Molecular mechanisms underlining regulation of HSC niche formation and maintenance

• Project/Area Number: 18H03998
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
• Research Institution: Osaka University
• Principal Investigator: NAGASAWA TAKASHI 大阪大学, 生命機能研究科, 教授 (80281690)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥43,810,000 (Direct Cost: ¥33,700,000、Indirect Cost: ¥10,110,000); Fiscal Year 2021: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000); Fiscal Year 2020: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000); Fiscal Year 2019: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000); Fiscal Year 2018: ¥12,090,000 (Direct Cost: ¥9,300,000、Indirect Cost: ¥2,790,000)
• Keywords: 微小環境 / 組織幹細胞 / 発生・分化 / 再生医学

Outline of Final Research Achievements

In bone marrow, the maintenance of hematopoietic stem cells (HSCs) require special microenvironments, known as HSC niches. A population of mesenchymal stem cells, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells are the major cellular component of HSC niches. The role of Runx transcription factors, Runx1 and Runx2, which are critical for development of HSCs and osteoblasts during ontogeny, respectively in HSC cellular niches remains unclear. We show that Runx1 and Runx2 are predominantly expressed in CAR cells and their progenitors and that mice lacking both Runx1 and Runx2 in CAR cells display an increase in fibrosis with markedly reduced hematopoietic stem and progenitor cells in bone marrow. In vitro, Runx1 is induced by the transcription factor Foxc1 and decreases fibrotic gene expression in CAR cells. Thus, HSC cellular niches require Runx1 or Runx2 to prevent their fibrotic conversion and maintain HSCs and hematopoiesis in adults.

Academic Significance and Societal Importance of the Research Achievements

骨髄のCAR細胞は造血幹細胞ニッチを構成し、ニッチ形成に必須で、それぞれ脂肪細胞、骨芽細胞への分化を抑制する転写因子Foxc1、Ebf1/3を特異的に高発現することから、骨髄特異的な細胞系列である。本研究で、CAR細胞が線維芽細胞に変化するのを抑制する転写因子Runx1とRunx2が発見され、CAR細胞が、他の線維芽細胞と異なる性質を持って造血幹細胞ニッチを形成する分子基盤の理解が深められた。また、この成果は、Runx1とRunx2の低下が、様々な造血器腫瘍の予後を悪化させる骨髄線維症の病態形成に関与している可能性を提示し、臨床医学においても重要である。

