Functional analysis and application of hematopoietic stem cells to chemicals that replacement for albumin function

• Project/Area Number: 20H03707
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: University of Tsukuba
• Principal Investigator: Yamazaki Satoshi 筑波大学, 医学医療系, 教授 (50625580)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2022: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥9,490,000 (Direct Cost: ¥7,300,000、Indirect Cost: ¥2,190,000)
• Keywords: 造血幹細胞 / アルブミン / PVA / アルブミン代替え物質 / ポリマー / 培養 / 増幅 / 化学ポリマー / 化合物 / 化学物質

Outline of Research at the Start

造血幹細胞の培養に必須であったアルブミンタンパク質を化学物質であるボリヴィニルアルコール(PVA)へ代替えすることで造血幹細胞の長期培養によると大幅な増殖系に成功し国内外で大きなインパクトを与えた。この発見は１つの研究の始まりでありPVA以外の化学物質においてもアルブミンタンパク質の代替えを可能とする未知なる物質は存在すると予想できる。以上のことから本研究課題はアルブミン代替え物質の性質を理解することでHSCの機能や細胞増幅を制御可能にする技術開発を目指し、マウスやヒトの造血幹細胞を培養可能にする新たな培養システムの構築を目的とする。

Outline of Final Research Achievements

By replacing the albumin protein, which was essential for the culture of hematopoietic stem cells, with the chemical bolivinyl alcohol (PVA), he succeeded in achieving a significant proliferation system for long-term hematopoietic stem cell culture, which had a great impact both in Japan and overseas. (Wilkinson et al., 2019). This discovery is the beginning of one research, and it can be expected that there are unknown substances other than PVA that can substitute for albumin protein. Based on the research and experience up to the present, the applicant has determined which substances are effective as substitutes for albumin, and that even very minute changes in the chemical formula can change the properties of hematopoietic stem cells and prevent the cell division and undifferentiation of hematopoietic stem cells. We recognize that maintenance plays an important role.

Academic Significance and Societal Importance of the Research Achievements

これらの研究は血液/免疫研究分野にとどまらず幹細胞研究や細胞培養学など様々な研究分野へ貢献したと考えている、さらには、化学分野と生物もしくは医学分野の大きな架け橋となる可能性を秘めている。実際に、本研究成果はヒト造血幹細胞の増幅を可能にし（Sakurai et al., Nature 2023）。組織幹細胞においても多能性幹細胞と同等のゲノム編集効率を実現した（Becker et al., 2023 in press）これらの研究は今研究課題独自のものであり独創性や創造性に関しても高いレベルにあり国内外の位置付けとしても先端的基礎研究になり得た。

