Elucidation of the pahogenesis of auto immune-bone marrow failure with human hematopoietic stem cells derived from iPS cells

• Project/Area Number: 17K09007
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Kanazawa University
• Principal Investigator: KATAGIRI Takamasa 金沢大学, 保健学系, 助教 (60621159)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 自己免疫疾患 / iPS細胞 / HLA / 骨髄移植 / 免疫不全マウス / 造血幹細胞 / 免疫学

Outline of Final Research Achievements

Hematopoietic stem cells are injured by auto immune cells in aplastic anemia. Hematopoietic stem cells escape the attack of T cells with various way to keep the production of blood cells as that way could directly effects on the hematopoiesis. The purpose of that research is that each clone could have the different ability of hematopoiesis in the situation of recovery. To clarify that difference, we set up mouse model that have human hematopoiesis by transplanted with hematopoietic stem cells derived from iPS cells. We found that the hematopoietic stem cells with specific phenotype have the advantage ability of hematopoiesis better than others, resulting in the specific clone contribute the hematopoiesis in the recovery situation with immune suppressive therapy.

Academic Significance and Societal Importance of the Research Achievements

本研究は、難治性血液疾患である再生不良性貧血における造血様相を明らかにすることを目的としている。本研究成果は、患者の体内で起きている造血をiPS細胞を用いて再現し、それらの動態を明らかにした学術的意義が高いものであり、病態形成過程を解明するための重要な成果である。本研究の成果は、日本血液学会、アメリカ血液学会などの年次学術集会や国際誌での論文発表を通して、再生不良性貧血患者およびPNH患者の新規治療法の解明につながるものであり、社会的意義が高い。

