: 8 Pages: e196-e196
  • DOI: 10.1097/txd.0000000000000713
  • Peer Reviewed / Open Access
• [Presentation] May Kidney Donor Profile Index (KDPI) Become the Predictive Factor after Simultaneous Pancreas-Kidney Transplantation from Marginal Donors? (2019)
  • Author(s): Shigehito Miyagi, Kazuaki Tokodai, Wataru Nakanishi, Ryuichi Nishimura, Atsushi Fujio, Yuta Kakizaki, Kengo Sasaki, Hideaki Sasajima, Michiaki Unno, Takashi Kamei and Masafumi Goto.
  • Organizer: International Pancreas & Islet Transplant Association (IPITA) 2019
  • Int'l Joint Research
• [Presentation] The Risks of Living Donor Liver Transplantation Using Small-for-size Grafts (2019)
  • Author(s): Shigehito Miyagi, Yoshihiro Shono, Kazuaki Tokodai, Wataru Nakanishi, Ryuichi Nishimura, Atsushi Fujio, Kengo Sasaki, Yuki Miyazaki, Yuta Kakizaki, Hideaki Sasajima, Michiaki Unno and Takashi Kamei.
  • Organizer: Congress of Asian Society of Transplantation (CAST) 2019
  • Int'l Joint Research
• [Presentation] The Cytoprotective Effects of Mesenchymal Stem Cells during Liver Transplantation from Donors after Cardiac Death in Swine (2019)
  • Author(s): Hideaki Sasajima1, Shigehito Miyagi1, Yuta Kakizaki1, Syuhei Yamada1,Takashi Kamei1, Michiaki Unno1, and Masafumi Goto2
  • Organizer: Congress of Asian Society of Transplantation (CAST) 2019
  • Int'l Joint Research
• [Presentation] Successful experiences of ABO incompatible adult liver transplantation: recipient's preoperative IgG titer was 1:4096 (2019)
  • Author(s): Yoshikatsu Saitoh1）, Shigehito Miyagi1), Kazuaki Tokodai1）, Wataru Nakanishi1）, Ryuichi Nishimura1）, Atsushi Fujio1）, Takashi Kamei1）, Michiaki Unno1）, Masafumi Goto1
  • Organizer: Congress of Asian Society of Transplantation (CAST) 2019
  • Int'l Joint Research
• [Presentation] The Effects of Short-Term Normothermic and Subnormothermic Perfusion after Cold Preservation on Liver Transplantation from Donors after Cardiac Death (2019)
  • Author(s): Syuhei Yamada1, Shigehito Miyagi1, Yasuyuki Hara1, Yuta Kakizaki1, Hideaki Sasajima1, Keisei Fujimori1, Takashi Kamei1, Michiaki Unno1 and Masafumi Goto2.
  • Organizer: Congress of Asian Society of Transplantation (CAST) 2019
  • Int'l Joint Research
• [Presentation] Liver transplantation experiment of pig model for clinical surgeons (2019)
  • Author(s): Shuehi Yamada, Yuta kakizaki, Shigehito Miyagi, Kazuaki Tokodai, Wataru Nakanishi, Ryuichi Nishimura,Atsushi Fujio, Takeshi Naito, Unno Michiaki, Takashi Kamei
  • Organizer: 日本消化器外科学会
• [Presentation] Liver transplantation for the patients with multiple laparotomies including Kasai’s carryover cases (2019)
  • Author(s): Shigehito Miyagi, Kazuaki Tokodai, Wataru Nakanishi, Ryuichi Nishimura, Atsushi Fujio, Kengo Sasaki, Yuki Miyazaki, Hideaki Sasajima, Takeshi Naito, Takashi Kamei and Michiaki Unno.
  • Organizer: 日本消化器外科学会
• [Presentation] SustainableでAttractiveな 肝胆膵移植外科医育成体制の構築 (2019)
  • Author(s): 宮城重人、戸子台和哲、中西渉、西村隆一、藤尾淳、 佐々木健吾、宮崎勇希、笹嶋秀憲、 内藤剛、亀井尚、海野倫明
  • Organizer: 日本肝移植学会
• [Presentation] 肝動脈・門脈再建困難症例に対する再建戦略とpitfall (2019)
  • Author(s): 宮城重人、戸子台和哲、中西渉、西村隆一、藤尾淳、佐々木健吾、宮崎勇希、笹嶋秀憲 亀井尚、海野倫明
  • Organizer: 日本肝移植学会
• [Presentation] 血液型不適合肝移植の現状と リスクファクターの検討 (2019)
  • Author(s): 宮城重人、戸子台和哲、中西渉、西村隆一、藤尾淳、 佐々木健吾、宮崎勇希、柿崎裕太 後藤昌史、亀井尚、海野倫明
  • Organizer: 日本移植学会
• [Presentation] The risk factors for portal vein thrombosis after living donor liver transplantation in adults (2018)
  • Author(s): Shigehito Miyagi, Chikashi Nakanishi, Yasuyuki Hara, Wataru Nakanishi, Kazuaki Tokodai, Kenji Shimizu, Satomi Uematsu, Hiroyuki Kumata, Yuta Kakizaki, Masafumi Goto, Susumu Satomi, Michiaki Unno and Takashi Kamei.
