Induction of pancreatic beta cell expansion in transplanted mouse and human islets by targeting receptor of advanced glycation endo products

• Project/Area Number: 25293281
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Fukuoka University
• Principal Investigator: Yasunami Yohichi 福岡大学, 医学部, 教授 (00166521)
• Co-Investigator(Kenkyū-buntansha): KODAMA Shohta 福岡大学, 医学部, 教授 (90549338) ; ITOH Takeshi 福岡大学, 医学部, 講師 (70634400) ; MISUMI Yoshio 福岡大学, 医学部, 准教授 (10148877)
• Co-Investigator(Renkei-kenkyūsha): TANIGUCHI Masaru 国立研究開発法人理化学研究所, 統合生命医科学研究センター, グループディレクター (80110310) ; WATARAI Hiroshi 東京大学, 医科学研究所, 准教授 (70415339)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: 膵島移植 / 糖尿病 / β細胞再生 / ヒト膵島 / 移植膵島再生 / 膵島再生

Outline of Final Research Achievements

The aim of the present study is to determine whether expansion of transplanted islets is induced when the injury of transplanted islets is prevented after transplantation. For those purposes, RAGE-/- vs wild-type mouse islets are used as donors since RAGE signals have been reported to be involved in beta cell failure. It was found that RAGE-/- islets are not only protected from the injuries but also expand after transplantation. The array analysis revealed that the beneficial effect of RAGE-/- islets was mediated through the upregulation of GLP-1 R expression. In addition, RAGE inhibitors including soluble form RAGE (sRAGE) was found to have the similar beneficial effect when applied to wild-type islets prior to transplantation. In case of human islets, the effect of sRAGE was not evident when treated human islets were grafted beneath the kidney capsule of STZ-diabetic NOD/scid mice and therefore, the effects of other RAGE inhibitors are currently under investigation.

