Long-term islet graft survival induced by regulating HMGB-1

• Project/Area Number: 22591527
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Fukushima Medical University
• Principal Investigator: SAITO Takaharu 福島県立医科大学, 医学部, 博士研究員 (60508795)
• Co-Investigator(Kenkyū-buntansha): SAITO Takuro 福島県立医科大学, 医学部, 医監兼教授 (20305361) ; SATO Yoshihiro 福島県立医科大学, 医学部, 博士研究員 (60347218) ; ANAZAWA Takayuki 福島県立医科大学, 医学部, 助教 (90566811) ; ISE Kazuya 福島県立医科大学, 医学部, 講師 (90363746) ; GOTOH Mitsukazu 福島県立医科大学, 医学部, 教授 (50162160)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 膵島移植 / High-mobility group box 1 / calreticulin / binding immunoglobulin protein / 細胞死 / DAMPｓ / HMGB-1 / マイトマイシンC

Research Abstract

Cellular stress or damage causes expression and release of endogenous molecules, such as damage-associated molecular patterns (DAMPs) molecules. High-mobility group box 1 (HMGB1) released from damaged islets has been shown to be associated with poor islet graft outcome, however, few studies evaluated implication of other endogenous molecules such as calreticulin as categorized DAMPs, and binding immunoglobulin protein (Bip) as categorized resolution-associated molecular patterns (RAMPs). Immediately after isolation, HMGB1, calreticulin as categorized DAMPs, and Bip, as categorized resolution-associated molecular patterns (RAMPs), signals were found in the cytoplasm of islet cells, more intensively as compared to those in islets in native pancreas. After culture for 1 day, only some of peripheral islet cells showed signals for these molecules, while central damaged areas, composed of necrotic cells but not apoptotic cells, strongly expressed these signals. Our findings suggest that necrotic process of the cells in central area after islet isolation and subsequent culture leads to express and release of not only DAMPs but also RAMPs, which might be responsible for counterbalance the DAMPs. A better understanding of the biological response to both DAMPs and RAMPs in isolated/cultured islets would improve its efficacy of islet transplantation.