Research Products

• [Journal Article] Runx1 and Runx2 inhibit fibrotic conversion of cellular niches for hematopoietic stem cells (2022)
  • Author(s): Yoshiki Omatsu, Shota Aiba, Tomonori Maeta, Kei Higaki, Kazunari Aoki, Hitomi Watanabe, Gen Kondoh, Riko Nishimura, Shu Takeda, Ung-il Chung, Takashi Nagasawa
  • Journal Title: Nature Communications Volume: in press
• [Journal Article] A multistate stem cell dynamics maintains homeostasis in mouse spermatogenesis (2021)
  • Author(s): Nakagawa Toshinori、Jorg David J.、Watanabe Hitomi、Mizuno Seiya、Han Seungmin、Ikeda Tatsuro、Omatsu Yoshiki、Nishimura Keiko、Fujita Miyako、Takahashi Satoru、Kondoh Gen、Simons Benjamin D.、Yoshida Shosei、Nagasawa Takashi
  • Journal Title: Cell Reports Volume: 37 Issue: 3 Pages: 109875-109875
  • DOI: 10.1016/j.celrep.2021.109875
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of CXCL12-abundant reticular cells in human adult bone marrow (2021)
  • Author(s): 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, Nagasawa T.
  • Journal Title: Br J Haematol . Volume: x Issue: 3 Pages: 659-668
  • DOI: 10.1111/bjh.17396
  • Peer Reviewed / Open Access
• [Journal Article] Identification of microenvironmental niches for hematopoietic stem cells and lymphoid progenitors - bone marrow fibroblastic reticular cells with salient features (2021)
  • Author(s): Omatsu Yoshiki、Nagasawa Takashi
  • Journal Title: International Immunology Volume: 33 Issue: 12 Pages: 821-826
  • DOI: 10.1093/intimm/dxab092
  • Peer Reviewed
• [Journal Article] Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness (2021)
  • Author(s): Isringhausen Stephan、Mun YeVin、Kovtonyuk Larisa、Krautler Nike J.、Suessbier Ute、Gomariz Alvaro、Spaltro Gianluca、Helbling Patrick M.、Wong Hui Chyn、Nagasawa Takashi、Manz Markus G.、Oxenius Annette、Nombela-Arrieta Cesar
  • Journal Title: Journal of Experimental Medicine Volume: 218 Issue: 12
  • DOI: 10.1084/jem.20192070
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Group 2 innate lymphoid cells support hematopoietic recovery under stress conditions (2021)
  • Author(s): Sudo Takao、Motomura Yasutaka、Okuzaki Daisuke、Hasegawa Tetsuo、Yokota Takafumi、Kikuta Junichi、Ao Tomoka、Mizuno Hiroki、Matsui Takahiro、Motooka Daisuke、Yoshizawa Ryosuke、Nagasawa Takashi、Kanakura Yuzuru、Moro Kazuyo、Ishii Masaru
  • Journal Title: Journal of Experimental Medicine Volume: 218 Issue: 5 Pages: 20200817-20200817
  • DOI: 10.1084/jem.20200817
  • Peer Reviewed / Open Access
• [Journal Article] Upregulation of VCAM-1 in lymphatic collectors supports dendritic cell entry and rapid migration to lymph nodes in inflammation (2021)
  • Author(s): Arasa Jorge、Collado-Diaz Victor、Kritikos Ioannis、Medina-Sanchez Jessica Danielly、Friess Mona Carina、Sigmund Elena Caroline、Schineis Philipp、Hunter Morgan Campbell、Tacconi Carlotta、Paterson Neil、Nagasawa Takashi、Kiefer Friedemann、Makinen Taija、Detmar Michael、Moser Markus、Lammermann Tim、Halin Cornelia
  • Journal Title: Journal of Experimental Medicine Volume: 218 Issue: 7
  • DOI: 10.1084/jem.20201413
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CXCR4 in tumor epithelial cells mediates desmoplastic reaction in pancreatic ductal adenocarcinoma. (2020)
  • Author(s): Morita, T., Kodama, Y., Shiokawa, M., Kuriyama, K., Marui, S., Kuwada, T., Sogabe, Y., Matsumori, T., Kakiuchi, N., Tomono, T., Mima, A., Ueda, T., Tsuda, M., Yamauchi, Y., Nishikawa, Y., Sakuma, Y., Ota, Y., Maruno, T., Uza, N., Nagasawa, T., Chiba, T., and Seno, H.
  • Journal Title: Cancer Res. Volume: 80 Issue: 19 Pages: 4058-4070
  • DOI: 10.1158/0008-5472.can-19-2745
  • Peer Reviewed
• [Journal Article] Pathologic angiogenesis in the bone marrow of humanized sickle cell mice is reversible by blood transfusion. (2020)
  • Author(s): Park, S.Y., Matte, A., Jung, Y., Ryu, J., Wilson, A.B., Han, E.Y.A., Liu, M., Carbone, C., Melisi, D., Nagasawa, T., Locascio, J.J., Lin, C.P., Silberstein, L.E.*, and De Franceschi, L.
  • Journal Title: Blood Volume: - Issue: 23 Pages: 2071-2084
  • DOI: 10.1182/blood.2019002227
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Remodeling of light and dark zone follicular dendritic cells governs germinal center responses. (2020)
  • Author(s): Pikor, N.B., Morbe, U., Lutge, M., Gil-Cruz, C., Perez-Shibayama, C., Novkovic, M., Cheng, H.W., Nombela-Arrieta, C., Nagasawa, T., Linterman, M.A., Onder, L., and Ludewig, B.
  • Journal Title: Nat Immunol. Volume: 21 Issue: 6 Pages: 649-659
  • DOI: 10.1038/s41590-020-0672-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transient microglial absence assists postmigratory cortical neurons in proper differentiation (2020)
  • Author(s): Yuki Hattori, Yu Naito, Yoji Tsugawa, Shigenori Nonaka, Hiroaki Wake, Takashi Nagasawa, Takaki Miyata