Research Products

• [Journal Article] Natural killer cell function changes by the Japanese Kampo Medicine Juzentaihoto in General fatigue patients (2020)
  • Author(s): Ogawa-Ochiai Keiko、Katagiri Takamasa、Sato Yuki、Shirai Akiko、Ishiyama Ken、Takami Akiyoshi、Morishita Eriko
  • Journal Title: Advances in Integrative Medicine Volume: 999 Issue: 1 Pages: 999-999
  • DOI: 10.1016/j.aimed.2019.12.003
  • Peer Reviewed
• [Journal Article] Clonal hematopoiesis by SLIT1-mutated hematopoietic stem cells due to a breakdown of the autocrine loop involving Slit1 in acquired aplastic anemia (2019)
  • Author(s): Hosokawa K, Mizumaki H, Elbadry M, Saito C, Espinoza JL, An DTT, Katagiri T, Harashima A, Kikuchi A, Kanai A, Matsui H, Inaba T, Taniwaki M, Yamamoto Y, Nakao S
  • Journal Title: Leukemia Volume: 33 Issue: 11 Pages: 2732-2766
  • DOI: 10.1038/s41375-019-0510-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Escape hematopoiesis by HLA-B5401-lacking hematopoietic stem progenitor cells in men with acquired aplastic anemia. (2019)
  • Author(s): Mahmoud I. Elbadry、Mizumaki Hiroki、Hosokawa Kohei、J. Luis Espinoza、Nakagawa Noriharu、Chonabayashi Kazuhisa、Yoshida Yoshinori、Katagiri Takamasa、Hosomichi Kazuyoshi、Zaimoku Yoshitaka、Imi Tatsuya、Mai Anh Thi Nguyen、Fujii Youichi、Tajima Atsushi、Ogawa Seishi、Takenaka Katsuto、Akashi Koichi、Nakao Shinji
  • Journal Title: Haematologica Volume: 印刷中 Issue: 10 Pages: 210856-210856
  • DOI: 10.3324/haematol.2018.210856
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sustained clonal hematopoiesis by HLA-lacking hematopoietic stem cells without driver mutations in aplastic anemia. (2018)
  • Author(s): Imi Tatsuya, Katagiri Takamasa, Hosomichi Kazuyoshi, Zaimoku Yoshitaka, Hoang Nguyen Viet, Nakagawa Noriharu, Tajima Atsushi, Yoshizato Tetsuichi, Ogawa Seishi, Nakao Shinji.
  • Journal Title: Blood Advances Volume: 2 Issue: 9 Pages: 1000-1012
  • DOI: 10.1182/bloodadvances.2017013953
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immune-Mediated Hematopoietic Failure after Allogeneic Hematopoietic Stem Cell Transplantation: A Common Cause of Late Graft Failure in Patients with Complete Donor Chimerism (2018)
  • Author(s): Maruyama Kana、Aotsuka Nobuyuki、Kumano Yoshihisa、Sato Naoko、Kawashima Naomi、Onda Yoshiyuki、Maruyama Hiroyuki、Katagiri Takamasa、Zaimoku Yoshitaka、Nakagawa Noriharu、Hosomichi Kazuyoshi、Ogawa Seishi、Nakao Shinji
  • Journal Title: Biol Blood Marrow Transplant Volume: 24 Issue: 1 Pages: 43-49
  • DOI: 10.1016/j.bbmt.2017.08.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack (2018)
  • Author(s): Espinoza J. Luis、Elbadry Mahmoud I.、Chonabayashi Kazuhisa、Yoshida Yoshinori、Katagiri Takamasa、Harada Kenichi、Nakagawa Noriharu、Zaimoku Yoshitaka、Imi Tatsuya、Hassanein Hassan A.、Khalifa A. Noreldin Amal、Takenaka Katsuto、Akashi Koichi、Hamana Hiroshi、Kishi Hiroyuki、Akatsuka Yoshiki、Nakao Shinji
  • Journal Title: Blood Adv Volume: 2 Issue: 4 Pages: 390-400
  • DOI: 10.1182/bloodadvances.2017013342
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of an HLA class I allele closely involved in the auto-antigen presentation in acquired aplastic anemia (2017)
  • Author(s): Zaimoku Y, Takamatsu H, Hosomichi K, Ozawa T, Nakagawa N, Imi T, Maruyama H, Katagiri T, Kishi H, Tajima A, Muraguchi A, Kashiwase K, Nakao S
  • Journal Title: Blood Volume: 印刷中 Issue: 21 Pages: 2908-2916
  • DOI: 10.1182/blood-2016-11-752378
  • Peer Reviewed / Open Access
• [Presentation] Identification of T-Cell Receptors Specific to Antigens Presented By HLA-B4002 and B5401 in Acquired Aplastic Anemia. (2019)
  • Author(s): Kohei Hosokawa, Eiji Kobayashi, Yoshiki Akatsuka, Luis Espinoza, Noriharu Nakagawa, Tanabe Mikoto, Noriaki Tsuji, Takeshi Yoroidaka, Hiroki Mizumaki, Thi Mai Anh Nguyen, Takamasa Katagiri, Kiyomi Shitaoka, Hiroshi Hamana, Hiroyuki Kishi, Shinji Nakao
  • Organizer: 61th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Natural Killer Cell Function Changes by the Japanese Kampo Medicine Juzentaihoto in General Fatigue Patients (2019)
  • Author(s): Keiko Ogawa, Takamasa Katagiri, Eriko Morishita, Akiyoshi Takami
  • Organizer: 2019 AMERICAN PUBLIC HEALTH ASSOCIATION
  • Int'l Joint Research
• [Presentation] THE IDENTIFICATION OF A COMMON LOSS-OF-FUNCTION MUTATION ACROSS DIFFERENT HLA CLASS ALLELES FREQUENTLY DETECTED IN PATIENTS WITH ACQUIRED APLASTIC ANEMIA (2019)
  • Author(s): Hiroki Mizumaki, Kazuyoshi Hosomichi, Mikoto Tanabe, Takeshi Yoroidaka, Tatsuya Imi, Kohei Hosokawa, Takamasa Katagiri, Hiroyuki Takamatsu, Tatsuhiko Ozawa, Fumihiro Azuma, Hiroyuki Kishi, Atsushi Tajima, Shinji Nakao
