Variable SATB1 levels regulate hematopoietic stem cell heterogeneity with distinct lineage fate

• Project/Area Number: 17K09952
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Osaka University
• Principal Investigator: DOI YUKIKO 大阪大学, 医学部附属病院, 医員 (60722288)
• Co-Investigator(Kenkyū-buntansha): 金倉 譲 大阪大学, 医学系研究科, 教授 (20177489) ; 横田 貴史 大阪大学, 医学系研究科, 講師 (60403200)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 造血幹細胞 / リンパ球初期分化 / SATB1 / 血球分化

Outline of Final Research Achievements

SATB1 is involved in regulating HSC heterogeneity. HSCs from SATB1/Tomato-knock-in reporter mice were classified based on SATB1/Tomato intensity, with transplantation experiments revealing robust self-renewal as well as stronger differentiation toward the lymphoid lineage along with high SATB1 levels. Importantly, SATB1－ and SATB1+ HSCs were interconvertible upon serial transplantation, with SATB1+ HSCs showing higher reconstituting and lymphopoietic potentials in primary recipients relative to SATB1- HSCs, whereas both HSCs exhibited equally efficient reconstituted lympho-hematopoiesis in secondary recipients. Single-cell-transplantation experiments also confirmed the HSC fluctuation at the clonal level by displaying diverse levels of SATB1 expression in individual reconstituted HSCs. These results suggest that SATB1 levels regulate the maintenance of HSC multipotency, with variations contributing to heterogeneity and fluctuation in the HSC population.

Academic Significance and Societal Importance of the Research Achievements

我々の身体は、造血幹細胞が自己複製能力と多分化能力の両方を備えているために、生涯にわたる造血を行うことができる。その二つは相反した性質であり、細胞内部の経時的な変化無くしては実現できないが、その仕組みは分かっていなかった。我々は、造血幹細胞のSATB1発現強度が高い際にはリンパ球系へ分化しやすく、かつ自己複製する過程において、SATB1発現強度の異なる、即ち分化能力の異なる遺伝子発現状態を取りうるとことを示した。このことは数学・物理学的な観点から計算によって示されており、我々の研究は、それを実際の生命現象を通して観察することに成功した。

Research Products

• [Journal Article] Variable SATB1 Levels Regulate Hematopoietic Stem Cell Heterogeneity with Distinct Lineage Fate (2018)
  • Author(s): Yukiko Doi, Takafumi Yokota, Yusuke Satoh, Daisuke Okuzaki, Masahiro Tokunaga, Tomohiko Ishibashi, Takao Sudo, Tomoaki Ueda, Yasuhiro Shingai, Michiko Ichii, Akira Tanimura, Sachiko Ezoe, Hirohiko Shibayama, Terumi Kohwi-Shigematsu, Junji Takeda, Kenji Oritani, and Yuzuru Kanakura
  • Journal Title: Cell Reports Volume: 23 Issue: 11 Pages: 3223-3235
  • DOI: 10.1016/j.celrep.2018.05.042
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] リンパ球造血に関する最近の知見 (2017)
  • Author(s): 横田 貴史
  • Journal Title: 実験医学 Volume: 11月号 Pages: 137-137
• [Presentation] SATB1 expression is useful to identify the lymphoid-lineage-biased trajectory of functionally fluctuating hematopoietic stem cells. (2017)
  • Author(s): Yukiko Doi, Takafumi Yokota, Yusuke Satoh, Takao Sudo, Michiko Ichii, Sachiko Ezoe, Kenji Oritani, Terumi Kohwi-Shigematsu, Yuzuru Kanakura
  • Organizer: 第46回日本免疫学会