Signal Transduction

TEL +81-6-6879-8316


Tissue homeostasis in all organs is maintained via a highly hierarchal architecture of blood vessels, which is precisely regulated in an organ-specific manner. It has been recently clarified that blood vessels provide a vascular niche for tissue specific stem cells by secreting angiocrine signals and work as a pipeline connecting between distant organs for repairing tissue/organ damage mediating with intercrine-signals.

In our laboratory, we are examining how blood vessel diversity is regulated, focusing on the processes of angiogenesis and blood vessel maturation, for the development of novel methods to regulate vascular diseases such as cancer and aging related diseases. In addition to the molecular analysis focusing on Angiopoitin/Tie2 and apelin/APJ ligand-receptor system, we recently established the concept of “vascular promotion” in tumor that allows to deliver anti-cancer drug into tumor microenvironment by activating lipid mediator receptor LPA4 (Figure 1, Takara et al., Cell Reports 2017). Moreover, we have identified endothelial stem cells in pre-existing blood vessels and showed their utility for vascular regeneration (Wakabayashi et al. Cell Stem Cell 2018).

Figure 1: LPA4 activation promotes mature blood vessel formation in tumor and allows delivery of anticancer drug into tumor (Takara et al. Cell Reports 2017).
Figure 2: Endothelial stem cell population is responsible for organ specific vascular formation. Schema shows the example of vascular regeneration occurring in liver vascular injury (Wakabayashi et al. Cell Stem Cell 2018).

Principal Investigator

Nobuyuki Takakura Professor

Research field

Regulation of tumor angiogenesis / Tissue repair and regeneration by stem cell population

Education history

1988.3 M.D. Mie University, Faculty of Medicine
1997.3 Ph.D. Kyoto University Graduate School of Medicine

Research and career history

1988.4 Medical Staff as a Physician, 2nd Department of Internal Medicine of Mie University (-1993.3)
1998.3 Instructor, Kumamoto University Graduate School of Medicine
1999.10 Assistant Professor, Kumamoto University Graduate School of Medicine
2000.10 Associate Professor, Molecular Embryology and Genetics Kumamoto University Graduate School of Medicine
2001.4 Professor, Department of Stem Cell Biology Cancer Research Institute, Kanazawa University
2006.4-  Professor, Department of Signal Transduction Research Institute for Microbial Diseases,Osaka University
2018.8- Professor, Immunology Frontier Research Center,Osaka University


