Toshio SUDA

Professor Suda has been studying hematopoietic stem cells (HSCs) and the HSC niche for more than thirty years. HSCs give rise to additional stem cells (self-renewal) and to progenitor cells (differentiation). This fate decision is determined by both cell autonomous programs and by the surrounding microenvironment, or niche. Our past work encompasses the study of the intrinsic and extrinsic regulation of HSCs, purification of potent HSCs, analyses of cell differentiation processes, identification of cytokine signaling in hematopoiesis, and the characterization of HSC niches.

sudato@z3.keio.jp

Biosketch

Senior Principal Investigator, Cancer Science Institute of Singapore, NUS
Professor, Department of Medicine, Yong Loo Lin School of Medicine, NUS

Year(s) Degree (if applicable) Institute
1985 PhD Jichi Medical School
1974 MD Yokohama City University, Japan
2013 – Present Senior Principal Investigator, Cancer Science Institute of Singapore, NUS
2002 – 2015 Professor, Developmental Biology, The Sakaguchi Laboratory, School of Medicine, Keio University
1992 – 2002 Professor, Dept. of Hemopoiesis School of Medicine, Kumamoto University
1991 – 1992 Associate Professor, Hematology, Jichi Medical School
1984 – 1991 Assistant Professor, Hematology, Jichi Medical School
1982 – 1984 Research Associate, Div. of Hemopoiesis, Medical University of South Carolina
1978 – 1982 Research Associate, Div. of Hemopoiesis, Jichi Medical School
2013 Japanese Society of Hematology (JSH) Award
2014 Donald Metcalf Award by International Society of Experimental Hematology (ISEH)

Research

We will base our work on the hypothesis that the bone marrow (BM) microenvironment known as the stem cells niche is essential for the maintenance of HSC quiescence in cell cycle and regulates the fate of hematopoietic stem cells (HSCs). We will aim for the regulation of stem cells by niche as niche therapy. We will dissect the niche as a functional unit of stem cell regulation, and aim to expand stem cells using ex vivo artificial niches and improve the method of BM transplantation.

First, we will dissect the cellular and molecular character of the endosteal and perivascular niches, and clarify the direct negative feedback from progenitor cells to HSCs. This will elucidate the hematopoietic homeostasis of stem cells. Second, we hope to develop methods for maintaining and expanding stem cells ex vivo by reducing mitochondrial reactive oxygen species production.

This process will involve the integration of various methodologies including metabolome analysis,bio-imaging and bioinformatics. Especially, we will establish state-of-the-art metabolomics technology in HSCs in NUS.

We will also clarify whether stem cell- and niche-aging relates to pathogenesis of malignancies. We will identify leukemic and multiple myeloma stem cells and their niches in seeking to develop a novel treatment for these intractable diseases. We will further study abnormal cytokine networks in chronic myelogenous leukemia and the vascular and osteoblastic niches in myeloma. Migration of cancer stem cells is another challenge with potentially high impact. We will extend our study on HSC migration to cancer metastasis by introducing the concept of epithelial cell suppression for stem cell expansion. Moreover, we investigate the onset and progression of myelofibrosis and other fibrotic disorders (liver cirrhosis and pulmonary fibrosis). These studies will elucidate the pathophysiology of diseases and would provide critical clues to develop novel treatment and preemptive measures for the diseases.

Lab Members

Selected Publications

1. Yamashita M, Nitta E, Suda T. Aspp1 preserves hematopoietic stem cell pool Integrity and prevents malignant transformation. Cell Stem Cell. 17(1):23-34, 2015

2. Nakamura-Ishizu A, Takubo K, Kobayashi H, Suzuki-Inoue, Suda T: CLEC-2 in megakaryocytes is critical for maintenance of hematopoietic stem cells in bone marrow. J Exp Med, 212: 2133-2146, 2015

3. Karigane D, Kobayashi H, Morikawa T, Ootomo Y, Sakai M, Nagamatsu G, Kubota Y, Goda N, Matsumoto M, Nishimura EK, Soga T, Otsu K, Suematsu M, Okamoto S, Suda T, Takubo K. p38? activates purine metabolism to initiate hematopoietic stem/progenitor cell cycling in response to stress. Cell Stem Cell. 19:192-204, 2016

4. Ito K, Turcotte R, Cui J, Zimmerman SE, Pinho S, Mizoguchi T, Arai F, Runnels JM, Alt C, Teruya-Feldstein J, Mar  JC, Singh R, inkel T, Suda T, Lin CP, Frenette PS, Ito K: Self renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance. Science, 354(6316):1156-1160, 2016

5. Hosokawa K, MacArthur BD, Matsumoto-Ikushima Y, Toyama H, Masuhiro Y, Hanazawa S, Suda T, Arai F:  Pot1 maintains hematopoietic stem cell activity under stress. Nat Comm
2017 Oct 6;8(1):804. doi: 10.1038/s41467-017-00935-4

6. Umemoto T, Hashimoto M, Matsumura T, Nakamura-Ishizu A, SudaT:, Ca2+-Mitochondrial axis drives cell division in hematopoietic stem cells. J Exp Med, 2018
Aug 6;215(8):2097-2113. doi: 10.1084/jem.2018042Jun 26. pii: jem.20180421

7. Nakamura-Ishizu N, Matsumura T, Stumpf PS, Umemoto T, Takizawa H, Takihara Y, O’Neil A, Majeed ABBA, MacArthur BD., Suda T: Thrombopoietin metabolically primes hematopoietic stem cells to megakaryocyte lineage differentiation. Cell Reports, 25:1772-1785,2018

8. Tan DQ, Li Y, Yang C, Li J, Tan SH, Chin DWL, Nakamura-Ishizu A, Yang H, Suda T. PRMT5 Modulates Splicing for Genome Integrity and Preserves Proteostasis of Hematopoietic Stem Cells. Cell Rep. 2019 Feb 26;26(9):2316-2328.e6. doi: 10.1016/j.celrep.2019.02.001.
PMID:30811983

9. Yokomizo T, Watanabe N, Umemoto T, Matsuo J, Harai,  Kihara Y,2Koga S, Nakamura E, Tada N, Sato T, Takaku T, Shimono A, Takizawa H, Ogawa M, Nakagata N,8 Mori S, Kurokawa M,7 Tenen DG,3 Osato M, Suda T, Komatsu N: Hlf expression marks the developmental pathway for hematopoietic stem cells but not for erythroid-myeloid progenitors J Exp. Med, in press