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Fumio Arai Last modified date:2018.07.03

Professor / Department of Stem Cell Biology and Medicine
Department of Stem Cell Biology and Medicine
Faculty of Medical Sciences




Academic Degree
Ph.D.
Field of Specialization
Stem cell biology
Research
Research Interests
  • Elucidation of the molecular mechanism of asymmetric cell division of hematopoietic stem cells
    keyword : Asymmetric cell division
    2014.04.
  • Elucidation of the molecular mechanism that regulates the self-renewal activity of hematopoietic stem cells
    keyword : hematopoietic stem cells, niche, asymmetric/symmetric cell divisions
    2011.04~2017.03.
Academic Activities
Reports
1. Fumio Arai, Hiroki Yoshihara, Hosokawa Kentaro, Yuka Nakamura, Yumiko Gomei, Hiroko Iwasaki, Toshio Suda, Niche Regulation of Hematopoietic Stem Cells in the Endosteum The Role of Thrombopoietin/Mp1 Signaling in the Maintenance of Quiescent Hematopoietic Stem Cells, ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, HEMATOPOIETIC STEM CELLS VII, BLACKWELL PUBLISHING, 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXEN, ENGLAND, 巻: 1176 ページ: 36-46, During postnatal life, the bone marrow (BM) supports both the self-renewal and differentiation of hematopoietic stem cells (HSCs) in specialized niches. The interaction of HSCs with their niches also regulates the quiescence of HSCs. HSC quiescence is critical to ensure lifelong hematopoiesis and to protect the HSC pool from myelotoxic insult and premature exhaustion under conditions of hematopoietic stress. Here we identified long-term (LT)-HSCs expressing the thrombopoietin (THPO) receptor, Mp1, as a quiescent population in adult BM. THPO was produced by bone-lining cells in the endosteum. Inhibition and stimulation of the THPO/Mp1 pathway produced opposite effects on the quiescence of LT-HSC. Exogenous THPO transiently increased the quiescent LT-HSC population, such as side-population and pyronin Y-negative cells. In contrast, administration of an anti-Mp1 neutralizing antibody, AMM2, suppressed the quiescence of LT-HSCs and enabled HSC engraftment without irradiation, indicating that inhibition of THPO/Mp1 signaling reduces HSC-niche interactions. Moreover, it suggests that inhibiting the HSC-niche interaction could represent a novel technique for bone marrow transplantation without irradiation. Altogether, these data suggest that the THPO/Mp1 signaling pathway is a novel niche component in the endosteum, and in the steady-state condition, this signaling pathway plays a critical role in the regulation of LT-HSCs in the osteoblastic niche.
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Papers
1. Kentaro Hosokawa, Ben D. MacArthur, Yoshiko Matsumoto Ikushima, Hirofumi Toyama, Yoshikazu Masuhiro, Shigemasa Hanazawa, Toshio Suda, Fumio Arai, The telomere binding protein Pot1 maintains haematopoietic stem cell activity with age., Nature Communications, 10.1038/s41467-017-00935-4, 8, 1, 2017.10.
2. Hosokawa, Kentaro, Arai, Fumio, Yoshihara, Hiroki, Iwasaki, Hiroko, Hembree, Mark, Yin, Tong, Nakamura, Yuka, Gomei, Yumiko, Takubo, Keiyo, Shiama, Haruko, Matsuoka, Sahoko, Li, Linheng, Suda, Toshio, Cadherin-Based Adhesion Is a Potential Target for Niche Manipulation to Protect Hematopoietic Stem Cells in Adult Bone Marrow, 6, 3, 197-198, 2010.03.
3. Hosokawa, Kentaro, Arai, Fumio, Yoshihara, Hiroki, Iwasaki, Hiroko, Nakamura, Yuka, Gomei, Yumiko, Suda, Toshio, Knockdown of N-cadherin suppresses the long-term engraftment of hematopoietic stem cells, 116, 4, 554-563, 2010.07, During postnatal life, the bone marrow (BM) supports both self-renewal and differentiation of hematopoietic stem cells (HSCs) in specialized microenvironments termed stem cell niches. Cell-cell and cell-extracellular matrix interactions between HSCs and their niches are critical for the maintenance of HSC properties. Here, we analyzed the function of N-cadherin in the regulation of the proliferation and long-term repopulation activity of hematopoietic stem/progenitor cells (HSPCs) by the transduction of N-cadherin shRNA. Inhibition of N-cadherin expression accelerated cell division in vitro and reduced the lodgment of donor HSPCs to the endosteal surface, resulting in a significant reduction in long-term engraftment. Cotransduction of N-cadherin shRNA and a mutant N-cadherin that introduced the silent mutations to shRNA target sequences rescued the accelerated cell division and reconstitution phenotypes. In addition, the requirement of N-cadherin for HSPC engraftment appears to be niche specific, as shN-cad-transduced lineage (-)Sca-1(+)c-Kit(+) cells successfully engrafted in spleen, which lacks an osteoblastic niche. These findings suggest that N-cad-mediated cell adhesion is functionally required for the establishment of hematopoiesis in the BM niche after BM transplantation. .
