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Stem Cell Biology and Developmental Immunology

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Overview

We isolated a chemokine, CXCL12 (SDF-1/PBSF) as a molecule that stimulates the growth of B cell precursors (Nagasawa, T., et al. PNAS 1994) and have found its multiple physiological functions in development (Nagasawa, T., et al. Nature 1996). We have shown that the primary physiologic receptor for CXCL12 is CXCR4, which also functions as a coreceptor for strains of HIV-1 (Tachibana, K., et al. Nature 1998) and that CXCL12-CXCR4 signaling is essential for colonization of bone marrow by hematopoietic cells including hematopoietic stem cells (HSCs)(Ara, T., et al. Immunity 2003), colonization of gonads by primordial germ cells (PGCs) during ontogeny (Ara, T., et al. PNAS 2003), maintenance of a pool of HSCs in adult bone marrow (Sugiyama, T., et al. Immunity 2006), development of immune cells, including B cells (Nagasawa, T. Nat. Rev. Immunol. 2006), vascularization of the gastrointestinal tract and cardiogenesis (Tachibana, K., et al. Nature 1998).

In recent years, we have identified a population of reticular cells, which express CXCL12 at high levels, termed CXCL12 abundant reticular (CAR) cells within bone marrow (Sugiyama, T., et al. Immunity 2006) and indicated that CAR cells are adipo-osteogenic progenitors and function as the special microenvironment niches for HSCs, B cells and erythroid cells, and that CXCL12 and SCF produced by CAR cells maintain hematopoietic stem and progenitor cells (Omatsu, Y., et al. Immunity 2010). Recently, we found that the transcription factor Foxc1 was preferentially expressed in CAR cells in the marrow, enhancing CXCL12 and SCF expression and was essential for inhibiting adipogenic processes in CAR progenitors, and development and maintenance of the HSPC niche (Omatsu, Y., et al. Nature 2014). We are studying the roles of CXCL12-CXCR4 signaling and CAR cells in hematopoiesis to understand the spatiotemporal regulation of lymphohematopoiesis by environmental factors within bone marrow.

Figure 1
The reticular cells with long processes, which express CXCL12 at high levels, termed CXCL12 abundant reticular (CAR) cells are adipo-osteogenic progenitors and function as niches critical for proliferation of HSCs and lymphoid and erythroid progenitors and maintenance of HSCs in an undifferentiated state. The transcription factor Foxc1 is preferentially expressed in CAR cells in the marrow and is essential for inhibiting adipogenic processes in CAR progenitors, and development and maintenance of the HSPC niche.

Principal Investigator

Takashi Nagasawa Professor

Research field

Microenvironmental niches for hematopoietic stem cells (HSCs) and immune cells Immunology

Education history

1987.3 Nagoya University Faculty of Medicine Graduated
1993.3 Osaka University Graduate School, Division of Medicine Completed

Research and career history

1987.7  Resident in internal medicine, Osaka University Hospital (-1988.6)
1988.7  Resident in internal medicine, Osaka Prefectural Hospital Organization (-1989.3)
1995.4  JSPS Research Fellow (-1995.9)
1995.10  Researcher, Research Institute, Osaka Medical Center for Maternal and Child Health (-2002.3)
2002.4  Professor, Institute for Frontier Medical Sciences, Kyoto University (-2015.12)
2016 Professor, Graduate School of Frontier Bioscience Osaka University
2016 Professor, Division of Medicine, Graduate School of Medicine, Osaka University
2017.4 Professor, Osaka University Immunology Frontier Research Center

Prize

2019.6 Japan Academy Prize
2014.11 Takeda Prize for Medical Science 
1998.12 The Japanese Society for Immunology Prize 

Members

  • Takashi Nagasawa Professor
    nagasawa.takashi.fbsosaka-u.ac.jp

Achievements

Publications

  • Omatsu, Y., Aiba, S., Maeta, T., Higaki, K., Aoki, K., Watanabe, H., Kondoh, G., Nishimura, R., Takeda, S., Chung, U.I., and *Nagasawa, T.
    Runx1 and Runx2 inhibit fibrotic conversion of cellular niches for hematopoietic stem cells.
    Nat Commun. 13(1);2654. (2022). May 12