Research Products

• [Journal Article] Chemically defined cytokine-free expansion of human haematopoietic stem cells (2023)
  • Author(s): Sakurai Masatoshi、Ishitsuka Kantaro、Ito Ryoji、Wilkinson Adam C.、Kimura Takaharu、Mizutani Eiji、Nishikii Hidekazu、Sudo Kazuhiro、Becker Hans Jiro、Takemoto Hiroshi、Sano Tsubasa、Kataoka Keisuke、Takahashi Satoshi、Nakamura Yukio、Kent David G et al.
  • Journal Title: Nature Volume: 615 Issue: 7950 Pages: 127-133
  • DOI: 10.1038/s41586-023-05739-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Development of low-cost <i>ex vivo</i> hematopoietic stem cell expansion (2022)
  • Author(s): 木村 隆治、山崎 聡
  • Journal Title: Rinsho Ketsueki Volume: 63 Issue: 10 Pages: 1422-1429
  • DOI: 10.11406/rinketsu.63.1422
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Blocking PD-L1-PD-1 improves senescence surveillance and ageing phenotypes (2022)
  • Author(s): Wang, T. W., Y. Johmura, N. Suzuki, S. Omori, T. Migita, K. Yamaguchi, S. Hatakeyama, S. Yamazaki, E. Shimizu, S. Imoto, Y. Furukawa, A. Yoshimura, and M. Nakanishi
  • Journal Title: Nature Volume: 611 Issue: 7935 Pages: 358-364
  • DOI: 10.1038/s41586-022-05388-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification and characterization of in vitro expanded hematopoietic stem cells (2022)
  • Author(s): Che James L C、Bode Daniel、Kucinski Iwo、Cull Alyssa H、Bain Fiona、Becker Hans J、Jassinskaja Maria、Barile Melania、Boyd Grace、Belmonte Miriam et al.
  • Journal Title: EMBO reports Volume: 23 Issue: 10
  • DOI: 10.15252/embr.202255502
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epigenetic traits inscribed in chromatin accessibility in aged hematopoietic stem cells (2022)
  • Author(s): Itokawa Naoki、Oshima Motohiko、Koide Shuhei、Takayama Naoya、Kuribayashi Wakako、Nakajima-Takagi Yaeko、Aoyama Kazumasa、Yamazaki Satoshi、Yamaguchi Kiyoshi、Furukawa Yoichi、Eto Koji、Iwama Atsushi
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 2691-2691
  • DOI: 10.1038/s41467-022-30440-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hematopoietic progenitor cells specifically induce a unique immune response in dental pulp under conditions of systemic inflammation (2022)
  • Author(s): Osaki Julia、Yamazaki Satoshi、Hikita Atsuhiko、Hoshi Kazuto
  • Journal Title: Heliyon Volume: 8 Issue: 2 Pages: e08904-e08904
  • DOI: 10.1016/j.heliyon.2022.e08904
  • Peer Reviewed / Open Access
• [Journal Article] Dual-antigen targeted iPSC-derived chimeric antigen receptor-T cell therapy for refractory lymphoma (2022)
  • Author(s): Harada Sakiko、Ando Miki、Ando Jun、Ishii Midori、Yamaguchi Tomoyuki、Yamazaki Satoshi、Toyota Tokuko、Ohara Kazuo、Ohtaka Manami、Nakanishi Mahito、Shin Chansu、Ota Yasunori、Nakashima Kazutaka、Ohshima Koichi、Imai Chihaya、Nakazawa Yozo、Nakauchi Hiromitsu、Komatsu Norio
  • Journal Title: Molecular Therapy Volume: 30 Issue: 2 Pages: 534-549
  • DOI: 10.1016/j.ymthe.2021.10.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] iPSC-Derived Neoantigen-Specific CTL Therapy for Ewing Sarcoma (2021)
  • Author(s): Ishii Midori、Ando Jun、Yamazaki Satoshi、Toyota Tokuko、Ohara Kazuo、Furukawa Yoshiki、Suehara Yoshiyuki、Nakanishi Mahito、Nakashima Kazutaka、Ohshima Koichi、Nakauchi Hiromitsu、Ando Miki
  • Journal Title: Cancer Immunology Research Volume: 9 Issue: 10 Pages: 1175-1186
  • DOI: 10.1158/2326-6066.cir-21-0193