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 1631-1631
  • DOI: 10.1038/s41467-020-15409-3
  • NAID: 120006841707
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dysregulated Expression of the Nuclear Exosome Targeting Complex Component Rbm7 in Nonhematopoietic Cells Licenses the Development of Fibrosis (2020)
  • Author(s): Fukushima Kiyoharu、Satoh Takashi、Sugihara Fuminori、Sato Yuki、Okamoto Toru、Mitsui Yuichi、Yoshio Sachiyo、Li Songling、Nojima Satoshi、Motooka Daisuke、Nakamura Shota、Kida Hiroshi、Standley Daron M.、Morii Eiichi、Kanto Tatsuya、Yanagita Motoko、Matsuura Yoshiharu、Nagasawa Takashi、Kumanogoh Atsushi、Akira Shizuo
  • Journal Title: Immunity Volume: 52 Issue: 3 Pages: 542-556
  • DOI: 10.1016/j.immuni.2020.02.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration. (2020)
  • Author(s): Matsushita, Y., Nagata, M., Kozloff, K.M., Welch, J.D., Mizuhashi, K., Tokavanich, N., Hallett, S.A., Link, D.C., Nagasawa, T., Ono, W., and Ono, N*.
  • Journal Title: Nat Commun. Volume: 11 Issue: 1 Pages: 332-332
  • DOI: 10.1038/s41467-019-14029-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mesenchymal Niche-Specific Expression of Cxcl12 Controls Quiescence of Treatment-Resistant Leukemia Stem Cells. (2020)
  • Author(s): Agarwal, P., Isringhausen, S., Li, H., Paterson, A.J., He, J., Gomariz, Á., Nagasawa, T., Nombela-Arrieta, C., and Bhatia, R*.
  • Journal Title: Cell Stem Cell. Volume: 26 Issue: 1 Pages: 123-123
  • DOI: 10.1016/j.stem.2019.11.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mesenchymal stromal cells in bone marrow express adiponectin and are efficiently targeted by an adiponectin promoter-driven Cre transgene. (2019)
  • Author(s): Mukohira H, Hara T, Abe S, Tani-Ichi S, Sehara-Fujisawa A, Nagasawa T, Tobe K, Ikuta K.
  • Journal Title: International Immunology Volume: 31 Issue: 11 Pages: 729-742
  • DOI: 10.1093/intimm/dxz042
  • NAID: 120006872738
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mesenchymal Niche-Specific Expression of Cxcl12 Controls Quiescence of Treatment-Resistant Leukemia Stem Cells. (2019)
  • Author(s): Agarwal, P., Isringhausen, S., Li, H., Paterson, A.J., He, J., Gomariz, Á., Nagasawa, T., Nombela-Arrieta, C., and Bhatia, R.
  • Journal Title: Cell Stem Cell Volume: 印刷中 Issue: 5 Pages: 769-784
  • DOI: 10.1016/j.stem.2019.02.018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Niches for hematopoietic stem cells and immune cell progenitors. (2019)
  • Author(s): Sugiyama, T., Omatsu, Y., and Nagasawa, T.
  • Journal Title: Int Immunol. Volume: 31 Issue: 1 Pages: 5-11
  • DOI: 10.1093/intimm/dxy058
  • Peer Reviewed
• [Journal Article] Resting zone of the growth plate houses a unique class of skeletal stem cells. (2018)
  • Author(s): Mizuhashi, K., Ono, W., Matsushita, Y., Sakagami, N., Takahashi, A., Saunders, T.L., Nagasawa, T., Kronenberg, H.M., and Ono, N.
  • Journal Title: Nature Volume: 563 Issue: 7730 Pages: 7730-7730
  • DOI: 10.1038/s41586-018-0662-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neutrophils instruct homeostatic and pathological states in naive tissues. (2018)
  • Author(s): Casanova-Acebes, M., Nicolás-Ávila, J.A., Li, J.L., García-Silva, S., Balachander, A., Rubio-Ponce, A., Weiss, L.A., Adrover, J.M., Burrows, K., A.-González, N., Ballesteros, I., Devi, S., （他5名）, Nagasawa, T., Soehnlein, O., Merad, M., Mortha, A., Ng, L.G., Peinado, H., and Hidalgo, A.
  • Journal Title: J Exp Med. Volume: 215 Issue: 11 Pages: 2778-2795
  • DOI: 10.1084/jem.20181468
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Quantitative spatial analysis of haematopoiesis-regulating stromal cells in the bone marrow microenvironment by 3D microscopy. (2018)
  • Author(s): Gomariz, A., Helbling, P.M., Isringhausen, S., Suessbier, U., Becker, A., Boss, A., Nagasawa, T., Paul, G., Goksel, O., Székely, G., Stoma, S., Nørrelykke, S.F., Manz, M.G., and Nombela-Arrieta, C.
  • Journal Title: Nat Commun. Volume: 9 Issue: 1 Pages: 2532-2532
  • DOI: 10.1038/s41467-018-04770-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Peripheral PDGFRα+gp38+ mesenchymal cells support the differentiation of fetal liver-derived ILC2. (2018)
  • Author(s): Koga, S., Hozumi, K., Hirano, K.I., Yazawa, M., Terooatea, T., Minoda, A., Nagasawa, T., Koyasu, S., and Moro, K.
  • Journal Title: J Exp Med. Volume: 215 Issue: 6 Pages: 1609-1626
  • DOI: 10.1084/jem.20172310
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 造血幹細胞と造血を維持する骨髄の微小環境（ニッチ） (2021)
  • Author(s): 長澤 丘司
  • Organizer: 第110回日本病理学会総会
  • Invited
• [Book] Bone Marrow Niche (2021)
  • Author(s): Takashi Nagasawa
  • Total Pages: 134
  • Publisher: Springer International Publishing
  • ISBN: 9783030860158