Repairing of radiation-induced tissue damage by extracellular vesicles that mediate interaction of tissue-specific stem cells

• Project/Area Number: 17H04264
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Radiation science
• Research Institution: Hiroshima University
• Principal Investigator: ICHINOHE TATSUO 広島大学, 原爆放射線医科学研究所, 教授 (80314219)
• Co-Investigator(Kenkyū-buntansha): 高山 英次 朝日大学, 歯学部, 准教授 (70533446) ; 三浦 康生 藤田医科大学, 医学部, 教授 (70605146) ; 前川 平 京都大学, 医学研究科, 教授 (80229286)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2019: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 被ばく医療 / 組織再生治療 / 間葉系幹細胞 / 細胞外小胞 / 間葉系細胞

Outline of Final Research Achievements

In this study, we aimed at establishing the scientific foundation of novel cellular treatment of radiation-induced organ damage as well as acute radiation syndrome by use of mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles (EVs). Using appropriate mouse hematopoietic cell transplantation models conditioned with total-body irradiation (TBI), we have revealed that systemic infusion of human bone marrow-MSC-derived nanovesicles prolonged the survival of mice with acute graft-versus-host disease (GVHD) and reduced the pathologic damage in multiple GVHD/TBI-targeted organs, particularly that of the gastrointestinal system. This effect was not reproducible when we used fibroblast-derived EVs, suggesting the special characteristics of MSC-derived EVs. Also by using microarrays of microRNA, we found that predominant presence of miR-125a-3p in BM-MSC-derived EVs as compared with fibroblast-derived EVs.

Academic Significance and Societal Importance of the Research Achievements

チェルノブイリ原子力発電所事故、東海村JCO臨界事故、福島第一原子力発電所事故等、現代社会は急性放射線障害が発生するリスクとの共存を求められている。また、放射線は、各種のX線検査、悪性腫瘍の治療など日常的な医療に汎用されているが、一部の患者に起こり得る医療用放射線使用に関連する組織障害への根本的な治療法は開発されていない。したがって、本研究の成果により、骨髄や脂肪組織に由来する間葉系幹細胞を放射線障害の細胞治療医薬品として開発する道筋が得られたことの意義は非常に大きい。