4. Yuka Nakamura, Fumio Arai, Hiroko Iwasaki, Kentaro Hosokawa, Isao Kobayashi, Yumiko Gomei, Yoshiko Matsumoto, Hiroki Yoshihara, Suda Toshio, Isolation and characterization of endosteal niche cell populations that regulate hematopoietic stem cells, 116, 9, 1422-1432, 2010.09, The endosteal niche is critical for the maintenance of hematopoietic stem cells (HSCs). However, it consists of a heterogeneous population in terms of differentiation stage and function. In this study, we characterized endosteal cell populations and examined their ability to maintain HSCs. Bone marrow endosteal cells were subdivided into immature mesenchymal cell-enriched ALCAM(-)Sca-1(+) cells, osteoblast-enriched ALCAM(+)Sca-1(-), and ALCAM(-)Sca-1(-) cells. We found that all 3 fractions maintained long-term reconstitution (LTR) activity of HSCs in an in vitro culture. In particular, ALCAM(+)Sca-1(-) cells significantly enhanced the LTR activity of HSCs by the up-regulation of homing- and cell adhesion-related genes in HSCs. Microarray analysis showed that ALCAM(-)Sca-1(+) fraction highly expressed cytokine-related genes, whereas the ALCAM(+)Sca-1(-) fraction expressed multiple cell adhesion molecules, such as cadherins, at a greater level than the other fractions, indicating that the interaction between HSCs and osteoblasts via cell adhesion molecules enhanced the LTR activity of HSCs. Furthermore, we found an osteoblastic marker(low/-) subpopulation in ALCAM(+)Sca-1(-) fraction that expressed cytokines, such as Angpt1 and Thpo, and stem cell marker genes. Altogether, these data suggest that multiple subsets of osteoblasts and mesenchymal progenitor cells constitute the endosteal niche and regulate HSCs in adult bone marrow..
5. Hiroki Yoshihara, Fumio Arai, Kentaro Hosokawa, Tetsuya Hagiwara, Keiyo Takubo, Yuka Nakamura, Yumiko Gomei, Hiroko Iwasaki, Sahoko Matsuoka, Kana Miyamoto, Hiroshi Miyazaki, Takao Takahashi, Toshio Suda, Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche, 1, 6, 685-697, 2007.12, Maintenance of hematopoietic stem cells (HSCs) depends on interaction with their niche. Here we show that the long-term (LT)-HSCs expressing the thrombopoietin (THPO) receptor, MPL, are a quiescent population in adult bone marrow (BM) and are closely associated with THPO-producing osteoblastic cells. THPO/MPIL signaling upregulated beta 1-integrin and cyclin-dependent kinase inhibitors in HSCs. Furthermore, inhibition and stimulation of THPO/MPL pathway by treatments with anti-MPL neutralizing antibody, AMM2, and with THPO showed reciprocal regulation of quiescence of LT-HSC. AMM2 treatment reduced the number of quiescent LT-HSCs and allowed exogenous HSC engraftment without irradiation. By contrast, exogenous THPO transiently increased quiescent HSC population and subsequently induced HSC proliferation in vivo. Altogether, these observations suggest that THPO/MPL signaling plays a critical role of LT-HSC regulation in the osteoblastic niche..
6. Keisuke Ito, Atsushi Hirao, Fumio Arai, Sahoko Matsuoka, Isao Hamaguchi, Kana Nomiyama, Hosokawa Kentaro, Kazuhiro Sakurada, Naomi Nakagata, Yasuo Ikeda, Tak W. Mak, Toshio Suda, Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells, 431, 7011, 997-1002, 2004.10, The 'ataxia telangiectasia mutated' (Atm) gene maintains genomic stability by activating a key cell-cycle checkpoint in response to DNA damage, telomeric instability or oxidative stress(1,2). Mutational inactivation of the gene causes an autosomal recessive disorder, ataxia-telangiectasia, characterized by immunodeficiency, progressive cerebellar ataxia, oculocutaneous telangiectasia, defective spermatogenesis, premature ageing and a high incidence of lymphoma(3,4). Here we show that ATM has an essential function in the reconstitutive capacity of haematopoietic stem cells (HSCs) but is not as important for the proliferation or differentiation of progenitors, in a telomere-independent manner. Atm(-/-) mice older than 24 weeks showed progressive bone marrow failure resulting from a defect in HSC function that was associated with elevated reactive oxygen species. Treatment with anti-oxidative agents restored the reconstitutive capacity of Atm(-/-) HSCs, resulting in the prevention of bone marrow failure. Activation of the p16(INK4a)-retinoblastoma (Rb) gene product pathway in response to elevated reactive oxygen species led to the failure of Atm(-/-) HSCs. These results show that the self-renewal capacity of HSCs depends on ATM-mediated inhibition of oxidative stress..
