Roles of bone marrow specific endothelial cells in the process of engraftment after hematopoietic stem cell transplantation

• Project/Area Number: 16K09866
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: Takahashi Satoshi 東京大学, 医科学研究所, 准教授 (60226834)
• Co-Investigator(Kenkyū-buntansha): 服部 浩一 順天堂大学, 医学(系)研究科(研究院), 特任先任准教授 (10360116)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 血液免疫学 / 血管内皮造血転換 / 造血幹細胞 / 増血促進 / 細胞・組織 / シグナル伝達 / 生体分子 / アンジオクライン因子 / 造血促進

Outline of Final Research Achievements

We could show that endothelial lineage cells which are one of the hematopoietic niche components play a key role in hematopoiesis in the bone marrow through the interaction with other lineage cells like mesenchymal stromal cell, mesenchymal stem cell and hematopoietic stem cell. A new concept in the hematology field is that of angiocrine factors that under pathophysiological conditions are released from endothelial cells so-called bone marrow specific endothelial cells and can promote hematopoiesis in bone marrow through a directly or indirectly mechanism. Therefore, we suggest that an abnormal function of endothelial lineage cells induces or exacerbates graft failure after hematopoietic stem cell transplantation represented by cord blood transplantation. Based on our study, we could present important data for the discussion about the clinical utility of cotransplatation with hematopoietic stem cells and endothelial lineage cells as a treatment of graft failure in the near future.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果を通じて、現行の臍帯血移植の最大の問題点である生着不全の病態での血管内皮系細胞の関与を明確化することによって、臍帯血移植において血管内皮系細胞との共移植の可能性について検討するための基盤的な情報を得ることができたと考えている。

