The regulation of lympho-hematopoiesis by bone marrow niches

• Project/Area Number: 22390096
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Kyoto University
• Principal Investigator: NAGASAWA Takashi 京都大学, 再生医科学研究所, 教授 (80281690)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2012: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2011: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2010: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: サイトカイン / 造血幹細胞 / ニッチ / 骨髄 / ケモカイン

Research Abstract

We generated mice that allowed selective ablation of CAR cells within bone marrow and determined the in vivo function of CAR cells as a niche for hematopoietic stem cells (HSCs) and lympho-hematopoietic progenitors. Short-term ablation of CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells in vivo severely impaired the production of SCF and CXCL12, and led to a marked reduction in cycling lymphoid and erythroid progenitors. HSCs from CAR cell-depleted mice were reduced in number and cell size, were more quiescent and had increased expression of early myeloid selector genes. Thus, CAR cells are the major producer of CXCL12 and SCF and are required for proliferation of HSCs and lymphoid and erythroid progenitors as well as maintenance of HSCs in an undifferentiated state.

Research Products

• [Journal Article] CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance (2013)
  • Author(s): Greenbaum, A., Hsu, Y.M., Day, R.B., Schuettpel,z L.G., Christopher, M.J., Borgerding, J.N., Nagasawa, T., *Link, D.C.
  • Journal Title: Nature Volume: 495 Issue: 7440 Pages: 227-230
  • DOI: 10.1038/nature11926
  • Peer Reviewed
• [Journal Article] Peripheral Nerve-Derived CXCL12 and VEGF-A Regulate the Patterning of Arterial Vessel Branching in Developing Limb Skin (2013)
  • Author(s): Li, W., Kohara, H., Uchida, Y., James, J.M., Soneji, K., Cronshaw, D.G., Zou, Y.R., Nagasawa, T., *Mukouyama, Y.S.
  • Journal Title: Dev. Cell Volume: Dev. Cell Issue: 4 Pages: 359-371
  • DOI: 10.1016/j.devcel.2013.01.009
  • Peer Reviewed
• [Journal Article] Reconstitution of mouse spermatogonial stem cell niches in culture (2012)
  • Author(s): Kanatsu-Shinohara, M., Inoue, K., Takashima, S.,Takehashi, M.,Ogonuki, N., Morimoto, H., Nagasawa, T., Ogura, A. and Shinohara, T
  • Journal Title: Cell Stem Cell Volume: 11(4) Issue: 4 Pages: 567-578
  • DOI: 10.1016/j.stem.2012.06.011
  • Peer Reviewed
• [Journal Article] Trans-mesenteric neural crest cells are the principal source of the colonic enteric nervous system. (2012)
  • Author(s): Nishiyama, C., Uesaka, T., Manabe, T., Yonekura, Y., Nagasawa, T., Newgreen, D.F., Young, H.M., *Enomoto, H.
  • Journal Title: Nat. Neurosci. Volume: 15(9) Issue: 9 Pages: 1211-1218
  • DOI: 10.1038/nn.3184
  • Peer Reviewed
• [Journal Article] Spi-B is critical for plasmacytoid dendritic cell function and development (2012)
  • Author(s): Sasaki, K. Hoshino, T. Sugiyama, C. Yamazaki, T. Yano, A. Iizuka, H. Hemmi, T. Tanaka, M. Saito, M. Sugiyama, Y. Fukuda, T. Ohta, K. Sato, A. Ainai, T. Suzuki, H. Hasegawa, N. Toyama-Sorimachi, H. Kohara, T. Nagasawa, T. Kaisho
  • Journal Title: Blood Volume: 120 Issue: 24 Pages: 4733-4743
  • DOI: 10.1182/blood-2012-06-436527
  • Peer Reviewed
• [Journal Article] The Endothelial Antigen ESAM Monitors Hematopoietic Stem Cell Status between Quiescence and Self-Renewal. (2012)
  • Author(s): Sudo, T.
  • Journal Title: J. Immunol. Volume: 189 Issue: 1 Pages: 200-210
  • DOI: 10.4049/jimmunol.1200056
  • Peer Reviewed
• [Journal Article] Constitutive Plasmacytoid Dendritic Cell Migration to the Splenic White Pulp Is Cooperatively Regulated by CCR7- and CXCR4-Mediated Signaling. (2012)
  • Author(s): Umemoto, E.
