Immunology and Cell Biology

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The most characteristic features in our laboratory is to establish a major new experimental method, such as "intravital 2-photon imaging of bone tissues in vivo", with which we have revealed a novel regulatory mechanism on osteoclastogenesis by controlling the movement of osteoclast precursors between blood and endosteum (Figure 1). In future this laboratory has two major goals described as follows:

First, one of the major research targets has been the bone biology, elucidating the complex system for bone homeostasis in vivo. We proposed an original concept that the regulation of migration and positioning of osteoclast precursors, e.g. by chemokines and lipid mediators, is a novel point of control for bone homeostasis, and is also a clinically relevant therapeutic target. In the future study, we will unravel the whole regulatory system in bone biology. As physician-scientists, we will try to develop the new remedy for treating bone resorptive disorders.

The other direction of our laboratory is the development of the novel imaging techniques and the application of this methodology to the elucidation of a wide array of biological phenomenon. We are planning to employ this new method to the visualization of the behaviors of various types of hematopoietic cells in the bone marrow to further clarify their modes of migration and differentiation in vivo. Bone marrow is important as a reservoir as well as a maturation site for neutrophils and monocytes, and also it has recently been proposed to have a special location ("niche") for maintaining pluripotent hematopoietic stem cells or leukemic stem cells. We have also been using our imaging technology to observe various tissues other than bone, including liver, lung, tumor etc. at the single cell level. Thus, the intravital imaging technology provides a rich spectrum of cellular movement and localization to analyze.

[Figure 1] In vivo imaging of bone tissues. Bone marrow spaces of LysM-EGFP transgenic mouse (left panel) and CSF1R-EGFP transgenic mouse (right panel) observed by intravital 2-photon microscopy for bone tissues are shown. Blood microvessels were visualized by injecting TexasRed-conjugated dextran (high molecular weight: up to 70kDa). Movies showing their dynamic movements are displayed in the original website of our laboratory. Scale bars represent 30μm.

Principal Investigator

Masaru Ishii Professor

Research field: bioimaging, bone metabolism, immunology, pharmacology
mishii atmark
Education history
2005 Ph.D. Osaka University Graduate School of Medicine (Osaka/Japan)
1998 M.D. Osaka University Medical School (Osaka/Japan)
Research and career history

2000 - 2005 Assistant Professor, Department of Pharmacology, Osaka University Graduate School of Medicine (Osaka/Japan)
2005- Principal Investigator, Department of Clinical Research, National Osaka-Minami Medical Center (Osaka/Japan)
(Sabbatical leave between 2006-2008)
2006 - 2008 Visiting Postdoctoral Fellow, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (Bethesda/USA)
(supported by the International Human Frontier Science Program)
2008 - Guest Researcher, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (Bethesda/USA)
2008 - Visiting Associate Professor, Osaka University Head, Laboratory of Biological Imaging, WPI-IFReC
2009- Associate Professor, Osaka University Head, Laboratory of Biological Imaging, WPI-IFReC
2011- Professor, Osaka University Head, Laboratory of Biological Imaging, WPI-IFReC
2013- Professor, Osaka University, Department of Immunology and Cell Biology Faculty of Medicine/Graduate School of Frontier Biosciences/IFReC


Junichi Kikuta Assistant Professor
jkikuta atmark
Hiroki Mizuno Assistant Professor
hmizuno atmark
Takao Sudo Assistant Professor
sudo atmark
Keizo Nishikawa Specially Appointed Associate Professor
nishi atmark
Szandor Simmons Specially Appointed Assistant Professor
simmons atmark
Takahiro Matsui Specially Appointed Assistant Professor
matsuit atmark
Yutaka Uchida Specially Appointed Assistant Professor
uchida atmark


