Role of bone marrow microenvironment for erythropoiesis

• Project/Area Number: 18K16107
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: University of Tsukuba
• Principal Investigator: Sakamoto Tatsuhiro 筑波大学, 附属病院, 病院講師 (60815398)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 骨髄微小環境 / 赤血球造血 / Nestin陽性細胞 / Notchシグナル / IL-6 / 局所炎症 / 造血微小環境 / 赤芽球分化 / マクロファージ / Nestin陽性間葉系細胞 / 赤芽球造血 / 間葉系幹細胞

Outline of Final Research Achievements

The BM microenvironment supporting　the hematopoiesis of each lineage has not remained unclear. In this research, we found that the Nestin-expressing cells in the bone marrow (BM) supported erythropoiesis in the BM specifically. The disruption of Notch signaling in Nestin-expressing cells impaired erythroid differentiation in the BM of the genetically modified mice. Additionally, in the BM of these mice, the erythroid-island-forming abilities of the macrophages were impaired. IL-6 hyperproduction was detected in these macrophages, and the anti-IL-6 receptor antibody could revert the impairment of erythropoiesis in the BM.

Academic Significance and Societal Importance of the Research Achievements

これまで骨髄における造血を支持する骨髄微小環境において各血球系統特異的な微小環境は明らかになっていなかった。本研究により骨髄微小環境構成細胞の一種であるNestin発現細胞特異的にNotchシグナルが欠損させた遺伝子改変マウスの骨髄で赤芽球造血が特異的に障害され、骨髄中の赤芽球島形成が障害され、赤芽球島を構成するマクロファージにおいてIL-6が過剰産生されていること、生体内における骨髄での赤芽球造血の障害が抗IL-6レセプター抗体の投与により改善することを示した。
赤芽球造血障害を起こす再生不良性貧血や骨髄異形成症候群などにおける病態解明、新規治療法の開発の端緒となる知見が得られたと考えている。