  • Journal Title: J. Immunol. Volume: 189 Issue: 1 Pages: 191-199
  • DOI: 10.4049/jimmunol.1200802
  • Peer Reviewed
• [Journal Article] Stromal cell-derived factor 1 regulates the actin organization of chondrocytes and chondrocyte hypertrophy. (2012)
  • Author(s): Murata, K.
  • Journal Title: PLoS One. Volume: 7 Issue: 5 Pages: 237-44
  • DOI: 10.1371/journal.pone.0037163
  • Peer Reviewed
• [Journal Article] Extracellul- ar matrix protein Tenascin-C is req- uired in the bone marrow microenvio- nment primed for hematopoietic rege- neration (2012)
  • Author(s): Nakamura-Ishizu A, Okuno Y, Omatsu Y, Okabe K, Morimoto J, Uede T, Nagasa- wa T, Suda T, Kubota Y
  • Journal Title: Blood Volume: 119 Issue: 23 Pages: 5429-5437
  • DOI: 10.1182/blood-2011-11-393645
  • Peer Reviewed
• [Journal Article] Bone marrow niches for hematopoietic stem cells and immune cells. (2012)
  • Author(s): Sugiyama, T.
  • Journal Title: Inflamm. Allergy Drug Targets Volume: 11 Issue: 3 Pages: 201-206
  • DOI: 10.2174/187152812800392689
  • Peer Reviewed
• [Journal Article] Bone marrow niches for hematopoietic stem cells and immune cells (2012)
  • Author(s): Sugiyama, T., Nagasawa, T.
  • Journal Title: Inflamm.Allergy Drug Targets Volume: (in press)
  • NAID: 120004287995
  • Peer Reviewed
• [Journal Article] Control of hematopoietic stem cells by the bone marrow stromal niche : the role of reticular cells (2011)
  • Author(s): Nagasawa, T., Omatsu, Y., Sugiyama, T.
  • Journal Title: Trends Immunol. Volume: 32 Issue: 7 Pages: 315-320
  • DOI: 10.1016/j.it.2011.03.009
  • Peer Reviewed
• [Journal Article] Emergency evacuation! Hematopoietic niches induce cell exit in infection (2011)
  • Author(s): Sugiyama, T., Nagasawa, T.
  • Journal Title: Immunity Volume: 34 Issue: 4 Pages: 463-465
  • DOI: 10.1016/j.immuni.2011.04.009
  • Peer Reviewed
• [Journal Article] Isolation and function of mouse tissue resident vascular precursors marked by myelin protein zero (2011)
  • Author(s): Kubota Y, Takubo K, Hirashima M, Nagoshi N, Kishi K, Sano K, Murakami M, Ema M, Omatsu Y, Takahashi S, Nagasawa T, Shibuya M, Okano H, Suda T
  • Journal Title: J Exp Med Volume: 208 Issue: 5 Pages: 949-960
  • DOI: 10.1084/jem.20102187
  • Peer Reviewed
• [Journal Article] CXCL12-CXCR4 chemokine signaling is essential for NK cell development in adult mice. (2011)
  • Author(s): Noda, M.
  • Journal Title: Blood Volume: VOL.117 Pages: 451-458
  • Peer Reviewed
• [Journal Article] Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. (2011)
  • Author(s): Lei, Y.
  • Journal Title: J.Exp.Med. Volume: VOL.208 Pages: 383-394
  • Peer Reviewed
• [Journal Article] C-X-C receptor type 4 promotes metastasis by activating p38 mitogen-activated protein kinase in myeloid differentiation antigen (Gr-1)-positive cells. (2011)
  • Author(s): Hiratsuka, S.
  • Journal Title: Proc.Natl.Acad.Sci.U S A. Volume: VOL.108 Pages: 302-307
  • Peer Reviewed
• [Journal Article] CXCL12-CXCR4 chemokine signaling is essential for NK cell development in adult mice. (2010)
  • Author(s): Noda, M., Omatsu, Y., Sugiyama, T., Oishi, S., Fujii, N., and *Nagasawa, T.