Iwamoto Y, Nishikawa K, Imai R, Furuya M, Uenaka M, Ohta Y, Morihana T, Ochi S, Penninger JM , Katayama I, Inohara I, Ishii M. (2016) Intercellular communication between keratinocytes and fibroblasts induces local osteoclast differentiation: a mechanism underlying cholesteatoma-induced bone destruction. Mol Cell Biol, 6(11):1610-20.
Maeda H, Kowada T, Kikuta J, Furuya M, Shirazaki M, Mizukami S, Ishii M*, Kikuchi K*. (2016) Real-time intravital imaging of pH variation associated with cell osteoclast activity and motility using designed small molecular probe. Nature Chem. Biol., 12(8):579-85.
Otani K, Naito Y, Sakaguchi Y, Seo Y, Takahashi Y, Kikuta J, Ogawa K, Ishii M. (2016) Cell-cycle-controlled radiation therapy was effective for treating a murine malignant melanoma cell line in vitro and in vivo. Sci. Rep., 6:30689.
Sekimoto R, Fukuda S, Maeda N*, Tsushima Y, Matsuda K, Mori T, Nakatsuji H, Nishizawa H, Kishida K, Kikuta J, Maijima Y, Funahashi T, Ishii M*, Shimomura I. (2015) Visualized macrophage dynamics and significance of S100A8 in obese fat. Proc. Natl. Acad. Sci. USA, 112: E2058-66.
Sano H, Kikuta J, Furuya M, Kondo N, Endo N, Ishii M. (2015) Intravital bone imaging by two-photon excitation microscopy to identify osteocytic osteolysis in vivo. Bone, 74:134-9.
Naito A, Yamamoto H, Kagawa Y, Naito Y, Okuzaki D, Otani K, Iwamoto Y, Maeda S, Kikuta J, Nishikawa K, Uemura M, Nishimura J, Hata T, Takemasa I, Mizushima T, Ishii H, Doki Y, Mori M, Ishii M. (2015) RFPL4A increases the G1 population and decreases sensitivity to chemotherapy in human colorectal cancer cells. J. Biol. Chem., 290(10):6326-37.
Nishikawa K, Iwamoto Y, Kobayashi Y, Katsuoka F, Kawaguchi S, Tsujita T, Nakamura T, Kato S, Yamamoto M, Takayanagi H, Ishii M. (2015) Dnmt3a regulates osteoclast differentiation by coupling to an S-adenosyl methionine-producing metabolic pathway. Nature Med., 21(3):281-7.
Nevius E, Pinho F, Dhodapkar M, Jin H, Nadrah K, Horowitz MC, Kikuta J, Ishii M, Pereira JP. (2015) Oxysterols and EBI2 promote osteoclast precursor migration to bone surfaces and regulate bone mass homeostasis. J. Exp. Med. 212(11):1931-46.
Simmons, Ishii M. (2014) Sphingosine-1-phosphate: a master regulator of lymphocyte egress and immunity. Arch. Immunol. Ther. Exp., 62(2); 103-115.
Nishikawa K, Iwamoto Y, Ishii M. (2014) Development of an in vitro culture method for stepwise differentiation of mouse embryonic stem cells and induced pluripotent stem cells into mature osteoclasts. J. Bone Miner. Metab., 32(3): 331-336.
Maeda S, Wada H, Naito Y, Nagano H, Simmons S, Kagawa Y, Naito A, Kikuta J, Ishii T, Tomimaru Y, Hama N, Kawamoto K, Kobayashi S, Eguchi H, Umeshita K, Ishii H, Doki Y, Mori M, Ishii M. (2014) Interferon-α acts on the S/G2/M phases to induce apoptosis in the G1 phase of an IFNAR2-expressing hepatocellular carcinoma cell line. J. Biol. Chem., 289(34): 23786-23795.
Kotani M, Kikuta J, Klauschen F, Chino T, Kobayashi Y, Yasuda H, Tamai K, Miyawaki A, Kanagawa O, Tomura M, Ishii M. (2013) Systemic circulation and bone recruitment of osteoclast precursors tracked by using fluorescent imaging techniques. J. Immunol., 190(2):605-12.
Kikuta J, Wada Y, Kowada T, Wang Z, Sun-Wada G-H, Nishiyama I, Mizukami S, Maiya N, Yasuda H, Kumanogoh A, Kikuchi K, Germain RN, Ishii M. (2013) Dynamic visualization of RANKL and Th17-mediated osteoclast function. J. Clin. Invest., 123(2): 866-873.
Kikuta J, Kawamura S, Okiji F, Shirazaki M, Sakai S, Saito H, Ishii M (2013) S1P-mediated osteoclast precursor monocyte migration is a critical point of control in antibone-resorptive action of active vitamin D. Proc. Natl. Acad. Sci. USA, 110(17): 7009-13.
Kagawa Y, Matsumoto S, Kamioka Y, Mimori M, Naito Y, Ishii T, Okuzaki D, Nishida N, Maeda S, Naito A, Kikuta J, Nishikawa K, Nishimura J, Haraguchi N, Takemasa I, Mizushima T, Ikeda M, Yamamoto H, Sekimoto M, Ishii H, Doki Y, Matsuda M, Kikuchi A, Mori M, Ishii M. (2013) Cell cycle-dependent Rho GTPase activity dynamically regulates cancer cell motility and invasion in vivo. PLoS One, 8(12): e83629.
Fukuhara S, Simmons S, Kawamura S, Inoue A, Orba Y, Tokudome T, Sunden Y, Arai Y, Moriwaki K, Ishida J, Uemura A, Kiyonari H, Abe T, Fukamizu A, Hirashima M, Sawa H, Aoki J, Ishii M*, Mochizuki N* The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice. J. Clin. Invest. 122: 1416-1426, 2012.
Ishii M, Kikuta J, Shimazu Y, Meier-Schellersheim M, Germain RN. Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo. J. Exp. Med., 207: 2793-2796, 2010.
Ishii M, Egen JG, Klauschen F, Meier-Schellersheim M, Saeki Y, Vacher J, Proia RL, Germain RN. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature, 458: 524-528, 2009.
Klauschen F, Ishii M, Qi, H., Bajénoff, M., Egen, J.G., Germain, R.N., Meier-Schellersheim, M. Quantifying cellular interaction dynamics in 3-D fluorescence microscopy data. Nature Protoc., 4:1305-1311, 2009.

Awards and Honors

2014  Japan Society for the Promotion of Science Prize
2013 Medical Research Encouragement Prize of The Japan Medical Association
2013 Distinguished Scientist Award, The Japanese Society for Bone and Mineral Research
2010 President’s Award (first prize), Commendation for Young Researchers, The Japan Foundation for Aging and Health
2010 The best President’s Award, Astellas Foundation for Research on Metabolic Disorders
2010 The Young Scientist’s Prize, The commendation for Science and Technology by the Minister of Education, Culture, Sports, Science and Technology
2007 Young Investigator's Award, Japanese College of Rheumatology
2006 Young Investigator's Award, Japanese Society of Allergology
2002 Young Investigator Award, The 2nd Annual G protein-coupled receptor symposium,American Society of Pharmacology and Experimental Therapeutics