一个Notch转激活到cis抑制开关是造血干细胞衰老的基础
Francesca Matteini1,2, Roshana Thambyrajah3,4,5, Sara Montserrat-Vazquez1,2
1Stem Cell Aging Group, Regenerative Medicine Program, The Bellvitge Institute for Biomedical Research, L'Hospitalet de Llobregat, Barcelona, Spain.
Blood
|October 7, 2025
概括
衰老的造血干细胞 (HSC) 失去再生能力. 减少的Notch信号,由于骨髓中的Jagged2减少,驱动HSC衰老和骨髓偏差扩张.
科学领域:
- 血液学 血液学 血液学
- 干细胞生物学 干细胞生物学
- 衰老研究研究 衰老研究
背景情况:
- 造血干细胞 (HSC) 维持血液平衡,但随着年龄的增长而下降.
- 缺口信号对于血液形成至关重要,但其在HSC衰老中的作用仍在争论中.
- 衰老的HSCs表现出改变的功能和扩张,影响了造血细胞的再生.
研究的目的:
- 研究Notch信号和Jagged2在HSC衰老中的作用.
- 阐明将利基信号与老化过程中的HSC内在变化联系在一起的机制.
- 了解HSC的分裂对称性和命运初始化是如何受老化影响的.
主要方法:
- 研究了年轻HSC中的Notch激活异质性.
- 在年轻小鼠的骨髓中操纵了Jagged2表达.
- 分析了HSC的分裂对称性,命运初始化和骨髓偏差扩张.
- 研究了HSC内在的Jag2上调及其对Notch信号的影响.
主要成果:
- 状突2表达调节了年轻的高细胞中的Notch激活.
- 减少的鼻状Jag2模仿了老年HSC表型,促进了骨髓偏向的HSC扩张.
- 当 Jag2 降低时,HSC 本质上调 Jag2,导致 Notch 信号的 cis 抑制.
- 这种开关会损害造血细胞的再生,并导致HSC衰老.
结论:
- 利基衍生的Jagged2 (外部转激活) 和HSC内在的Jag2 (cis抑制) 调节HSC的命运.
- 从外在的Notch激活转向内在的cis抑制是HSC衰老的基础.
- 了解这种交叉是保持高细胞再生潜力的关键.
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