  • Journal Title: Blood Volume: 117 Issue: 2 Pages: 451-458
  • DOI: 10.1182/blood-2010-04-277897
  • Peer Reviewed
• [Journal Article] The Essential Functions of Adipo-osteogenic Progenitors as the Hematopoietic Stem and Progenitor Cell Niche. (2010)
  • Author(s): Omatsu,Y., Sugiyama, T., Kohara, H., Kondoh, G., Fujii, N., Kohno, K., *Nagasawa, T
  • Journal Title: Immunity Volume: 33(3) Issue: 3 Pages: 2010-2010
  • DOI: 10.1016/j.immuni.2010.08.017
  • Peer Reviewed
• [Journal Article] The Essential Functions of Adipo-osteogenic Progenitors as the Hematopoietic Stem and Progenitor Cell Niche. (2010)
  • Author(s): Omatsu, T.
  • Journal Title: Immunity Volume: VOL.33 Pages: 387-399
  • Peer Reviewed
• [Journal Article] Bone marrow graft-versus-host disease : early destruction of hematopoietic niche after MHC-mismatched hematopoietic stem cell transplantation. (2010)
  • Author(s): Shono, Y.
  • Journal Title: Blood Volume: VOL.115 Pages: 5401-5411
  • Peer Reviewed
• [Journal Article] Dock 180 is a rac activator that regulates cardiovascular development by acting downstream of CXCR4. (2010)
  • Author(s): Sanematsu, F.
  • Journal Title: Circ.Res. Volume: VOL.107 Pages: 1102-1105
  • Peer Reviewed
• [Presentation] Lymphocyte development "The adipo-osteogenic progenitors with long processes function as niches for hematopoietic stem and progenitor cells" (2012)
  • Author(s): T. Nagasawa
  • Organizer: 第41回日本免疫学会学術集会 シンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 2012-12-05
• [Presentation] Adipo-osteogenic progenitors function as niches for hematopoietic stem and progenitor cells in the marrow (2012)
  • Author(s): T. Nagasawa
  • Organizer: The 9th Nikko International Symposium 2012, Understanding complex network systems in disease biology.
  • Place of Presentation: Tochigi
  • Year and Date: 2012-10-12
• [Presentation] Bone marrow niches controlling behavior of hematopoietic stem and progenitor cells (2012)
  • Author(s): 長澤丘司
  • Organizer: The 21st Hot Spring Harbor Symposium jointly with 9th Global COE international Symposium
  • Place of Presentation: 九州大学(福岡県)(招待講演)
  • Year and Date: 2012-01-22
• [Presentation] Bone marrow niches controlling behavior of hematopoietic stem and progenitor cells (2012)
  • Author(s): T. Nagasaw
  • Organizer: The 21st Hot Spring Harbor Symposium jointly with 9th Global COE international Symposium; Cell Migration in Biology and Medicine
  • Place of Presentation: Fukuoka
• [Presentation] Adipo-osteogenic progenitors constitute reticular niches for hematopoietic stem and progenitor cells (2011)
  • Author(s): T. Nagasawa
  • Organizer: The 23th Korean Society of Bone Metabolism Autumn Scientific Congress, Satellite Symposium:Bone and Hematopoietic System
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2011-11-19
• [Presentation] Adipo-osteogenic progenitors constitute reticular niches for hematopoietic stem and progenitor cells (2011)
  • Author(s): 長澤丘司
  • Organizer: The 23th Korean Sciety of Bone Metabolism Autumn Scientific Congress
  • Place of Presentation: ソウル(韓国)(招待講演)
  • Year and Date: 2011-11-19
• [Presentation] CXCL12 and reticular niches for hematopoietic stem and progenitor cells (2011)
  • Author(s): 長澤丘司
  • Organizer: 40th Annual Scientific Meeting of the ISEH Society for Hematology and Stem Cells
  • Place of Presentation: バンクーバー(カナダ)(招待講演)
  • Year and Date: 2011-08-26
• [Presentation] Bone marrow niches for hematopoietic stem and progenitor cells (2011)
  • Author(s): 長澤丘司
  • Organizer: 日本炎症・再生医学会
  • Place of Presentation: 国立京都国際会館(京都府)(招待講演)
  • Year and Date: 2011-06-03
• [Presentation] CXCL12 and reticular niches for hematopoietic stem and progenitor cells (2011)
  • Author(s): T. Nagasawa
  • Organizer: 40th Annual Scientific Meeting of the ISEH-Society for Hematology and Stem Cells, Break out session: Microenvironment.