  • Organizer: 24th Congress of the European Hematology Association
  • Int'l Joint Research
• [Presentation] 再生不良性貧血においてHLA-B4002によって提示される抗原特異的T細胞受容体の同定 (2019)
  • Author(s): 細川 晃平, 小林 栄治, 赤塚 美樹, エスピノーザ ルイス, 中川 紀温, 田辺 命, 辻 紀章, 鎧高 健志, 水牧 裕希, ティングエン マイアン, 片桐 孝和, 下岡 清美, 浜名 洋, 岸 裕幸, 中尾 眞二
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 再生不良性貧血患者において検出される異なるHLAクラスIアレル間に共通する機能喪失型変異の同定 (2019)
  • Author(s): 水牧 裕希, 細道 一善, 井美 達也, 田辺 命, 材木 義隆, 細川 晃平, 片桐 孝和, 高松 博幸, 小澤 龍彦, 東 史啓, 岸 裕幸, 田嶋 敦, 中尾 眞二
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] GPIアンカー型蛋白のCD109はTF-1細胞のTGF-βによる分化を抑制する (2019)
  • Author(s): 田辺 命, 中川 紀温, 細川 晃平, Thinguyen Maianh, Espinoza Luis, 丸山 佳奈, 片桐 孝和, 山崎 宏人, 中尾 眞二
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 再生不良性貧血の白血球では、異なるHLAクラスＩアレル間に共通するナンセンス変異が高頻度に検出される (2019)
  • Author(s): 水牧裕希、細道一善、井美達也、材木義隆、細川晃平、片桐孝和、高松博幸、小澤龍彦、東史啓、岸裕幸、田嶋敦、中尾眞二
  • Organizer: 第11回日本血液免疫療法学会学術集会
• [Presentation] Loss-of-Function Mutations in HLA-Class I Alleles in Acquire Aplastic Anemia: Evidence for the Involvement of Limited Class I Alleles in the Auto-Antigen Presentation of Aplastic Anemia. (2018)
  • Author(s): Hiroki Mizumaki, , Kazuyoshi Hosomichi, Tanabe Mikoto, Takeshi Yoroidaka, Tatsuya Imi, Yoshitaka Zaimoku, Kohei Hosokawa, Takamasa Katagiri, Hiroyuki Takamatsu, Tatsuhiko Ozawa, Fumihiro Azuma, Hiroyuki Kishi, Atsushi Tajima and Shinji Nakao.
  • Organizer: 60th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Escape Hematopoiesis By HLA-B5401-Lacking Hematopoietic Stem Progenitor Cells in Male Patients with Acquired Aplastic Anemia. (2018)
  • Author(s): Kohei Hosokawa, Mahmoud Ibrahim Elbadry, Hiroki Mizumaki, Luis Espinoza, Noriharu Nakagawa, Kazuhisa Chonabayashi, Yoshinori Yoshida, Takamasa Katagiri, Yoshitaka Zaimoku, Tatsuya Imi,, Nguyen Thi Mai Anh, Yoichi Fujii, Seishi Ogawa, Katsuto Takenaka, Koichi Akashi and Shinji Nakao.
  • Organizer: 60th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] The Depletion of TGF-β Co-Receptor CD109 Induces Erythroid Differentiation of TF-1 Cells: A Model of Preferential Commitment of Piga-Mutated Hematopoietic Stem Cells in Immune-Mediated Bone Marrow Failure. (2018)
  • Author(s): Tanabe Mikoto, Noriharu Nakagawa, Kohei Hosokawa, Luis Espinoza, Kana Maruyama, Takamasa Katagiri, Hirohito Yamazaki and Shinji Nakao.
  • Organizer: 60th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Bystander Proliferation of Piga-Mutated Hematopoietic Progenitor Cells in Acquired Aplastic Anemia Patients Possessing HLA Class I Allele-Lacking Leukocytes. (2018)
  • Author(s): Takeshi Yoroidaka, Kohei Hosokawa, Tatsuya Imi, Takamasa Katagiri, Fumihiro Azuma and Shinji Nakao.
  • Organizer: 60th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] B*54:01欠失血球陽性再生不良性貧血は効率に男性に発症する (2018)
  • Author(s): 細川晃平、Elbadry Mahmoud、Espinoza Luis、蝶名林和久、吉田善紀、水牧裕希、中川紀温、片桐孝和、井美達也、竹中克斗、赤司浩一、浜名洋、岸裕幸、赤塚美樹、中尾眞二
  • Organizer: 第10回血液免疫療法学会学術集会
• [Presentation] Limited class I HLAs are involved in the auto-antigen presentation in acquired aplastic anemia. (2018)
  • Author(s): Mikoto Tanabe, Hiroki Mizumaki, Tatsuya Imi, Takeshi Yoroidaka, Noriharu Nakagawa, Ken Ishiyama, Hirohito Yamazaki, Yoshitaka Zaimoku, Takamasa Katagiri, Kazuyoshi Hosomichi, Atsushi Tajima and Shinji Nakao
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 十全大補湯による NK 細胞機能増強効果の検討 (2018)
  • Author(s): 佐藤祐樹、片桐孝和、森広太朗、小川恵子、森下英理子
  • Organizer: 第57回日本臨床検査医学会東海・北陸支部総会
• [Presentation] 十全大補湯によるNK細胞機能増強効果の検討 (2017)
  • Author(s): 佐藤 祐樹、片桐 孝和、小川 恵子、森下 英理子
  • Organizer: 第42回北陸臨床病理集団会
• [Presentation] ヒトiPS細胞由来造血幹細胞を用いた6pLOHマウスモデルの作製 (2017)
  • Author(s): 河内 佑紀、佐藤 佑樹、片桐 孝和、森下 英理子
  • Organizer: 第42回北陸臨床病理集団会
• [Presentation] The hematopoietic reconstitution of mice with HLA(-) HSPCs derived from aplastic anemia patients (2017)
  • Author(s): Mahmoud I. Elbadry、Luis Espinoza、Takamasa Katagiri、Noriharu Nakagawa、Tatsuya Imi、Yoshinori Yoshida、Kazuhisa Chonabayashi、Katsuto Takenaka、Koichi Akashi、Shinji Nakao
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Molecular mechanisms of clonal hematopoiesis by SLIT1-mutant HSC clones in acquired aplastic anemia (2017)
  • Author(s): Kohei Hosokawa、Luis Espinoza、Dao Thi An、Chizuru Saito、Takamasa Katagiri、 Ai Harashima、Akinori Kanai、Akari Kazami、Hirotaka Matsui、Toshiya Inaba、 Masafumi Taniwaki、Yasuhiko Yamamoto、Shinji Nakao
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 再生不良性貧血患者の6pLOH 造血幹前駆細胞による長期クローン性造血のメカニズム (2017)
  • Author(s): 井美達也、片桐孝和、細道一善、中川紀温、材木義隆、石山謙、山口正木、田嶋敦、中尾眞二
  • Organizer: 第79回日本血液学会学術集会
• [Remarks] 金沢大学研究者情報
  • URL: http://ridb.kanazawa-u.ac.jp/public/detail.php?id=4033