Research Products

• [Journal Article] The fibrinolytic factor tPA drives LRP1-mediated melanoma growth and metastasis (2019)
  • Author(s): Salama Y, Lin SY, Dhahri D, Hattori K, Heissig B
  • Journal Title: FASEB J Volume: 33 Issue: 3 Pages: 3465-3480
  • DOI: 10.1096/fj.201801339rrr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Which is more important for the selection of cord blood units for haematopoietic cell transplantation: the number of CD34-positive cells or total nucleated cells? (2018)
  • Author(s): Nakasone H, Tabuchi K, Uchida N, Ohno Y, Matsuhashi Y, Takahashi S, Onishi Y, Onizuka M, Kobayashi H, Fukuda T, Ichinohe T, Takanashi M, Kato K, Atsuta Y, Yabe H, Kanda Y.
  • Journal Title: Br J Haematol. Volume: - Issue: 1 Pages: 166-169
  • DOI: 10.1111/bjh.15418
  • Peer Reviewed
• [Journal Article] Refractory Graft-Versus-Host Disease-Free, Relapse-Free Survival as an Accurate and Easy-to-Calculate Endpoint to Assess the Long-Term Transplant Success. (2018)
  • Author(s): Kawamura K, Nakasone H, Kurosawa S, Yoshimura K, Misaki Y, Gomyo A, Hayakawa J, Tamaki M, Akahoshi Y, Kusuda M, Kameda K, Wada H, Ishihara Y, Sato M, Terasako-Saito K, Kikuchi M, Kimura SI, Tanihara A, Kako S, Kanamori H, Mori T, Takahashi S, Taniguchi S, Atsuta Y, Kanda Y.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 24(7) Issue: 7 Pages: 1521-1526
  • DOI: 10.1016/j.bbmt.2018.02.004
  • Peer Reviewed
• [Journal Article] HLA discrepancy between graft and host rather than that graft and first donor impact the second transplant outcome. (2018)
  • Author(s): Maeda Y, Ugai T, Kondo E, Ikegame K, Murata M, Uchida N, Miyamoto T, Takahashi S, Ohashi K, Nakamae H, Fukuda T, Onizuka M, Eto T, Ota S, Hirokawa M, Ichinohe T, Atsuta Y, Kanda Y, Kanda J.
  • Journal Title: Haematologica. Volume: Dec.6 Issue: 5 Pages: 1055-1061
  • DOI: 10.3324/haematol.2018.204438
  • Peer Reviewed
• [Journal Article] Cryopreserved CD34+ Cell Dose, but Not Total Nucleated Cell Dose, Influences Hematopoietic Recovery and Extensive Chronic GVHD after Single-Unit Cord Blood Transplantation in Adult Patients. (2017)
  • Author(s): Konuma T, Kato S, Oiwa-Monna M, Tanoue S, Ogawa M, Isobe M, Tojo A, Takahashi S.
  • Journal Title: Biol Blood Marrow Transplant Volume: In press Issue: 7 Pages: 1142-1150
  • DOI: 10.1016/j.bbmt.2017.03.036
  • Peer Reviewed
• [Journal Article] Long-term persistent donor–recipient mixed chimerism without disease recurrence after myeloablative single-unit cord blood transplantation in adult acute myeloid leukemia following myelodysplastic syndrome (2017)
  • Author(s): Tanoue Susumu、Konuma Takaaki、Takahashi Satoshi、Watanabe Eri、Sato Natsuko、Watanabe Nobukazu、Isobe Masamichi、Kato Seiko、Ooi Jun、Tojo Arinobu
  • Journal Title: Leukemia & Lymphoma Volume: 58 Issue: 12 Pages: 2973
  • DOI: 10.1080/10428194.2017.1318440
  • URL: https://localhost/en/publications/89011862-c365-474d-9304-4995c658e3ee
  • Peer Reviewed
• [Journal Article] Severe infusion-related toxicity after a second unrelated cord blood transplantation (2017)
  • Author(s): Tanoue Susumu、Konuma Takaaki、Kato Seiko、Oiwa-Monna Maki、Isobe Masamichi、Tojo Arinobu、Takahashi Satoshi
  • Journal Title: Cytotherapy Volume: 19 Issue: 8 Pages: 1013-1014
  • DOI: 10.1016/j.jcyt.2017.05.004
  • Peer Reviewed
• [Journal Article] Quality of Life after Allogeneic Hematopoietic Cell Transplantation According to Affected Organ and Severity of Chronic Graft-versus-Host Disease (2017)
  • Author(s): Kurosawa S, Oshima K, Yamaguchi T, Yanagisawa A, Fukuda T, Kanamori H, Mori T, Takahashi S, Kondo T, Kohno A, Miyamura K, Umemoto Y, Teshima T, Taniguchi S, Yamashita T1 Inamoto Y, Kanda Y, Okamoto S, Atsuta Y.
  • Journal Title: Biology of Blood and Marrow Transplantation Volume: 23 Issue: 10 Pages: 1749-1758
  • DOI: 10.1016/j.bbmt.2017.06.011
  • Peer Reviewed
• [Journal Article] Alloimmune hemolysis due to major RhE incompatibility after unrelated cord blood transplantation (2017)
  • Author(s): Isobe Masamichi、Konuma Takaaki、Abe-Wada Yuka、Hirata Kyoko、Ogami Kazuo、Kato Seiko、Oiwa-Monna Maki、Tanoue Susumu、Nagamura-Inoue Tokiko、Takahashi Satoshi、Tojo Arinobu
  • Journal Title: Leukemia & Lymphoma Volume: 59 Issue: 4 Pages: 1000-1003
  • DOI: 10.1080/10428194.2017.1352095
  • Peer Reviewed
• [Journal Article] The angiogenic factor Egfl7 alters thymogenesis by activating Flt3 signaling (2017)
  • Author(s): Salama Yousef、Hattori Koichi、Heissig Beate
  • Journal Title: Biochem Biophys Res Commun Volume: 490 Issue: 2 Pages: 209-216
  • DOI: 10.1016/j.bbrc.2017.06.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pharmacological targeting of plasmin prevents lethality and tissue damage in a murine model of macrophage activation syndrome (2017)