  • *Nakagawa, T., Jörg, D.J., Watanabe, H., Mizuno, S., Han, S., Ikeda, T., Omatsu, Y., Nishimura, K., Fujita, M., Takahashi, S., Kondoh, G., Simons, B.D., *Yoshida, S., and *Nagasawa, T.
    A multistate stem cell dynamics maintains homeostasis in mouse spermatogenesis.
    Cell Rep. 37(3);109875. (2021). Oct 19

  • Aoki, K., Kurashige, M., Ichii, M., Higaki, K., Sugiyama, T., Kaito, T., Ando, W., Sugano, N., Sakai, T., Shibayama, H., HANDAI Clinical Blood Club, Takaori-Kondo, A., Morii, E., Kanakura, Y., and *Nagasawa, T.
    Identification of CXCL12-abundant reticular cells in human adult bone marrow.
    Br. J. Haematol. 193(3);659-668. (2021). May

  • Omatsu, Y., Higaki, K., and Nagasawa, T.
    Cellular Niches for Hematopoietic Stem Cells and Lympho-Hematopoiesis in Bone Marrow During Homeostasis and Blood Cancers.
    Curr Top Microbiol Immunol. 434;33-54. (2021).

  • Omatsu, Y., and Nagasawa, T. 
    Identification of microenvironmental niches for hematopoietic stem cells and lymphoid progenitors-bone marrow fibroblastic reticular cells with salient features.
    Int Immunol. 33(12);821-826. (2021). Nov 25

  • Sugiyama, T., Omatsu, Y., and Nagasawa, T.
    Niches for Hematopoietic Stem Cells and Immune Cell Progenitors.
    Int Immunol. 31(1);5-11. (2019). Feb 6

  • Seike, M., Omatsu, Y., Watanabe, H., Kondoh, G., and *Nagasawa, T.
    Stem cell niche-specific Ebf3 maintains the bone marrow cavity.
    Genes Dev. 32(5-6);359-372. (2018). Mar 1

  • Shimoto, M., Sugiyama, T., and *Nagasawa, T.
    Numerous niches for hematopoietic stem cells remain empty during homeostasis.
    Blood 129;2124-2131. (2017). Apr 13 

  • Nagasawa, T.
    CXCL12/SDF-1 and CXCR4.
    Front. Immunol. 6;301. (2015). Jun 12  Review.

  • Omatsu, Y., and *Nagasawa, T.
    The critical and specific transcriptional regulator of the microenvironmental niche for  hematopoietic stem and progenitor cells.
    Curr. Opin. Hematol. 22(4);330-336. (2015). Jul  Review.

  •  Omatsu, Y., Seike, M., Sugiyama, T., Kume, T., and *Nagasawa, T.
    Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation.
    Nature 508(7497);536-540. (2014). Apr 24 Epub 2014 Mar 2.

  • *Nagasawa, T.
    CXC chemokine ligand 12 (CXCL12) and its receptor CXCR4.
    J. Mol. Med. 92;433-439. (2014). May Epub 2014 Apr 11.  Review.

  • Greenbaum, A., Hsu, Y.M.S., Day, R.B., Schuettpelz, L.G., Christopher, M.J., Borgerding, J.N., Nagasawa, T., and *Link, D.C.
    CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance.

    Nature 495(7440);227-230. (2013). Mar 14

  • Noda, M., Omatsu, Y., Sugiyama, T., Oishi, S., Fujii, N., and *Nagasawa, T.
    CXCL12-CXCR4 chemokine signaling is essential for NK-cell development in adult mice.
    Blood 117;451-458. (2011). Jan 13.

  • *Nagasawa, T., Omatsu, Y., and Sugiyama, T.
    Control of hematopoietic stem cells by the bone marrow stromal niche: the role of reticular cells.
    Trends Immunol. 32; 315-320. (2011). July, Epub 2011 Apr 29. Review.

