Mechanisms of hematopoietic stem cell aging regulated by epigenetic system

• Project/Area Number: 17K09900
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kobe University
• Principal Investigator: Nitta Eriko 神戸大学, 医学研究科, 助教 (80401123)
• 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 / エピジェネティクス / 老化 / ポリコーム複合体 / クロマチンリモデリング / シングルセル / 骨髄不全

Outline of Final Research Achievements

Bmi1 defines the regenerative capacity of HSCs. We attempted to ameliorate the age-related decline in HSC function by modulating Bmi1 expression. The forced expression of Bmi1 did not attenuate myeloid-biased differentiation of aged HSCs. However, single cell transplantation assays revealed that the sustained expression of Bmi1 augmented the multi-lineage repopulating capacity of aged HSCs. ChIP-sequencing of Bmi1 combined with an RNA sequence analysis showed that the majority of Bmi1 direct target genes are developmental regulator genes marked with a bivalent histone domain. The sustained expression of Bmi1 strictly maintained the transcriptional repression of their target genes and enforced expression of HSC signature genes in aged HSCs. Therefore, the manipulation of Bmi1 expression is a potential approach against impairments in HSC function with aging.
Bmi1 also keeps the adipogenic differentiation program repressed in BM stromal cells to maintain the integrity of the HSC niche.

Academic Significance and Societal Importance of the Research Achievements

老化に伴う幹細胞機能の低下は、組織の、さらには個体の老化を引き起こす要因であり、幹細胞の老化機構の解明は人類の老化を解き明かし、老化の予防法の開発に役立つものである。本研究により、加齢に伴う幹細胞機能の低下にはBmi1による標的遺伝子抑制の減弱が一因となっていることが明らかとなり、さらにはBmi1を強制発現することで標的遺伝子の抑制を保ち、幹細胞機能を維持することができた。Bmi1をはじめとしたエピジェネティクス因子により、老化を制御する可能性を示唆した。

Research Products

• [Journal Article] Bmi1 counteracts hematopoietic stem cell aging by repressing target genes and enforcing the stem cell gene signature. (2020)
  • Author(s): Nitta E, Itokawa N, Yabata S, Koide S, Hou LB, Oshima M, Aoyama K, Saraya A, Iwama A.
  • Journal Title: Biochem Biophys Res Commun Volume: 521 Issue: 3 Pages: 612-619
  • DOI: 10.1016/j.bbrc.2019.10.153
  • Peer Reviewed / Open Access
• [Journal Article] Bmi1 restricts the adipogenic differentiation of bone marrow stromal cells to maintain the integrity of the hematopoietic stem cell niche (2019)
  • Author(s): Kato Yuko、Hou Li-Bo、Miyagi Satoru、Nitta Eriko、Aoyama Kazumasa、Shinoda Daisuke、Yamazaki Satoshi、Kuribayashi Wakako、Isshiki Yusuke、Koide Shuhei、Si Sha、Saraya Atsunori、Matsuzaki Yumi、van Lohuizen Maarten、Iwama Atsushi
  • Journal Title: Experimental Hematology Volume: 76 Pages: 24-37
  • DOI: 10.1016/j.exphem.2019.07.006
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Regulation of hematopoietic stem cell aging by Polycomb group protein Bmi1. (2017)
  • Author(s): 仁田英里子
  • Organizer: 第79回日本血液学会学術集会
• [Remarks] 神戸大学大学院医学研究科 生体構造解剖学分野
  • URL: http://structure.med.kobe-u.ac.jp
• [Remarks] 神戸大学大学院医学研究科 生理学・細胞生物学講座 生体構造解剖学分野
  • URL: http://www.med.kobe-u.ac.jp/anato1/Anat1_home.html