Elucidation of key signals for successful engraftment of transplanted bone marrow cells

• Project/Area Number: 18K16114
• 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: Osaka University
• Principal Investigator: Sudo Takao 大阪大学, 生命機能研究科, 助教 (80631184)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 造血幹細胞 / 造血幹細胞ニッチ / 生体イメージング / ストレス造血 / 活性化シグナル

Outline of Final Research Achievements

The cell-cycle status of hematopoietic stem and progenitor cells (HSPCs) becomes activated following chemotherapy-induced stress, thereby promoting bone marrow (BM) regeneration; however, the underlying molecular mechanism remains elusive. In this study, we show that injured BM environments support the recovery of HSPCs from 5-fluorouracil (5-FU)-induced stress by secreting growth factors.
Mechanistically, IL-33 released from chemo-sensitive BM cells activates MyD88-mediated secretion of growth factors. Thus, injured BM environments may function by ‘sensing’ the damaged BM spaces and subsequently supporting hematopoietic recovery under stress conditions.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果から、「抗癌剤投与後の骨髄機能の回復はどのような機序で起こるのか」という疑問の一端を解決した。本研究結果は、骨髄移植の際に、骨髄を破壊する前処置が造血幹細胞の生着に促進的に働くこと理由を説明するモデルとも捉えられる。
本研究から得られた結果は、今後造血幹細胞移植ソースとしての造血幹細胞を体外増幅する際に必要な情報をもたらしうる、という点で意義が大きい。

Research Products

• [Journal Article] Thrombomodulin induces anti-inflammatory effects by inhibiting the rolling adhesion of leukocytes in vivo. (2020)
  • Author(s): Nishizawa S, Kikuta J, Seno S, Kajiki M, Tsujita R, Mizuno H, Sudo T, Ao T, Matsuda H, Ishii M.
  • Journal Title: J Pharmacol Sci. Volume: 143 Issue: 1 Pages: 17-22
  • DOI: 10.1016/j.jphs.2020.01.001
  • Peer Reviewed / Open Access
• [Journal Article] Endothelial Cell-Selective Adhesion Molecule Contributes to the Development of Definitive Hematopoiesis in the Fetal Liver (2019)
  • Author(s): Ueda Tomoaki、Yokota Takafumi、Okuzaki Daisuke、Uno Yoshihiro、Mashimo Tomoji、Kubota Yoshiaki、Sudo Takao、Ishibashi Tomohiko、Shingai Yasuhiro、Doi Yukiko、Ozawa Takayuki、Nakai Ritsuko、Tanimura Akira、Ichii Michiko、Ezoe Sachiko、Shibayama Hirohiko、Oritani Kenji、Kanakura Yuzuru
  • Journal Title: Stem Cell Reports Volume: 13 Issue: 6 Pages: 992-1005
  • DOI: 10.1016/j.stemcr.2019.11.002
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a novel arthritis-associated osteoclast precursor macrophage regulated by FoxM1. (2019)
  • Author(s): Hasegawa T, Kikuta J, Sudo T, Matsuura Y, Matsui T, Simmons S, Ebina K, Hirao M, Okuzaki D, Yoshida Y, Hirao A, Kalinichenko VV, Yamaoka K, Takeuchi T, Ishii M.
  • Journal Title: Nat Immunol. Volume: 20 Issue: 12 Pages: 1631-1643
  • DOI: 10.1038/s41590-019-0526-7
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 5-FUによるストレス後骨髄環境が 造血幹・前駆細胞の増殖を促進する (2019)
  • Author(s): 数藤 孝雄、石井 優
  • Organizer: 第29回日本サイトメトリー学会学術集会
• [Presentation] Stressed microenvironments support hematopoietic recovery through cytokine production (2019)
  • Author(s): Takao Sudo, Masaru Ishii
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Stressed bone marrow environments accelerate hematopoietic recovery through cytokine (2019)
  • Author(s): Takao Sudo, Masaru Ishii
  • Organizer: 17th International Congress of Immunology
  • Int'l Joint Research
• [Presentation] Dynamic analysis of Hematopoietic stem cells and their niches using bone marrow imaging techniques (2019)
  • Author(s): 吉澤 亮輔、数藤 孝雄、石井 優
  • Organizer: 第81回日本血液学会学術集会