Research Products

• [Journal Article] Mitomycin-C treatment significantly reduces central damage of islets in culture (2012)
  • Author(s): Saito T, Saito T, Sato Y, Ise K, Anazawa T, Oshibe I, Haga J, Yamamoto M, Waguri S, Gotoh M.
  • Journal Title: Pancreas. Volume: 41(2) Issue: 2 Pages: 245-252
  • DOI: 10.1097/mpa.0b013e31822461c7
  • Peer Reviewed
• [Journal Article] Improved islet yield and function by use of a chloride channel blocker during collagenase digestion. (2011)
  • Author(s): Anazawa T, Sato Y, Saito T, Tsuchiya T, Kenjo A, Kimura T, Haga J, Miyake M, Waguri S, Hazama A, Gotoh M.
  • Journal Title: Transplantation Volume: 92(8) Issue: 8 Pages: 871-877
  • DOI: 10.1097/tp.0b013e31822e6eb4
  • Peer Reviewed
• [Journal Article] Reversal of diabetes by the creation of neo-islet tissues into a subcutaneous site using islet cell sheets. (2011)
  • Author(s): Saito T, Ohashi K, Utoh R, Shimizu H, Ise K, Suzuki H, Yamato M, Okano T, Gotoh M
  • Journal Title: Transplantation Volume: 92(11) Issue: 11 Pages: 1231-1236
  • DOI: 10.1097/tp.0b013e3182375835
  • Peer Reviewed
• [Presentation] Inhibition of chloride ion influx into islet cells protects islets during pancreatic islet isolation (2011)
  • Author(s): Anazawa T, Tsuchiya T, Kenjo A, Haga J, Sato T, Sato N, Saito T, Sato Y, Miyake M, Hazama A, Gotoh M
  • Organizer: The 13th World congress of International pancreas and islet transplantation association
  • Place of Presentation: Prague, Czech Republic
• [Presentation] Mitomycin-C treatment protects islets from the progression of central damage during culture (2011)
  • Author(s): Haga J, Saito T, Anazawa T, Tsuchiya T, Kenjo A, Sato S, Sato N, Saito T, Ise K, Yamamoto M, Waguri S, Gotoh M
  • Organizer: The 13th World congress of International pancreas and islet transplantation association
  • Place of Presentation: Prague, Czech Republic.
• [Presentation] Functional Islet Tissue Engineering in Subcutaneous Site Using Fabricated Islet Cell Sheets. (2011)
  • Author(s): Shimizu H, Ohashi K, Saito T, Utoh R, Ise K, Yamato M, Okano T, Gotoh M
  • Organizer: The 13th World congress of International pancreas and islet transplantation association
  • Place of Presentation: Prague, Czech Republic.
• [Presentation] Cl-チャネル阻害による細胞保護効果の膵島分離への応用-臨床膵島移植確立への細胞生理学的アプローチ- (2011)
  • Author(s): 穴澤貴行, 土屋貴男, 見城 明, 芳賀淳一郎, 佐藤 哲, 三宅将生, 狹間章博, 後藤満一
  • Organizer: 第111回日本外科学会定期学術集会
  • Place of Presentation: 東京
• [Presentation] 重症低血糖発作を伴うインスリン依存性糖尿病に対する心停止ドナーからの膵島移植:日本膵・膵島移植研究会事務局報告. (2011)
  • Author(s): 穴澤貴行, 土屋貴男, 伊勢一哉, 見城明, 齋藤拓朗, 後藤満一
  • Organizer: 第47回日本移植学会総会
  • Place of Presentation: 仙台
• [Presentation] Mitomycin-C treatment protects islets from the progression of central damage during culture (2011)
  • Author(s): Haga J, Saito T, Anazawa T, Tsuchiya T, Kenjo A, Sato S, Sato N, Saito T, Ise K, Yamamoto M, Waguri S, Gotoh M
  • Organizer: The 13th World congress of International pancreas and islet transplantation association
  • Place of Presentation: Prague, Czech Republic
• [Presentation] Functional Islet Tissue Engineering in Subcutaneous Site Using Fabricated Islet Cell Sheets (2011)
  • Author(s): Shimizu H, Ohashi K, Saito T, Utoh R, Ise K, Yamato M, Okano T, Gotoh M
  • Organizer: The 13th World congress of International pancreas and islet transplantation association
  • Place of Presentation: Prague, Czech Republic
• [Presentation] Cl-チャネル阻害による細胞保護効果の膵島分離への応用-臨床膵島移植確立への細胞生理学的アプローチ- (2011)
  • Author(s): 穴澤貴行, 土屋貴男, 見城明, 芳賀淳一郎, 佐藤哲, 三宅将生, 狹間章博, 後藤満一
  • Organizer: 第111回日本外科学会定期学術集会
  • Place of Presentation: 東京(誌上開催)
• [Presentation] 重症低血糖発作を伴うインスリン依存性糖尿病に対する心停止ドナーからの膵島移植:日本膵・膵島移植研究会事務局報告 (2011)
  • Author(s): 穴澤貴行, 土屋貴男, 伊勢一哉, 見城明, 齊藤拓朗, 後藤満一
  • Organizer: 第47回日本移植学会総会
  • Place of Presentation: 仙台
• [Presentation] Mitomycin-C treatment significantly reduces central necrotic damage of islets in culture. (2010)
  • Author(s): Saito T
  • Organizer: The 23th International Congress of The Transplantation Society
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2010-08-16
• [Presentation] Mitomycin-C treatment significantly reduces central necrotic damage of islets in culture (2010)
  • Author(s): Saito T, Saito T, Sato Y, Ise K, OshibeI, Waguri S, Gotoh M
  • Organizer: The 23th International Congress of The Transplantation Society
  • Place of Presentation: Vancouver, Canada