7. Fumio Arai, Hirao Atsushi, Ohmura Masako, Hidetaka Sato, Sahoko Matsuoka, Keiyo Takubo, Keisuke Ito, Gou Young Koh, Toshio Suda, Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche, 118, 2, 149-161, 2004.07, The quiescent state is thought to be an indispensable property for the maintenance of hematopoietic stem cells (HSCs). Interaction of HSCs with their particular microenvironments, known as the stem cell niches, is critical for adult hematopoiesis in the bone marrow (BM). Here, we demonstrate that HSCs expressing the receptor tyrosine kinase Tie2 are quiescent and antiapoptotic, and comprise a side-population (SP) of HSCs, which adhere to osteoblasts (OBs) in the BM niche. The interaction of Tie2 with its ligand Angiopoietin-1 (Ang-1) induced cobblestone formation of HSCs in vitro and maintained in vivo long-term repopulating activity of HSCs. Furthermore, Ang-1 enhanced the ability of HSCs to become quiescent and induced adhesion to bone, resulting in protection of the HSC compartment from myelosuppressive stress. These data suggest that the Tie2/Ang-1 signaling pathway plays a critical role in the maintenance of HSCs in a quiescent state in the BM niche..
Presentations
1. Fumio Arai, Function of Pot1 in the maintenance of hematopoietic stem cell activity under stress, 5th International Conference on Tissue Engineering & Regenerative Medicine, 2016.09.
2. Fumio Arai, Pot1 maintains hematopoietic stem cell activity under stress, Japan Society for the Promotion of Science and National University of Singapore joint symposium, 2016.01.
3. Fumio Arai, Introduction of hematopoietic stem cell niche, ISEH 44th Annual Scientific Meeting, 2015.09.
4. Fumio Arai, Pot1a regulates self-renewal activity of hematopoietic stem cells, 4th International Conference on Tissue Engineering & Regenerative Medicine, 2015.07.
5. Fumio Arai, Role of Pot1 in the regulation of hematopoietic stem cell activity, 2015 US-Japan Meeting on Malignant Hematopoiesis and Stem Cells, 2015.03.
6. Arai, Fumio, Regulation of hematopoietic stem cells in the niche, Hematopoietic Stem Cells VII., 2011.09.
7. Arai, Fumio, Regulation of Hematopoietic Stem Cells in the Niche, International Society of Inflammation and Regeneration, 2011.06.
8. Arai, Fumio, Hematopoietic Stem Cells in the Niche, 2009 World Stem Cell Summit.
9. Arai, Fumio, Hematopoietic Stem Cell Niche in Bone Marrow, 2nd Annual Congress of Regenerative Medicine & Stem Cell at CMBF 2009.
10. Arai, Fumio, Niche regulation of hematopoietic stem cells in the endosteum, International Conference and Workshop. Hematopoietic Stem Cells VII..
11. Arai, Fumio, Regulation of the hematopoietic stem cell and its interaction with the osteoblastic niche, Gordon Research Conference, Bone & Teeth.
12. Arai, Fumio, Maintenance of stem cells in the niche, International Conference and Workshop. Hematopoietic Stem Cells VI., 2006.09.
13. Arai, Fumio, Regulation of hematopoietic stem cells in the osteoblastic niche, 1st International Conference on Osteoimmunology: Interaction of the Immune and Skeletal Systems..
14. Arai, Fumio, Regulation of hematopoietic stem cell and its interaction with stem cell niche., Hiroshima conference on education and science in dentistry, 2006.01.
15. Arai, Fumio, Ito, Keisuke, Suda, Toshio, Hematopoietic stem cells and their niche., The International Society on Thrombosis & Haemostasis 20th Congress..
Membership in Academic Society
  • International Society for Experimental Hematology
  • International Society for Stem Cell Research
  • American Society of Hematology
  • The Japanese Society of Hematology