Research Products

• [Journal Article] Early administration of cyclosporine may reduce the incidence of cytokine release syndrome after HLA-haploidentical hematopoietic stem-cell transplantation with post-transplant cyclophosphamide (2021)
  • Author(s): Kurita Naoki、Sakamoto Tatsuhiro、Kato Takayasu、Kusakabe Manabu、Yokoyama Yasuhisa、Nishikii Hidekazu、Sakata-Yanagimoto Mamiko、Obara Naoshi、Hasegawa Yuichi、Chiba Shigeru
  • Journal Title: Annals of Hematology Volume: 100 Pages: 1295-1301
  • DOI: 10.1007/s00277-021-04439-6
  • Peer Reviewed
• [Journal Article] Haploidentical transplantation from a related donor as first-line treatment for fulminant aplastic anemia (2020)
  • Author(s): 槇島 健一、長谷川 雄一、千葉 滋、小原 直、坂本 竜弘、加藤 貴康、日下部 学、錦井 秀和、栗田 尚樹、横山 泰久、坂田（柳元） 麻実子
  • Journal Title: Jpn. J. Clin. Hematol. Volume: 61 Issue: 10 Pages: 1464-1468
  • DOI: 10.11406/rinketsu.61.1464
  • NAID: 130007937040
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] VAV1 mutations contribute to development of T-cell neoplasms in mice (2020)
  • Author(s): Fukumoto Kota、Sakata-Yanagimoto Mamiko、Fujisawa Manabu、Sakamoto Tatsuhiro、Miyoshi Hiroaki、Suehara Yasuhito、Nguyen Tran B.、Suma Sakurako、Yanagimoto Shintaro、Shiraishi Yuichi、Chiba Kenichi、Bouska Alyssa、Kataoka Keisuke、Ogawa Seishi、Iqbal Javeed、Ohshima Koichi、Chiba Shigeru
  • Journal Title: Blood Volume: 136 Pages: 3018-3032
  • DOI: 10.1182/blood.2020006513
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Philadelphia chromosome-positive acute lymphoblastic leukemia complicated by bone marrow necrosis during consolidation chemotherapy (2020)
  • Author(s): 石塚 幹太郎、錦井 秀和、横山 泰久、坂田（柳元） 麻実子、長谷川 雄一、品川 篤司、千葉 滋、小原 直、周山 拓也、松岡 亮太、丸山 ゆみ子、坂本 竜弘、日下部 学、加藤 貴康、栗田 尚樹
  • Journal Title: Jpn. J. Clin. Hematol. Volume: 61 Issue: 5 Pages: 462-467
  • DOI: 10.11406/rinketsu.61.462
  • NAID: 130007852244
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Notch signaling in Nestin-expressing cells in the bone marrow maintains erythropoiesis via macrophage integrity (2019)
  • Author(s): Sakamoto Tatsuhiro、Obara Naoshi、Nishikii Hidekazu、Kato Takayasu、Luan Cao Sy、Fujimura Ryosuke、Yagita Hideo、Sakata-Yanagimoto Mamiko、Takahashi Satoru、Chiba Shigeru
  • Journal Title: Stem cells Volume: 印刷中 Pages: 924-936
  • DOI: 10.1002/stem.3011
  • Peer Reviewed / Open Access
• [Journal Article] Prominence of nestin-expressing Schwann cells in bone marrow of patients with myelodysplastic syndromes with severe fibrosis (2019)
  • Author(s): Cao-Sy Luan、Obara Naoshi、Sakamoto Tatsuhiro、Kato Takayasu、Hattori Keiichiro、Sakashita Shingo、Nannya Yasuhito、Ogawa Seishi、Harada Hironori、Sakata-Yanagimoto Mamiko、Nishikii Hidekazu、Chiba Shigeru
  • Journal Title: Int J Hematol Volume: 109 Pages: 309-318
  • DOI: 10.1007/s12185-018-02576-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Durable Leukemic Remission and Autologous Marrow Recovery with Random Chromosomal Abnormalities after Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia (2019)
  • Author(s): Nishikii Hidekazu、Kurita Naoki、Shinagawa Atsushi、Sakamoto Tatsuhiro、Kusakabe Manabu、Yokoyama Yasuhisa、Kato Takayasu、Sakata-Yanagimoto Mamiko、Obara Naoshi、Hasegawa Yuichi、Nakamura Naoya、Chiba Shigeru
  • Journal Title: Case Report in Hematology Volume: 2019 Pages: 1-5
  • DOI: 10.1155/2019/9710790
  • NAID: 120007128070
  • Peer Reviewed / Open Access
• [Journal Article] The prognosis of disseminated intravascular coagulation associated with hematologic malignancy and its response to recombinant human thrombomodulin (2019)