  • Nobuyuki Takakura Professor
  • Bal Zeynep Assistant Professor



  • Wakabayashi T, Naito H, Suehiro JI, Lin Y, Kawaji H, Iba T, Kouno T, Ishikawa-Kato S, Furuno M, Takara K, Muramatsu F, Weizhen J, Kidoya H, Ishihara K, Hayashizaki Y, Nishida K, Yoder MC, Takakura N. CD157 Marks Tissue-Resident Endothelial Stem Cells with Homeostatic and Regenerative Properties. Cell Stem Cell. 2018 Mar 1;22(3):384-397.e6.
  • Takara K, Eino D, Ando K, Yasuda D, Naito H, Tsukada Y, Iba T, Wakabayashi T, Muramatsu F, Kidoya H, Fukuhara S, Mochizuki N, Ishii S, Kishima H, Takakura N. Lysophosphatidic acid receptor 4 activation augments drug delivery in tumors by tightening endothelial cell-to-cell contact. Cell Rep. 2017 Aug 29;20(9):2072-2086.
  • Naito H, Wakabayashi T, Kidoya H, Muramatsu F, Takara K, Eino D, Yamane K, Iba T, Takakura N. Endothelial Side Population Cells Contribute to Tumor Angiogenesis and Antiangiogenic Drug Resistance. Cancer Res. 2016 Jun 1;76(11):3200-10.
  • Kidoya H, Naito H, Muramatasu F, Yamakawa D, Jia W, Ikawa M, Sonobe T, Tsuchimochi H, Shirai M, Adams RH, Fukamizu A, Takakura N. APJ Regulates Parallel Juxtapositional Alignment of Arteries and Veins in the skin. Dev Cell 33:247-259, 2015.
  • Sawane M, Kajiya K, Kidoya H, Takagi M, Muramatsu F, Takakura N. Apelin inhibits diet-induced obesity by enhancing lymphatic and blood vessel integrity. Diabetes. 62: 1970-1980. 2013
  • Muramatsu F, Kidoya H, Naito H, Sakimoto S, Takakura N. microRNA-125b inhibits tube formation of blood vessels through translational suppression of VE-cadherin. Oncogene 32: 414-421. 2013
  • Kidoya H, Kunii N, Naito H, Muramatsu F, Okamoto Y, Nakayama T, Takakura N. The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy. Oncogene 31: 3254-3264, 2012
  • Sakimoto S, Kidoya H, Naito H, Kamei M, Sakaguchi H, Goda N, Fukamizu A, Nishida K, Takakura N. A role for endothelial cells in promoting the maturation of astrocytes through the apelin/APJ system in mice. Development 139: 1327-1335, 2012
  • Naito H, Kidoya H, Sakimoto S, Wakabayashi T, Takakura N. Identification and characterization of a resident vascular stem/progenitor cell population in preexisting blood vessels. EMBO J 31, 842-855, 2012
    Kidoya H, Naito H, and Takakura N. Apelin induces enlarged and non-leaky blood vessels for functional recovery from ischemia. Blood 115, 3166-3174, 2010.
  • Nagahama Y, Ueno M, Miyamoto S, Morii E, Minami T, Mochizuki N, Saya H, Takakura N. PSF1, a DNA replication factor expressed widely in stem and progenitor cells, drives tumorigenic and metastatic properties. Cancer Res 70, 1215-1224, 2010.
  • Ueno M, Itoh M, Sugihara K, Asano M, and Takakura N. Both alleles of PSF1 are required for maintenance of pool size of immature hematopoietic cells and acute bone marrow regeneration. Blood 113: 555-562, 2009.
    Kidoya H, Ueno M, Yamada Y, Mochizuki N, Nakata M, Yano T, Fujii R, and Takakura N. Spatial and temporal role of the apelin/APJ system in the caliber size regulation of blood vessels during angiogenesis. EMBO J 27:522-534, 2008.
  • Huang X, Yamada Y, Kidoya H, Naitoh H, Nagahama Y, Kong L, Katoh S, Li W, Ueno M, and Takakura N. EphB4 overexpression on B16 melanoma cells affects arterial-venous patterning in tumor angiogenesis. Cancer Res 67:9800-9808, 2007.
  • Yamada Y, and Takakura N. Physiological pathway of differentiation of hematopoietic stem cell population into mural cells. J Exp Med 203: 1055-1065, 2006.
  • Okamoto R, Ueno M, Yamada Y, Takahashi N, Sano H, and and Takakura N. Hematopoietic cells regulate the angiogenic switch during tumorigenesis. Blood 105: 2757-2763, 2005.
  • Yamada Y, Oike Y, Ogawa H, Ito Y, Fujisawa H, Suda T, and Takakura N. Neuropilin-1 on hematopoietic cells as a source of vascular development. Blood 101:1801-1809, 2003.
  • Takakura N, Watanabe T, Suenobu S, Yamada Y, Noda T, Ito Y, Satake M, and Suda T. A role for hematopoietic stem cells in promoting angiogenesis. Cell 102, 2, 199-209, 2000.
  • Takakura N, Huang XL, Naruse T, Hamaguchi I, Dumont DJ, Yancopoulos GD, Suda T. Critical role of the TIE2 endothelial cell receptor in the development of definitive hematopoiesis. Immunity 9 : 677-86, 1998.
  • Takakura N, Kodama H, Nishikawa S, and Nishikawa S. Preferential proliferation of murine colony-forming units in culture in a chemically defined condition with a macrophage colony-stimulating factor-negative stromal cell clone. J Exp Med 184 : 2301-9, 1996.