  • Omatsu, Y., Sugiyama, T., Kohara, H., Kondoh, G., Fujii, N., Kohno, K., and *Nagasawa, T.
    The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and 
    progenitor cell niche.
    Immunity 33(3);387-399. (2010). Sep 24. (IF; 24.221 (2010), 21.637 (2011))

  • Kohara, H., Omatsu, Y., Sugiyama, T., Noda, M., Fujii, N., and *Nagasawa, T.
    Development of plasmacytoid dendritic cells in bone marrow stromal cell niches requires CXCL12-CXCR4 chemokine signaling.
    Blood 110;4153-4160. (2007). Dec 15

  • Sugiyama, T., Kohara, H., Noda, M., and *Nagasawa, T.
    Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches.
    Immunity 25;977-988. (2006). Dec

  • *Nagasawa, T.
    Microenvironmental niches in the bone marrow required for B-cell development.
    Nat. Rev. Immunol. 6(2);107-116. (2006). Feb.  Review.

  • Ara, T., Tokoyoda, K., Okamoto, R., Koni, P.A., and *Nagasawa, T.
    The role of CXCL12 in the organ-specific process of artery formation.
    Blood 105;3155-3161. (2005). Apr 15

  • Tokoyoda, K., Egawa, T., Sugiyama, T., Choi, B.I., and *Nagasawa, T.
    Cellular niches controlling B lymphocyte behavior within bone marrow during development.
    Immunity 20;707-718. (2004). Jun

  • Ara, T., Nakamura, Y., Egawa, T., Sugiyama, T., Abe, K., Kishimoto, T., Matsui, Y., and *Nagasawa, T.
    Impaired colonization of the gonads by primordial germ cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1)
    Proc. Natl. Acad. Sci. USA. 100;5319-5323. (2003).

  • Ara, T., Itoi, M., Kawabata, K., Egawa, T., Tokoyoda, K., Sugiyama, T., Fujii, N., Amagai, T., and *Nagasawa, T.
    A role of CXCL12/SDF-1/PBSF and its receptor CXCR4 in fetal and adult T cell 
    development in vivo.
    J. Immunol. 170;4649-4655. (2003).

  • Ara, T., Tokoyoda, K., Sugiyama, T., Egawa, T., Kawabata, K., and *Nagasawa, T.
    Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny.
    Immunity 19;257-267. (2003). (cover photo). Aug

  • Egawa, T., Kawabata, K., Kawamoto, H., Amada, K., Okamoto, R., Fujii, N., Kishimoto, T., Katsura, Y., and Nagasawa, T. 
    The earliest stages of B cell development require a chemokine stromal cell-derived factor/pre-B cell growth-stimulating factor.
    Immunity 15;323-334. (2001). Aug

  • Tachibana, K., Hirota, S., Iizasa, H., Yoshida, H., Kawabata, K., Kataoka, Y., Kitamura, Y., Matsushima, K., Yoshida, N., Nishikawa, S., Kishimoto, T., and *Nagasawa, T.
    The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract.
    Nature 393(6685);591-594. (1998). Jun 11

  • Tachibana, K., Nakajima, T., Sato, A., Igarashi, K., Shida, H., Iizasa, H., Yoshida, N., Yoshie, O., Kishimoto, T., and *Nagasawa, T.
    CXCR4/fusin is not a species-specific barrier in murine cells for HIV-1 entry.
    J. Exp. Med. 185(10);1865-1870. (1997). May 19

  • Murakami, T., Nakajima, T., Koyanagi, Y., Tachibana, K., Fujii, N., Tamamura, H., Yoshida, N., Waki, M., Matsumoto, A., Yoshie, O., Kishimoto, T., Yamamoto, N.,
    and *Nagasawa, T.
    A small molecule CXCR4 inhibitor that blocks T cell line-tropic HIV-1 infection.
    J. Exp. Med. 186(8);1389-1393. (1997). Oct 20

  • *Nagasawa, T., Hirota, S., Tachibana, K., Takakura, N., Nishikawa, S., Kitamura, Y., Yoshida, N., Kikutani, H., and Kishimoto, T.
    Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1.
    Nature 382(6592);635-638. (1996). Aug 15

  • Nagasawa, T., Kikutani, H., and Kishimoto, T.
    Molecular cloning and structure of a pre-B-cell growth-stimulating factor.
    Proc. Natl. Acad. Sci. USA. 91(6);2305-2309. (1994). Dec

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