  • Place of Presentation: Vancouver, Canada
• [Presentation] The chemokine CXCL12 and niches for hematopoietic stem cells and immune cells (2010)
  • Author(s): T.Nagasawa
  • Organizer: 14th International Congress of Immunology.
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-24
• [Presentation] The chemokine CXCL12 and bone marrow niches for hematopoietic stem cells (HSCs) and immune cells. (2010)
  • Author(s): T.Nagasawa
  • Organizer: 3rd International Conference on Osteoimmunology.
  • Place of Presentation: Fira, Santorini, Greece
  • Year and Date: 2010-06-21
• [Presentation] The chemokine CXCL12 and niches for hematopoietic stem cells and immune cells. (2010)
  • Author(s): T. Nagasawa
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: Kobe
• [Presentation] The chemokine CXCL12 and bone marrow niches for HSCs and immune cells (2010)
  • Author(s): T. Nagasawa
  • Organizer: The 3rd International Conference on Osteoimmunology: Interactions of the Immune and Skeletal Systems
  • Place of Presentation: Fira, Greece
• [Presentation] 骨髄の造血幹細胞ニッシェと脂肪・骨前駆細胞CAR細胞
  • Author(s): 長澤 丘司
  • Organizer: 第118回日本解剖学会総会・全国学術集会 シンポジウム 骨髄幹細胞ニッチと神経―免疫―内分泌クロストーク
  • Place of Presentation: サンポートホール高松・かがわ国際会議場・高松
  • Invited
• [Presentation] The adipo-osteogenic progenitors with long processes function as niches for hematopoietic stem and progenitor cells
  • Author(s): T. Nagasawa
  • Organizer: 第41回日本免疫学会学術集会 シンポジウム
  • Place of Presentation: 神戸国際会議場・神戸
  • Invited
• [Presentation] 免疫担当細胞の産生と造血幹細胞・前駆細胞ニッシェ
  • Author(s): 長澤 丘司
  • Organizer: 第41回日本免疫学会学術集会 レビュートーク
  • Place of Presentation: 神戸国際会議場・神戸
  • Invited
• [Presentation] Adipo-osteogenic progenitors function as niches for hematopoietic stem and progenitor cells in the marrow
  • Author(s): T. Nagasawa
  • Organizer: The 9th Nikko International Symposium 2012, Understanding complex network systems in disease biology.
  • Place of Presentation: Jich Medical University, Shimotsuke, Tochigi
  • Invited
• [Presentation] 骨髄の脂肪・骨前駆細胞 CAR細胞と造血幹細胞ニッシェ
  • Author(s): 長澤 丘司
  • Organizer: 第30回 日本骨代謝学会学術集会 カレント コンセプト1 骨髄とがん細胞
  • Place of Presentation: 京王プラザホテル・東京
  • Invited
• [Presentation] 骨髄の造血幹細胞・造血ニッシェ
  • Author(s): 長澤 丘司
  • Organizer: 第33回 日本炎症・再生医学会 シンポジウム 炎症と骨・骨髄
  • Place of Presentation: ホテル日航福岡・福岡
  • Invited
• [Presentation] 骨髄の微小環境（ニッシェ）による造血幹細胞と造血の制御
  • Author(s): 長澤 丘司
  • Organizer: 第12回 日本加齢医学会総会 シンポジウム 24
  • Place of Presentation: パシフィコ横浜会議センター・横浜
  • Invited
• [Presentation] 骨髄の脂肪・骨前駆細胞CAR細胞と造血幹細胞ニッシェ
  • Author(s): 長澤 丘司
  • Organizer: 第101回 日本病理学会総会 ワークショップ 造血幹細胞の病理：最先端研究から診断まで。
  • Place of Presentation: 京王プラザホテル・東京
  • Invited