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. With that, we will aim for the regulation of stem cells by niche, or niche therapy. By focusing on the areas of stem cell niches, stem cell aging and cancer stem cells, we hope to provide novel insights to the development of niche therapy. We will further translate our findings into clinical settings, which would contribute to stem cell transplantation as well as treatment of hematological diseases.

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.

Selected Publications:

  1. Kobayashi H, Kobayashi CI, Nakamura-Ishizu A, Karigane D, Haeno H, Yamamoto KN, Sato T, Ohteki T, Hayakawa Y, Barber GN, Kurokawa M, Suda T, Takubo K. Bacterial c-di-GMP affects hematopoietic stem/progenitors and their niches through STING. Cell Rep. 11(1):71-84, 2015
  2. 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
  3. 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
  4. Nakamura-Ishizu A, Takizawa H, Suda T: The analysis, roles and regulation of quiescence in hematopoietic stem cells. Development 15: 4656-66, 2014
  5. Ito K, Suda T: Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 141: 243-56, 2014
  6. Okabe K, Kobayashi S, Yamada T, Kurihara T, Tai-Nagara I, Miyamoto T, Mukouyama YS, Sato TN, Suda T, Ema M, Kubota Y: Neurons limit angiogenesis by titrating VEGF in retina. Cell : 159: 584-96, 2014
  7. Kobayashi I, Kobayashi-Sun J, Kim AD, Pouget C, Fujita N, Suda T, Traver D: Jam1a-Jam2a interactions regulate haematopoietic stem cell fate through Notch signalling. Nature 512: 319-23, 2014
  8. Tai-Nagara I, Matsuoka S, Ariga H, Suda T: Mortalin and DJ-1 coordinately regulate hematopoietic stem cell function through the control of oxidative stress. Blood 123: 41-50, 2014
  9. Kobayashi CI, Takubo K, Kobayashi H, Nakamura-Ishizu A, Honda H, Kataoka K, Kumano K, Akiyama H, Sudo T, Kurokawa M, Suda T: The IL-2/CD25 axis maintains distinct subsets of chronic myeloid leukemia-initiating cells. Blood 123: 2540-9, 2014
  10. Takubo K, Nagamatsu G, Kobayashi CI, Nakamura-Ishizu A, Kobayashi H, Ikeda E, Goda N, Rahimi Y, Johnson RS, Soga T, Hirao A, Suematsu M, Suda T: Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12: 49-61, 2013
Name Toshio SUDA
Affiliations Senior Principal Investigator, Cancer Science Institute of Singapore, NUS
Professor, Department of Medicine, Yong Loo Lin School of Medicine, NUS
Email sudato[at]z3.keio.jp / csits[at]nus.edu.sg

Education

Institute Degree (if applicable) Year(s)
Jichi Medical School PhD 1985
Yokohama City University, Japan MD 1974

Professional Experience

Senior Principal Investigator, Cancer Science Institute of Singapore, NUS 2013 – Present
Professor, Developmental Biology, The Sakaguchi Laboratory, School of Medicine, Keio University 2002 – 2015
Professor, Dept. of Hemopoiesis School of Medicine, Kumamoto University 1992 – 2002
Associate Professor, Hematology, Jichi Medical School 1991 – 1992
Assistant Professor, Hematology, Jichi Medical School 1984 – 1991
Research Associate, Div. of Hemopoiesis, Medical University of South Carolina 1982 – 1984
Research Associate, Div. of Hemopoiesis, Jichi Medical School 1978 – 1982

Mitsuhiro ENDO

PhD
Senior Research Scientist

csime[at]nus.edu.sg

Directed differentiation of pluripotent stem cells towards hematopoietic stem cells.

Takayoshi MATSUMURA

MD, PhD
Senior Research Scientist

csitkm[at]nus.edu.sg

To elucidate the pathophysiology of stem cell niche through the identification of stemness-related cis-regulatory elements using zebrafish and transgenic mouse as models.

Ayako NAKAMURA-ISHIZU

MD, PhD
Senior Research Scientist

To delineate the niche through the identification of cell specific production of Thrombopoietin (TPO), which regulating HSC quiescence.

Yuji TAKIHARA

MD, PhD
Senior Research Scientist

ytakihara[at]nus.edu.sg

Imaging study on the interaction between stem cells and niche

Jessica Leonie K BERLIER

Research Fellow

Relationship between the mesenchymal stem cells (MSC) and the hematopoietic stem cell (HSC) niche

YANG Chong

Research Fellow

Investigate the potential role of glycol and lipid metabolism in hematopoietic stem cell

A’qilah BANU

Research Assistant

Therapeutic approaches to stem cell niche

Aled O’NEILL

PhD Student

To elucidate the mechanisms of megakaryopoiesis and thrombopoiesis through thrombopoietin signalling in haematopoietic stem cells

Darren TAN

PhD Student

Metabolic function of PRMT5 in hematopoietic stem cells

Tamie ENDO

Laboratory Executive

To elucidate the role of cellular energy metabolism for maintaining hematopoietic stem cell homeostasis

Japanese Society of Hematology (JSH) Award 2013
Donald Metcalf Award by International Society of Experimental Hematology (ISEH) 2014