  • Author(s): Kurita Naoki、Sakamoto Tatsuhiro、Kato Takayasu、Kusakabe Manabu、Yokoyama Yasuhisa、Nishikii Hidekazu、Sakata-Yanagimoto Mamiko、Obara Naoshi、Hasegawa Yuichi、Chiba Shigeru
  • Journal Title: Thromb Res Volume: 173 Pages: 57-64
  • DOI: 10.1016/j.thromres.2018.11.014
  • Peer Reviewed
• [Journal Article] High efficacy of eculizumab treatment for fulminant hemolytic anemia in primary cold agglutinin disease (2019)
  • Author(s): Makishima Kenichi、Obara Naoshi、Ishitsuka Kantaro、Sukegawa Shinichiro、Suma Sakurako、Kiyoki Yusuke、Baba Naoko、Sakamoto Tatsuhiro、Kato Takayasu、Kusakabe Manabu、Nishikii Hidekazu、Kurita Naoki、Yokoyama Yasuhisa、Sakata-Yanagimoto Mamiko、Hasegawa Yuichi、Chiba Shigeru
  • Journal Title: Ann Hematol Volume: 98 Pages: 1031-1032
  • DOI: 10.1007/s00277-018-3521-4
  • NAID: 120007128039
  • Peer Reviewed
• [Journal Article] An Unprecedented Case of p190 BCR-ABL Chronic Myeloid Leukemia Diagnosed during Treatment for Multiple Myeloma: A Case Report and Review of the Literature (2018)
  • Author(s): Miki Kosuke、Obara Naoshi、Makishima Kenichi、Sakamoto Tatsuhiro、Kusakabe Manabu、Kato Takayasu、Kurita Naoki、Nishikii Hidekazu、Yokoyama Yasuhisa、Sakata-Yanagimoto Mamiko、Hasegawa Yuichi、Chiba Shigeru
  • Journal Title: Case Reports in Hematology Volume: 2018 Pages: 1-5
  • DOI: 10.1155/2018/7863943
  • NAID: 120007128268
  • Peer Reviewed
• [Journal Article] Liquid biopsy for the identification of intravascular large B-cell lymphoma (2018)
  • Author(s): Suehara Yasuhito、Sakata-Yanagimoto Mamiko、et al
  • Journal Title: Haematologica Volume: in press
  • DOI: 10.3324/haematol.2017.178830
  • Peer Reviewed / Open Access
• [Presentation] トロンボポエチン受容体作動薬治療を受けた再生不良性貧血患者の骨髄細胞における遺伝子変異の検討 (2021)
  • Author(s): Tatsuhiro Sakamoto, Naoshi Obara, Yasuhito Nannya, Manabu Kusakabe1), Takayasu Kato1), Naoki Kurita1), Yasuhisa Yokoyama, Hidekazu Nishikii, Mamiko Sakata-Yanagimoto, Yuichi Hasegawa, Shigeru Chiba
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Notch signaling in nestin-expressing bone marrow stromal cells supports erythropoietic niche (2019)
  • Author(s): Tatsuhiro Sakamoto
  • Organizer: The 10th JSH INTERNATIONAL SYMPOSIUM
  • Int'l Joint Research
• [Presentation] BONE MARROW ERYTHROPOIETIC DEFECT ACCOMPANYING EXTRAMEDULLARY HEMATOPOIESIS IS MIMICKED BY DOWNREGULATION OF NOTCH SIGNALING IN SPECIFIC MICROENVIRONMENT. (2018)
  • Author(s): Tatsuhiro Sakamoto , Naoshi Obara , Hidekazu Nishikii , Takayasu Kato , Ryosuke Fujimura , Luan Cao Sy , Mamiko Sakata-Yanagimoto , Satoru Takahashi , Shigeru Chiba
  • Organizer: 23rd Congress of EHA
  • Int'l Joint Research
• [Presentation] Bone Marrow Erythropoiesis is Maintained by Notch Signaling in Specific Bone Marrow Microenvironment (2018)
  • Author(s): Tatsuhiro Sakamoto , Naoshi Obara , Hidekazu Nishikii , Takayasu Kato , Ryosuke Fujimura , Luan Cao Sy , Mamiko Sakata-Yanagimoto , Satoru Takahashi , Shigeru Chiba
  • Organizer: The 9th JSH International Symposium 2018
  • Int'l Joint Research
• [Presentation] Impairment of bone marrow erythropoiesis is induced by disruption of Notch signaling in specific bone marrow microenvironment (2018)
  • Author(s): Tatsuhiro Sakamoto , Naoshi Obara , Hidekazu Nishikii , Takayasu Kato , Ryosuke Fujimura , Luan Cao Sy , Mamiko Sakata-Yanagimoto , Satoru Takahashi , Shigeru Chiba
  • Organizer: The 16th Stem Cell Research Symposium
• [Book] The Peripheral T‐Cell Lymphomas (2021)
  • Author(s): Tatsuhiro Sakamoto, Mamiko Sakata-Yanagimoto, Owen A. O'Connor M.D., Ph.D.,Won Seog KimPier Luigi Zinzani M.D., Ph.D., et al.
  • Total Pages: 392
  • Publisher: WILEY
  • ISBN: 9781119671312