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Polyvinyl alcohol hydrolysis rate and molecular weight influence human and murine HSC activity ex vivo (2021)
  • Author(s): Sudo Kazuhiro、Yamazaki Satoshi、Wilkinson Adam C.、Nakauchi Hiromitsu、Nakamura Yukio
  • Journal Title: Stem Cell Research Volume: 56 Pages: 102531-102531
  • DOI: 10.1016/j.scr.2021.102531
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunohistological score of transcription factor 21 had a positive correlation with its urinary excretion and proteinuria in immunoglobulin A nephropathy (2021)
  • Author(s): Takahashi-Kobayashi M, Usui J, Yaguchi M, Yamazaki S, Kawamura T, Kaneko S, Seshan SV, Yamagata K.
  • Journal Title: Histol Histopathol Volume: 10 Pages: 1093-1098
  • Peer Reviewed
• [Journal Article] Non-conditioned bone marrow chimeric mouse generation using culture-based enrichment of hematopoietic stem and progenitor cells (2021)
  • Author(s): Ochi Kiyosumi、Morita Maiko、Wilkinson Adam C.、Iwama Atsushi、Yamazaki Satoshi
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 3568-3568
  • DOI: 10.1038/s41467-021-23763-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] DHODH inhibition synergizes with DNA-demethylating agents in the treatment of myelodysplastic syndromes (2021)
  • Author(s): Kayamori Kensuke、Nagai Yurie、Zhong Cheng、Kuribayashi Wakako、Oshima Motohiko、Nakajima-Takagi Yaeko、Yamashita Masayuki、Mimura Naoya、Becker Hans Jiro、Izawa Kiyoko、Yamazaki Satoshi、Iwano Satoshi、Ito Ryoji、Lennox William、Sheedy Josephine、Yokote Koutaro、Iwama Atsushi
  • Journal Title: Blood Advances Volume: 5 Issue: 2 Pages: 438-450
  • DOI: 10.1182/bloodadvances.2020001461
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche (2021)
  • Author(s): Kuribayashi W, Oshima M, Itokawa N, Koide S, Nakajima-Takagi Y, Yamashita M, Yamazaki S, Rahmutulla B, Miura F, Ito T, Kaneda A, Iwama A.
  • Journal Title: J Exp Med Volume: 218 Issue: 3
  • DOI: 10.1084/jem.20192283
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcription factor 21 expression in injured podocytes of glomerular diseases (2020)
  • Author(s): Usui J, Yaguchi M, Yamazaki S, Takahashi-Kobayashi M, Kawamura T, Kaneko S, Seshan SV, Ronco P, Yamagata K.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 11516-11516
  • DOI: 10.1038/s41598-020-68422-3
  • NAID: 120007165470
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activated HoxB4-induced Hematopoietic Stem Cells from Murine Pluripotent Stem Cells via Long-Term Programming (2020)
  • Author(s): Izawa K, Yamazaki S, Becker HJ, Bhadury J, Kakegawa T, Sakaguchi M, Tojo A.
  • Journal Title: Exp Hematol Volume: 89 Pages: 68-79
  • DOI: 10.1016/j.exphem.2020.08.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The impact of cell maturation and tissue microenvironments on the expression of endosomal Toll-like receptors in monocytes and macrophages (2020)
  • Author(s): Sato R, Reuter T, Hiranuma R, Shibata T, Fukui R, Motoi Y, Murakami Y, Tsukamoto H, Yamazaki S, Liu K, Saitoh SI, Latz E, Miyake K.
  • Journal Title: Int Immunol Volume: 32 Issue: 12 Pages: 785-798
  • DOI: 10.1093/intimm/dxaa055
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo. (2020)
  • Author(s): Omori S, Wang TW, Johmura Y, ..., Sakamoto T (15番目), ..., Nakanishi M.
  • Journal Title: Cell Metab Volume: 32 Issue: 5 Pages: 814-828