  • Author(s): 1.Shimazu H, Munakata S, Tashiro Y, Salama Y, Eiamboonser S, Ohta Y, Onoda H, Tsuda Y, Okada Y, Nakauchi H, Heissig B and Hattori K
  • Journal Title: Blood Volume: 印刷中 Issue: 1 Pages: 59-72
  • DOI: 10.1182/blood-2016-09-738096
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The role of plasmin in the pathogenesis of murine multiple myeloma (2017)
  • Author(s): Eiamboonsert S, Salama Y, Watarai H, Dhahri D, Tsuda Y, Okada Y, Hattori K, Heissig B.
  • Journal Title: Biochem Biophys Res Commun. Volume: 488 Issue: 2 Pages: 387-392
  • DOI: 10.1016/j.bbrc.2017.05.062
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of graft-versus-host disease on outcomes after unrelated cord blood transplantation. (2017)
  • Author(s): Kanda J, Morishima Y, Terakura S, Wake A, Uchida N, Takahashi S, Ono Y, Onishi Y, Kanamori H, Aotsuka N, Ozawa Y, Ogawa H, Sakura T, Ohashi K, Ichinohe T, Kato K, Atsuta Y, Teshima T, Murata M.
  • Journal Title: Leukemia Volume: 31(3) Issue: 3 Pages: 663-668
  • DOI: 10.1038/leu.2016.288
  • Peer Reviewed / Open Access
• [Journal Article] Multiple allogeneic progenitors in combination function as a unit to support early transient hematopoiesis in transplantation. (2016)
  • Author(s): Ishida T, Takahashi S, Lai CY, Nojima M, Yamamoto R, Takeuchi E, Takeuchi Y, Higashihara M, Nakauchi H, Otsu M.
  • Journal Title: J Exp Med. Volume: Aug.22:213(9) Issue: 9 Pages: 1865-80
  • DOI: 10.1084/jem.20151493
  • Peer Reviewed / Open Access
• [Presentation] アンジオクラインシステムによる組織修復とリモデリング制御機構 (2019)
  • Author(s): 服部浩一, 高橋聡 Heissig Beate.
  • Organizer: 第18回日本再生医療学会総会
• [Presentation] HSC expansion and mobilization from bone marrow niche (2018)
  • Author(s): Hattori K
  • Organizer: JOINT WORK SHOP NORWAY AND JAPAN IN REGENERATIVE MEDICINE
• [Presentation] Angiocrine system regulates macrophage -dependent aberrant tissue repair and remodeling (2018)
  • Author(s): Hattori K, Takahashi S and Heissig B
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] アンジオクラインシステムによるGVHD病態制御機構の解明. (2018)
  • Author(s): 服部浩一、Heissig Beate、高橋聡
  • Organizer: 第10回日本血液疾患免疫療法学会学術集会
• [Presentation] 生着不全 - 病態と対策 (2018)
  • Author(s): 高橋 聡
  • Organizer: 第40回日本造血細胞移植学会総会
  • Invited
• [Presentation] New strategy using cellular therapy to enhance early hematopoietic/ immunological recovery after cord blood transplant in Japan． JSHCT-KSBMT Joint Symposium (2018)
  • Author(s): Satoshi Takahashi.
  • Organizer: 第40回日本造血細胞移植学会総会
  • Invited
• [Presentation] 我が国の造血幹細胞移植におけるＨＬＡ適合度と成績 (2017)
  • Author(s): 高橋 聡
  • Organizer: 第1回関東ＨＬＡ研究会
  • Invited
• [Presentation] Enhanced hematopoietic recovery with mixed cord blood units-derived stem cells. (2017)
  • Author(s): Satoshi Takahashi
  • Organizer: The Fifth China cord blood transplantation Summit Forum 2017.
  • Int'l Joint Research / Invited
• [Presentation] Virus-specific T cell therapy in Japan． (2017)
  • Author(s): Satoshi Takahashi
  • Organizer: 8th Asian Cellular Therapy Organization（ACTO)．
  • Int'l Joint Research / Invited
• [Presentation] アンジオクライン因子による間葉系幹細胞動態制御機構 (2017)
  • Author(s): 服部浩一、高橋聡、Heissig Beate
  • Organizer: 第17回日本再生医療学会
• [Presentation] Functional analysis of the fibrinolytic system in the pathogenesis of hemophagocytic syndrome. (2017)
  • Author(s): Shimazu H. Tashiro Y. Nakauchi H. Heissig B, Hattori K.
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Angiocrine factors expand mesenchymal stromal cells n bone marrow niche (2017)
  • Author(s): Hattori K, Takahashi S and Heissig B
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Clinical impact of HLA disparity and anti-HLA antibody in cord blood transplants (2016)
  • Author(s): Satoshi Takahashi
  • Organizer: The 4th International CBT Summit and the National CME of the Advance of Unrelated CBT.
  • Place of Presentation: Hefei, China
  • Year and Date: 2016-06-24
  • Int'l Joint Research
• [Presentation] Clinical impact of HLA disparity and anti-HLA antibody in cord blood transplants (2016)
  • Author(s): Satoshi Takahashi
  • Organizer: 2016 European Society for Blood and Marrow Transplantation (EBMT) Meeting.
  • Place of Presentation: Valencia, Spain.
  • Year and Date: 2016-04-04
  • Int'l Joint Research
• [Book] 動物／疾患モデルの 作製技術・病態解析・評価手法 (2017)
  • Author(s): 服部浩一
  • Total Pages: 428
  • Publisher: 技術情報協会
• [Book] 炎症性腸疾患と線溶系 (2017)
  • Author(s): 服部浩一
  • Total Pages: 75
  • Publisher: 日本血栓止血学会雑誌
• [Book] V. 造血細胞移植 ３．臍帯血移植． P284-289. 血液疾患最新の治療 (2017)
  • Author(s): 高橋 聡
  • Publisher: 南江堂、編集 小澤敬也・中尾眞二・松村到、
• [Book] X.白血病学（下） －最新の基礎、臨床研究‐白血病治療の副作用・合併症対策と支持療法 2. 造血幹細胞移植の副作用と対策． (5)生着不全とその対策．． (2016)
  • Author(s): 高橋 聡
  • Publisher: 日本臨床 74巻 増刊号10（2016.12.20）