We base our work on the hypothesis that the bone marrow (BM) microenvironment known as the stem cells niche is essential for the maintenance of hematopoietic stem cells (HSC) quiescence in cell cycle and regulates the fate of HSCs. We 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 for BM transplantation.

To elucidate the hematopoietic homeostasis of stem cells, we will first investigate the cellular and molecular characteristics of the endosteal and perivascular niches, and clarify the direct negative feedback loop from progenitor cells to HSCs. Subsequently, we aim 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. Importantly, we will establish state-of-the-art metabolomics technology in HSCs in NUS (See Figure)

(Dev Cell, 2020)

We will also be focusing our studies in the following other areas:

• Deciphering the relationship between stem cell- and niche-aging to the pathogenesis of malignancies
• Identification of leukemic and multiple myeloma stem cells and their niches
• Study of abnormal cytokine networks in chronic myelogenous leukemia, and the vascular and osteoblastic niches in myeloma
• Study of HSC migration to cancer metastasis by introducing the concept of epithelial cell suppression for stem cell expansion as migration of cancer stem cells has become a potentially high impact challenge.

These studies will elucidate the pathophysiology of diseases and will provide critical clues to develop novel treatments and preemptive measures for the diseases.

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, 2019 Jul 1;216(7):1599-1614. doi: 10.1084/jem.20181399. Epub 2019 May 10

10. Nakamura-Ishizu A, Chin D, Matsumura T, Tan DQ, Mochizuki MK, Jianwen D, Suda T. Prolonged maintenance of hematopoietic stem cells that escape from Thrombopoietin deprivation. Blood. 2021 Mar 3:blood.2020005517. doi: 10.1182/blood.2020005517. Online ahead of print. PMID: 33657206