Unraveling bone marrow erythropoiesis niche

• Project/Area Number: 15K15359
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: University of Tsukuba
• Principal Investigator: Chiba Shigeru 筑波大学, 医学医療系, 教授 (60212049)
• Co-Investigator(Renkei-kenkyūsha): OBARA Naoshi 筑波大学, 医学医療系, 教授 (70422178)
• Research Collaborator: NISHIKII Hidekazu ; SAKAMOTO Tatsuhiro ; Luan Cao Sy
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 骨髄ストローマ / 赤芽球 / nestin / NOTCH / Rbpj / 幹細胞ニッチ / Notch / 赤芽球造血

Outline of Final Research Achievements

Cells that help blood production in the bone marrow were analyzed using genetically modified mice. It was demonstrated that erythrocyte production in the bone marrow is impaired if a specific signaling (NOTCH signaling) system is turned off in "nestin-expressing cells," one type of non-blood producing cells that are present in the bone marrow at a very low frequency. The mechanism for this observation was analyzed as follows: the abnormality in nestin-expressing bone marrow non-blood producing cells disturbs local environment and increases the secretion of a substance called interleukin 6 from "macrophages," which directly support erythrocyte production in the bone marrow. This causes adverse effect on erythropoietic production.

Research Products

• [Int'l Joint Research] Stanford University(米国)
• [Journal Article] Foxp3+ regulatory T cells maintain the bone marrow microenvironment for B cell lymphopoiesis. (2017)
  • Author(s): Pierini A*, Nishikii H*, Baker J, Kimura T, Kwon H-S, Pan Y, Chen Y, Alvarez M, Strober W, Velardi A, Shizuru JA, Wu JY, Chiba S, Negrin RS. (*equal contribution)
  • Journal Title: Nature Communication Volume: 8 Pages: 15068-15068
  • NAID: 120007129109
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft versus host disease. (2016)
  • Author(s): Nishikii H, Kim BS, Yokoyama Y, Chen Y, Baker J, Pierini A, Alvarez M, Mavers M, Maas-Bauer K, Pan Y, Chiba S, Negrin RS.
  • Journal Title: Blood Volume: 128 Issue: 24 Pages: 2846-2858
  • DOI: 10.1182/blood-2016-06-723783
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Double somatic mosaic mutations in TET2 and DNMT3A-origin of peripheral T cell lymphoma in a case (2015)
  • Author(s): Nguyen TB, Sakata-Yanagimoto M, Nakamoto-Matsubara R, Enami T, Ito Y, Kobayashi T, Obara N, Hasegawa Y, Chiba S
  • Journal Title: Annals of Hematology Volume: EPUB ahead of print Issue: 7 Pages: 1221-1223
  • DOI: 10.1007/s00277-015-2332-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Abnormal Increase in a Distinct Subset of Nestin-Expressing Cells in the Bone Marrow of Myelodysplastic Syndromes. (2016)
  • Author(s): Luan Cao Sy, Naoshi Obara, Tatsuhiro Sakamoto, Takayasu Kato, Hidekazu Nishikii, Mamiko Sakata-Yanagimoto, Shigeru Chiba.
  • Organizer: The American Society of Hematology 58th Annual Meeting and Exposition
  • Place of Presentation: San Diego Convention Center, San Diego, CA, USA
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Notch Signaling in Bone Marrow Nestin-Expressing Cells Controls Balance of Erythropoiesis at the Bone Marrow and Spleen. (2016)
  • Author(s): Tatsuhiro Sakamoto, Naoshi Obara, Takayasu Kato, Luan Cao Sy, Hidekazu Nishikii, Mamiko Sakata-Yanagimoto, Satoru Takahashi, Shigeru Chiba.
  • Organizer: The American Society of Hematology 58th Annual Meeting and Exposition
  • Place of Presentation: San Diego Convention Center, San Diego, CA, USA
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] NOTCH signaling in bone marrow nestin-expressing cells is involved in regulating erythropoiesis. (2016)
  • Author(s): 坂本竜弘，小原 直，藤村亮介，加藤貴康，Luan Cao Sy，錦井秀和，坂田（柳元）麻実子，高橋 智，千葉 滋.
  • Organizer: 第78回 日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-13
• [Presentation] Localization and Characteristic of Nestin-expressing Cells in Human Bone Marrow and Their Abnormalities in Myelodysplastic Syndromes. (2016)
  • Author(s): Luan Cao Sy, Naoshi Obara, Tatsuhiro Sakamoto, Takayasu Kato, Hidekazu Nishikii, Satoshi Ikeda, Keiko Suzuki, Shigeru Chiba.
  • Organizer: The 5th JCA-AACR Special Joint Conference
  • Place of Presentation: ヒルトン東京ベイ（千葉県浦安市）
  • Year and Date: 2016-07-13
  • Int'l Joint Research
• [Presentation] Localization of distinct subsets of nestin-expressing cells in human bone marrow and their abnormalities in myelodysplastic syndromes (2016)
  • Author(s): Luan Cao Sy, Naoshi Obara, Tatsuhiro Sakamoto, Takayasu Kato, Hidekazu Nishikii, Satoshi Ikeda, Keiko Suzuki, Shigeru Chiba.
  • Organizer: The 14th Stem Cell Research Symposium
  • Place of Presentation: 淡路夢舞台（兵庫県淡路市）
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Abnormalities in nestin-expressing bone marrow stromal cells in MDS patients (2015)
  • Author(s): Noshi Obara，Tatsuhiro Sakamoto，Luan Cao Sy，Takayasu Kato，Sachie Suzuki，Naoki Kurita，Yasuhisa Yokoyama，Mamiko Sakata，Yuichi Hasegawa，Shigeru Chiba.
  • Organizer: 第77回 日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂、ANAクラウンプラザホテル金沢、ホテル日航金沢、ホテル金沢、金沢市アートホール、もてなしドーム
  • Year and Date: 2015-10-16