  • Organizer: 27th International Congress of The Transplantation Society
  • Int'l Joint Research
• [Presentation] The optimization of the hepatocyte surface modification procedures in terms of heparin and apyrase for improving hepatocyte engraftment (2018)
  • Author(s): Hiroyuki Ogasawara1, Yuji Teramura2,3, Takehiro Imura4, Akiko Inagaki4, Yoshikatsu Saito1, Muneyuki Matsumura1, Kengo Fukuoka1, Ibrahim Fathi4, Shigehito Miyagi1, Kristina Nilsson3, Kazuo Ohashi5, Michiaki Unno1, Takashi Kamei1, Susumu Satomi1, Bo Nilsson3, Elisabet Gustafson6, Masafumi Goto1,2
  • Organizer: 27th International Congress of The Transplantation Society
  • Int'l Joint Research
• [Presentation] A comparison of the transplant efficiency between intraportal and intrasplenic procedures in hepatocyte transplantation (2018)
  • Author(s): Hiroyuki Ogasawara1, Akiko Inagaki2, Takehiro Imura2, Yoshikatsu Saito1, Muneyuki Matsumura1, Kengo Fukuoka1, Ibrahim Fathi2, Shigehito Miyagi1, Kazuo Ohashi3, Michiaki Unno1, Takashi Kamei1, Susumu Satomi1 and Masafumi Goto1,2
  • Organizer: 27th International Congress of The Transplantation Society
  • Int'l Joint Research
• [Presentation] 心停止下摘出肝グラフトに対する移植前室温酸素化灌流の臓器保存効果 (2018)
  • Author(s): 柿﨑裕太，宮城重人，清水健司，熊田博之， 松村宗幸，宮﨑勇希，福岡健吾，植松智海，原康之，戸子台和哲，中西史，海野倫明，亀井尚
  • Organizer: 日本外科学会
• [Presentation] 生体肝移植における微小胆管に対する顕微鏡下胆道再建法の短期成績及び胆道狭窄の危険因子の検討 (2018)
  • Author(s): 宮城重人、中西史、戸子台和哲、原康之、中西渉、西村隆一、 清水健司、福岡健吾、松村宗幸、熊田博之、 里見進、亀井尚、海野倫明
  • Organizer: 日本肝移植研究会
• [Presentation] 脳死肝摘出オールジャパン体制は是か否か―肝膵腎移植を同チームで施行する立場から (2018)
  • Author(s): 宮城重人、戸子台和哲、中西 渉、西村隆一、藤尾淳、佐々木健吾、福岡健吾、 熊田博之、柿崎裕太、藤盛啓成、後藤昌史、亀井尚、海野倫明
  • Organizer: 日本移植学会
• [Presentation] 膵島との共移植が肝細胞生着へ及ぼす影響に関する検討 (2018)
  • Author(s): 齋藤純健1), 稲垣明子2), 猪村武弘2), 猪村梢2), Ibrahim Fathi2), 小笠原弘之1), 宮城重人1), 亀井尚1), 海野倫明1), 安波洋一3), 後藤昌史2)
  • Organizer: 日本臓器保存生物医学会
• [Presentation] 大動物を用いた心停止ドナー肝グラフトに対する間葉系幹細胞による保護効果の検証 (2018)
  • Author(s): 笹嶋秀憲, 宮城重人, 柿崎裕太
  • Organizer: 日本臓器保存生物医学会
• [Presentation] The Cytoprotective Effects of Mesenchymal Stem Cells on Liver Transplantation from Donors after Cardiac Death (2017)
  • Author(s): Hideaki Sasajima1, Shigehito Miyagi1, Yuta Kakizaki1, Takashi Kamei1, Michiaki Unno1, Susumu Satomi1, and Masafumi Goto
  • Organizer: 15th Congress of the Asian Society of Transplantation (CAST)
• [Presentation] Effect of the middle hepatic vein tributaries preserving technique just until graft retrieving on donors' surgical outcomes in living donor liver transplantation (2017)
  • Author(s): Koji Miyazwa, Shigehito Miyagi, Chikashi Nakanishi, Yasuyuki Hara, Kazuaki Tokodai, Wataru Nakanishi, et al (total11, second).
  • Organizer: 15th Congress of the Asian Society of Transplantation (CAST)
• [Presentation] 移植前肝細胞におけるviability評価法としてのADP/ATP assayの有用性に関する検証 (2017)
  • Author(s): 松村 宗幸, 猪村 武弘, 小笠原 弘之, 福岡 健吾, 稲垣 明子, 宮城 重人, 海野 倫明, 亀井 尚, 里見 進, 後藤 昌史
  • Organizer: 日本臓器保存生物医学会
• [Presentation] 心停止ドナー肝グラフトに対する 間葉系幹細胞による保護効果の検証 (2017)
  • Author(s): 笹嶋 秀憲 宮城 重人
  • Organizer: 日本臓器保存生物医学会
• [Presentation] ブタ心停止ドナーモデルにおける肝移植前酸素化室温灌流の臓器保存効果 (2017)
  • Author(s): 柿﨑裕太，宮城重人，清水健司，熊田博之，松村宗幸，宮﨑勇希，福岡健吾，植松智海，原康之，中西史，海野倫明，亀井尚
  • Organizer: 日本移植学会