Research Products

• [Journal Article] Adjusting the 17β-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy. (2016)
  • Author(s): Inada A, Inada O, Fujii NL, Nagafuchi S, Katsuta H, Yasunami Y, Matsubara T, Arai H, Fukatsu A, Nabeshima YI.
  • Journal Title: J Am Soc Nephrol. Volume: 27
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Plasma biomarker for detection of early stage pancreatic cancer and risk factors for pancreatic malignancy using antibodies for apolipoprotein-AII isoforms. (2015)
  • Author(s): Honda K, Kobayashi M, Okusaka T, Rinaudo JA, Huang Y, Marsh T, Sanada M, Sasajima Y, Nakamori S, Shimahara M, Ueno T, Tsuchida A, Sata N, Ioka T, Yasunami Y, Kosuge T, Miura N, Kamita M, Sakamoto T, Shoji H, Jung G, Srivastava S, Yamada T.
  • Journal Title: Scientific Reports Volume: Nov 9;5 Issue: 1 Pages: 15921-15921
  • DOI: 10.1038/srep15921
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] HMGB1-Mediated Early Loss of Transplanted Islets Is Prevented by Anti-IL-6R Antibody in Mice. (2014)
  • Author(s): Itoh T, Nitta T, Nishinakamura H, Kojima D, Mera T, Ono J, Kodama S, Yasunami Y.
  • Journal Title: Pancreas. Volume: 44(1) Issue: 1 Pages: 166-71
  • DOI: 10.1097/mpa.0000000000000188
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Long-term outcomes of clinical transplantation of pancreatic islets with uncontrolled donors after cardiac death: a multicenter experience in Japan. (2014)
  • Author(s): Anazawa T, Saito T, Goto M, Kenmochi T, Uemoto S, Itoh T, Yasunami Y, Kenjo A, Kimura T, Ise K, Tsuchiya T, Gotoh M.
  • Journal Title: Transplant Proc. Volume: 46(6) Issue: 6 Pages: 1980-4
  • DOI: 10.1016/j.transproceed.2014.06.006
  • Peer Reviewed / Open Access
• [Journal Article] HMGB1-mediated early loss of transplanted islets is prevented by anti-IL-6R antibody in mice. (2014)
  • Author(s): Itoh T, Nitta T, Nishinakamura H, Kojima D, Mera T, Ono J, Kodama S, Yasunami Y.
  • Journal Title: Pancreas Volume: In press
  • Peer Reviewed
• [Journal Article] Pretreatment of donor islets with the Na(+) /Ca(2+) exchanger inhibitor improves the efficiency of islet transplantation (2013)
  • Author(s): Mera T, Itoh T, Kita S, Kodama S, Kojima D, Nishinakamura H, Okamoto K, Ohkura M, Nakai J, Iyoda T, Iwamoto T, Matsuda T, Baba A, Omori K, Ono J, Watarai H, Taniguchi M, Yasunami Y.
  • Journal Title: Am J Transplant Volume: 13 Issue: 8 Pages: 2154-2160
  • DOI: 10.1111/ajt.12306
  • Peer Reviewed
• [Presentation] ドナー膵島のRAGEを標的にした移植膵島障害の新規制御法 (2016)
  • Author(s): 安波洋一、棟居聖一、新田直柔、濱口百合子、山本靖彦
  • Organizer: 第43回日本膵・膵島移植研究会
  • Place of Presentation: ホテルグランヴィア広島（広島市）
  • Year and Date: 2016-03-04
• [Presentation] Early loss of transplanted islets is prevented by targeting receptor for advanced glycation end products of donor islets in mice. (2015)
  • Author(s): Yasunami Y, Munesue S, Nitta N, Yamamoto Y.
  • Organizer: IPITA - IXA - CTS 2015 Joint Congress
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2015-11-15
  • Int'l Joint Research
• [Presentation] Rage of donor islets is a novel target to improve the efficiency of islet transplantation. (2015)
  • Author(s): Yasunami Y, Munesue S, Yamamoto Y, Yamamoto H.
  • Organizer: 12th International symposium on the Maillard Reaction
  • Place of Presentation: 東京大学 伊藤国際学術研究センター（東京）
  • Year and Date: 2015-09-01
  • Int'l Joint Research
• [Presentation] Addition of a specific Na+/Ca2+ exchanger inhibitor into collagenase solution prevents hypoxic damage of islets during isolation, facilitating to improve the efficiency of islet transplantation in mice. (2014)
  • Author(s): Itoh T, Mera T, Nishinakamura H, Kodama S, Yasunami Y.
  • Organizer: The 2014 World Transplant Congress
  • Place of Presentation: San Fransisco, USA
  • Year and Date: 2014-07-26 – 2014-07-31
• [Presentation] Expansion of Transplanted Islets by Co-transplantation of Adipose Tissue-derived Mesenchymal Stem Cells in Mice. (2014)
  • Author(s): Tanaka T, Itoh T, Matsumoto M, Kojima D, Mera T, Nishinakamura H, Kodama S, Ono J, Yanase T, Yasunami Y.
  • Organizer: 74th Scientific Sessions of American Diabetes Association
  • Place of Presentation: San Fransisco, USA
  • Year and Date: 2014-06-13 – 2014-06-17
• [Presentation] 脂肪組織由来間葉系幹細胞による移植膵島生着率改善と膵島量増加効果 (2014)
  • Author(s): 田中 智子，伊東 威，松本 征仁，小島 大望，米良 利之，西中村 瞳，小玉 正太，小野 順子，柳瀬 敏彦，安波 洋一
  • Organizer: 第41回日本膵･膵島移植研究会
  • Place of Presentation: 名古屋
• [Presentation] Pretreatment of Donor Islets with a Specific Inhibitor of Na+/Ca2+ Exchanger Prior to Transplantation Improves the Efficiency of Islet Transplantation. (2013)
  • Author(s): Itoh T, Mera T, Kita S, Kojima D, Nishinakamura H, Ono J, Iwamoto T, Kodama S, Yasunami Y.
  • Organizer: The 13th Congress of the Asian Society of Transplantation
  • Place of Presentation: Kyoto, Japan
• [Presentation] The early loss of transplanted islets is prevented by targeting Na+/Ca2+ exchanger of donor islets prior to transplantation. (2013)
  • Author(s): Itoh T, Mera T, Kita S, Kodama S, Kojima D, Nishinakamura H, Iwamoto T, Omori K, Ono J, Watarai H, Taniguchi M, Yasunami Y.
  • Organizer: The 14th World Congress of the International Pancreas and Islet Transplant Association (IPITA 2013)
  • Place of Presentation: Monterey, USA
• [Presentation] A novel strategy to improve the efficiency of islet transplantation targeting Na+/Ca2+ exchanger of donor islets prior to transplantation.
  • Author(s): Yasunami Y.
  • Organizer: The 12th Beta Cell Research and islet Transplantation Symposium
  • Place of Presentation: Seoul, Korea
  • Invited