Elucidation of the Mechanism of Functional Decline of Aged Hematopoietic Stem Cells and Attempts to Restore Their Function.

• Project/Area Number: 20K17370
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Koide Shuhei 東京大学, 医科学研究所, 特任研究員 (10845126)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 造血幹細胞 / 老化 / 造血器腫瘍 / シングルセル解析 / 加齢 / 分子シャペロン / 炎症

Outline of Research at the Start

本研究では、若齢期から高齢期のマウスを用いて加齢に伴い変化する造血幹細胞の特性を、シングルセル解析を用いて、遺伝子発現とクロマチン構造変化の観点から明らかにする。シングルセル解析を行うことにより、加齢と共に拡大する造血幹細胞の多様性を理解することが可能となる。これら一連の解析を通して、造血幹細胞の機能低下の機序を造血幹細胞の多様性の質的・量的変化の観点から理解し、加齢造血幹細胞の機能の再活性化につながる手法の創出を目指す。

Outline of Final Research Achievements

In this study, HSCs were collected from young, middle-aged, and aged mice, and single cell RNA-sequence analysis was performed to elucidate the molecular mechanisms of age-related functional decline in the transcriptome. The analysis revealed that the dysfunctional HSCs observed in aged mice were already manifested in middle-aged mice, and that the molecular chaperone Clusterin (Clu) was highly expressed in these mice.
Analysis of Clu reporter mice revealed that Clu-positive cells dominantly increase with age and that age-related hematopoietic defects are attributable to Clu expression.

Academic Significance and Societal Importance of the Research Achievements

近年世界的な高齢化を背景として、老化研究に対する高い注目が集まっている。本研究内容である造血幹細胞の老化は、加齢関連疾患としてしられる造血器腫瘍発症の母地として機能すると考えられている。
本研究成果として、加齢造血幹細胞の機能不全マーカーであるCluの同定に成功した。今後、Cluの発現制御を試みることで、白血病を始めとした老化関連疾患の予防、並びに治療法確立が期待される。

Research Products

• [Journal Article] CD244 expression represents functional decline of murine hematopoietic stem cells after in vitro culture (2022)
  • Author(s): Koide Shuhei、Sigurdsson Valgardur、Radulovic Visnja、Saito Kiyoka、Zheng Zhiqian、Lang Stefan、Soneji Shamit、Iwama Atsushi、Miharada Kenichi
  • Journal Title: iScience Volume: 25 Issue: 1 Pages: 103603-103603
  • DOI: 10.1016/j.isci.2021.103603
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Insufficiency of non-canonical PRC1 synergizes with JAK2V617F in the development of myelofibrosis (2021)
  • Author(s): Shinoda Daisuke、Nakajima-Takagi Yaeko、Oshima Motohiko、Koide Shuhei、Aoyama Kazumasa、Saraya Atsunori、Harada Hironori、Rahmutulla Bahityar、Kaneda Atsushi、Yamaguchi Kiyoshi、Furukawa Yoichi、Koseki Haruhiko、Shimoda Kazuya、Tanaka Tomoaki、Sashida Goro、Iwama Atsushi
  • Journal Title: Leukemia Volume: 36 Issue: 2 Pages: 452-463
  • DOI: 10.1038/s41375-021-01402-2
  • Peer Reviewed / Open Access
• [Journal Article] CD271 + CD51 + PALLADIN - Human Mesenchymal Stromal Cells Possess Enhanced Ossicle-Forming Potential (2021)
  • Author(s): Sezaki Maiko、Biswas Subinoy、Nakata Sayuri、Oshima Motohiko、Koide Shuhei、Ho Nicole Pui Yu、Okamoto Nobukazu、Miyamoto Takeshi、Iwama Atsushi、Takizawa Hitoshi
  • Journal Title: Stem Cells and Development Volume: 30 Issue: 14 Pages: 725-735
  • DOI: 10.1089/scd.2021.0021
• [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] PRC2 insufficiency causes p53-dependent dyserythropoiesis in myelodysplastic syndrome (2020)
  • Author(s): Aoyama K, Shinoda D, Suzuki E, Nakajima-Takagi Y, Oshima M, Koide S, Rizq O, Si S, Tara S, Sashida G, Iwama A.
  • Journal Title: Leukemia Volume: 4 Issue: 4 Pages: 1156-1165
  • DOI: 10.1038/s41375-020-01023-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Unraveling heterogeneity of aged hematopoietic stem cells by single-cell RNA sequence analysis (2021)
  • Author(s): Shuhei Koide
  • Organizer: 第83回日本血液学会学術集会