Research Products

• [Journal Article] Prognostic impact of melphalan dose and total body irradiation use in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation with reduced-intensity conditioning. (2019)
  • Author(s): Harada K, Yanada M, Machida S, Kanamori H, Onizuka M, Ozawa Y, Kobayashi H, Sawa M, Katayama Y, Ohashi K, Kanda J, Ichinohe T, Atsuta Y, Yano S.
  • Journal Title: Leuk Lymphoma. Volume: 60 Issue: 6 Pages: 1493-1502
  • DOI: 10.1080/10428194.2018.1535115
  • Peer Reviewed
• [Journal Article] Editorial: 細胞創薬の発展と細胞治療の展望. (2019)
  • Author(s): 一戸辰夫
  • Journal Title: 日本内科学会雑誌. Volume: 108 Pages: 1355-1358
  • Peer Reviewed
• [Journal Article] Cellular responses to ionizing radiation change quickly over time during early development in zebrafish (2019)
  • Author(s): Honjo Yasuko、Ichinohe Tatsuo
  • Journal Title: Cell Biology International Volume: - Issue: 5 Pages: 516-527
  • DOI: 10.1002/cbin.11117
  • Peer Reviewed / Open Access
• [Journal Article] Suppression effect of adipose tissue-derived mesenchymal stem cells isolated from β2-microglobulin-deficient mice. (2018)
  • Author(s): Masuda J, Takayama E, Ichinohe T, Strober W, Mizuno-Kamiya M, Ikawa T, Kitani A, Kawaki H, Fuss IJ, Kawamoto H, Seno A, Vaidyanath A, UmemuraN, Mizutani A, Kasai T, Honjo Y, Satoh A, Murakami H, Katsura Y, Kondoh N, Seno M
  • Journal Title: Exp Ther Med Volume: 16 Pages: 4277-4282
  • DOI: 10.3892/etm.2018.6689
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pharmacological targeting of bone marrow mesenchymal stromal/stem cells for the treatment of hematological disorders. (2017)
  • Author(s): Sugino N, Ichinohe T, Takaori-Kondo A, Maekawa T, Miura Y.
  • Journal Title: Inflammation and Regeneration. Volume: - Issue: 1 Pages: 1-7
  • DOI: 10.1186/s41232-017-0038-5
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bortezomib interferes with adhesion of B cell precursor acute lymphoblastic leukemia cells through SPARC up-regulation in human bone marrow mesenchymal stromal/stem cells. (2017)
  • Author(s): Iwasa M, Miura Y, Fujishiro A, Fujii S, Sugino N, Yoshioka S, Yokota A, Hishita T, Hirai H, Andoh A, Ichinohe T, Maekawa T.
  • Journal Title: Int J Hematol. Volume: 105 Issue: 5 Pages: 587-597
  • DOI: 10.1007/s12185-016-2169-x
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Isolation of mesenchymal stromal/stem cells from cryopreserved umbilical cord blood cells (2017)
  • Author(s): Fujii S, Miura Y, Iwasa M, Yoshioka S, Fujishiro A, Sugino N, Kaneko H, Nakagawa Y, Hirai H, Takaori-Kondo A, Ichinohe T, Maekawa T.
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 57 Issue: 1 Pages: 1-8
  • DOI: 10.3960/jslrt.16019
  • NAID: 130005709558
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of acute exposure to low-dose radiation on the characteristics of human bone marrow mesenchymal stromal/stem cells (2017)
  • Author(s): Fujishiro Aya、Miura Yasuo、Iwasa Masaki、Fujii Sumie、Sugino Noriko、Andoh Akira、Hirai Hideyo、Maekawa Taira、Ichinohe Tatsuo
  • Journal Title: Inflamm Regen Volume: 37 Issue: 1 Pages: 1-12
  • DOI: 10.1186/s41232-017-0049-2
  • Peer Reviewed / Open Access
• [Journal Article] Graft-Versus-Host Disease Amelioration by Human Bone Marrow Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles Is Associated with Peripheral Preservation of Naive T Cell Populations (2017)
  • Author(s): Fujii Sumie、Miura Yasuo、Fujishiro Aya、Shindo Takero、Shimazu Yutaka、Hirai Hideyo、Tahara Hidetoshi、Takaori-Kondo Akifumi、Ichinohe Tatsuo、Maekawa Taira
  • Journal Title: Stem Cells Volume: 36 Issue: 3 Pages: 434-445
  • DOI: 10.1002/stem.2759
  • NAID: 120006454670
  • Peer Reviewed / Open Access
• [Presentation] 高リスク患者におけるFBMレジメンの有用性. (2020)
  • Author(s): 枝廣太郎, 川瀬孝和, 藤野啓太, 土石川佳世, 美濃達治, 吉田徹巳, 名越久朗, 三原圭一郎, 福島伯泰, 一戸辰夫.
  • Organizer: 第42回日本造血細胞移植学会総会.
• [Presentation] 広島大学原医研血液内科 ～その開設から半世紀の診療の軌跡. (2019)
  • Author(s): 杉原清香, 久保田明子, 吉永信治, 田代聡, 一戸辰夫.
  • Organizer: 第60回原子爆弾後障害研究会
• [Presentation] Effects of ionizing radiation on zebrafish early embryogenesis. (2019)
  • Author(s): Honjo Y, Ichinohe T.
  • Organizer: 3rd International symposium of the Network-type Joint Usage/Research Center for Radiation Dissaster Medical Science
  • Int'l Joint Research
• [Presentation] Human BM-MSC derived extracellular vesicles modulate hematopoietic cells in GVHD mice. (2018)
  • Author(s): Fujii Sumie, Yasuo Miura, Aya Fujishiro, Takero Shindo, Yutaka Shimazu, Hideyo Hirai, Akifumi Takaori-Kondo, Tatsuo Ichinohe, Taira Maekawa.
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] ヒト骨髄間葉系幹細胞由来細胞外小胞はナイーヴ制御性T細胞を保持し、急性移植片対宿主病を緩和する. (2018)
  • Author(s): 藤井紀恵, 三浦康生, 藤城綾, 進藤岳郎, 島津裕, 平位英世, 高折晃史, 一戸辰夫, 前川平.
  • Organizer: 第40回日本造血細胞移植学会総会.
• [Presentation] Human bone marrow mesenchymal stromal/stem cell-derived extracellular vesicles ameliorate graft-versus-host diseases-related manifestations. (2017)
  • Author(s): Sumie Fujii, Yasuo Miura, Aya Fujishiro, Takero Shindo, Yutaka Shimazu, Hideyo Hirai, Akifumi-Takaori-Kondo, Tatsuo Ichinohe, Taira Maekawa.
  • Organizer: 59th Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] Next-generation sequencing-based immunobioinformatics: toward a comprehensive understanding of the human immune system. (2017)
  • Author(s): Tatsuo Ichinohe.
  • Organizer: 19th International symposium on Gnotobilology
  • Int'l Joint Research / Invited
• [Presentation] Bortezomib contributes to the elimination of B-ALL cells through SPARC upregulation in BM-MSCs. (2017)
  • Author(s): Masaki Iwasa, Yasuo Miura, Aya Fujishiro, Sumie Fujii, Noriko Sugino, Satoshi Yoshioka, Hideyo Hirai, Akira Andoh, Tatsuo Ichinohe, Taira Maekawa.
  • Organizer: 第79回日本血液学会学術集会
• [Remarks] 間葉系幹細胞由来の生体ナノ粒子が造血幹細胞移植後の免疫異常を修復することを明らかにしました
  • URL: https://www.hiroshima-u.ac.jp/news/43091
• [Remarks] Hiroshima University UPDATE February 2018
  • URL: https://www.hiroshima-u.ac.jp/en/koho_press/kohoshi/HUUpdate
• [Remarks] 広島大学原爆放射線医科学研究所 研究成果に係る報道発表・記者説明会
  • URL: https://www.hiroshima-u.ac.jp/rbm/research/press
• [Remarks] HIROSHIMA UNIVERSITY UPDATE February 2018
  • URL: https://www.hiroshima-u.ac.jp/en/koho_press/kohoshi/HUUpdate