  • DOI: 10.1016/j.cmet.2020.09.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficacy of the novel tubulin polymerization inhibitor PTC‐028 for myelodysplastic syndrome (2020)
  • Author(s): Zhong Cheng、Kayamori Kensuke、Koide Shuhei、Shinoda Daisuke、Oshima Motohiko、Nakajima‐Takagi Yaeko、Nagai Yurie、Mimura Naoya、Sakaida Emiko、Yamazaki Satoshi、Iwano Satoshi、Miyawaki Atsushi、Ito Ryoji、Tohyama Kaoru、Yamaguchi Kiyoshi、Furukawa Yoichi、Lennox William、Sheedy Josephine、Weetall Marla、Iwama Atsushi
  • Journal Title: Cancer Science Volume: 111 Issue: 12 Pages: 4336-4347
  • DOI: 10.1111/cas.14684
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 知の統合が創出する血液系研究の最前線 (2023)
  • Author(s): 山崎聡
  • Organizer: 第22回日本再生医療学会総会
  • Invited
• [Presentation] 生体外造血幹細胞増幅はなぜ可能になった？ (2022)
  • Author(s): 山崎聡
  • Organizer: 北日本血液研究会学術講演会
  • Invited
• [Presentation] 造血幹細胞増幅技術から応用への展開 (2022)
  • Author(s): 山崎聡
  • Organizer: 湘南鎌倉総合病院
  • Invited
• [Presentation] 対称・非対称分裂のバランス推定を用いた造血幹細胞プールの加齢変化予測 (2022)
  • Author(s): 山崎聡
  • Organizer: ソニー ウェブセミナー
  • Invited
• [Presentation] ゲノム編集造血幹細胞が創造する未来 (2022)
  • Author(s): 山崎聡
  • Organizer: 第40回日本骨代謝学会学術集会
  • Invited
• [Presentation] 造血幹細胞の恒常性と生体内動態 (2022)
  • Author(s): 山崎聡
  • Organizer: 新学術領域研究「細胞ダイバース」研究成果報告シンポジウム
  • Invited
• [Presentation] 造血幹細胞における移植後早期の変還 (2022)
  • Author(s): 山崎聡
  • Organizer: Meet The Hematologists in Tokyo
  • Invited
• [Presentation] Expanded Common myeloid progenitor act in concert with the spleen to support hematopoietic stem cell transplantation (2022)
  • Author(s): 山崎聡
  • Organizer: 第19回 幹細胞シンポジウム
  • Invited
• [Presentation] 造血幹細胞移植後の脾臓における造血挙動 (2022)
  • Author(s): 山崎聡
  • Organizer: 第44回日本造血・免疫細胞療法学会
  • Invited
• [Presentation] 造血幹細胞の増幅と応用 (2022)
  • Author(s): 山崎聡
  • Organizer: 「配偶子インテグリティ」 第5回オンラインセミナー
  • Invited
• [Presentation] ヒト造血幹細胞の増幅技術と応用へ (2022)
  • Author(s): 山崎聡
  • Organizer: 第21回日本再生医療学会総
  • Invited
• [Presentation] ヒト造血幹細胞の増幅 (2022)
  • Author(s): 山崎聡
  • Organizer: 第6回理論免疫学研究会
  • Invited
• [Presentation] Expanding bona fide HSCs (2021)
  • Author(s): Satoshi Yamazaki
  • Organizer: 63rd ASH Annual Meeting
  • Int'l Joint Research / Invited
• [Presentation] Edited Hematopoietic stem cell cloning (2021)
  • Author(s): 山崎聡
  • Organizer: 74th IRCMS seminar Mini Symposium
  • Invited
• [Presentation] 造血幹細胞の増幅技術開発とその臨床応用に向けて (2021)
  • Author(s): 山崎聡
  • Organizer: 理研BRC設立20周年記念シンポジウム
  • Invited
• [Presentation] 造血幹細胞の増幅技術開発とその臨床応用に向けて (2021)
  • Author(s): 山崎聡
  • Organizer: BioJapan2021
  • Invited
• [Presentation] To The future from development of ex vivo hematopoietic stem cells expansion 造血幹細胞の増幅技術から見えてくる未来 (2021)
  • Author(s): 山崎聡
  • Organizer: 日本組織培養学会 第 93 回大会
  • Invited
• [Presentation] 造血幹細胞増幅技術を用いた将来の展望 (2021)
  • Author(s): 山崎聡
  • Organizer: 第42回日本炎症・再生医学会
  • Invited
• [Presentation] 生体外におけるヒトiPS細胞由来造血幹細胞の増幅技術開発 (2021)
  • Author(s): 山崎 聡
  • Organizer: 第20回日本再生医療学会総会
  • Invited
• [Presentation] 造血幹細胞の増幅を用いた完全なるゲノム編集とその応用 (2021)
  • Author(s): 山崎 聡
  • Organizer: 第20回日本再生医療学会総会
  • Invited
• [Presentation] 造血幹細胞の増幅とぞの技術開発で見えてくる未来 (2021)
  • Author(s): 山崎 聡
  • Organizer: 日本化学会１０１春季年会
  • Invited
• [Presentation] 造血幹細胞の生体外増幅 (2020)
  • Author(s): 山崎 聡
  • Organizer: 日本再生医療学
  • Invited
• [Presentation] 細胞学研究の最先端 (2020)
  • Author(s): 山崎 聡
  • Organizer: 第38回日本ヒト細胞学会学術集会
  • Invited
• [Presentation] 造血幹細胞の増幅の可能性 (2020)
  • Author(s): 山崎 聡
  • Organizer: 第27回日本輸血・細胞治療学会秋季シンポジウム
  • Invited