复制压力是衰老血造干细胞功能衰退的强有力的驱动因素
Johanna Flach1, Sietske T Bakker2, Mary Mohrin2
11] The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hem/Onc Division, University of California San Francisco, San Francisco, California 94143, USA [2] Institute of Experimental Cancer Research, Comprehensive Cancer Center, 89081 Ulm, Germany.
Nature
|August 1, 2014
概括
衰老的造血干细胞 (HSC) 由于减少的MCM酶而经历复制压力,导致功能下降. 这突出了MCM作为HSC再生疗法的目标.
科学领域:
- 血液学 血液学 血液学
- 细胞生物学 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) 对于终身血液生产至关重要,但随着年龄的增长而下降.
- 尽管数量扩大,但老年HSC表现出功能减弱和移植移植受损.
- 在老化过程中驱动HSC功能衰退的确切机制在很大程度上是未知的.
研究的目的:
- 研究老年造血干细胞功能衰退的分子驱动因素.
- 为了确定细胞周期缺陷和DNA损伤在老化HSCs的原因.
- 探索HSC再生的潜在治疗点.
主要方法:
- 对年轻与老老鼠HSC细胞细胞周期进展和DNA完整性的分析.
- 评估迷你染色体维护 (MCM) 螺旋酶表达和DNA复制分叉动态.
- 在静止年龄的HSC中研究核细胞相关的DNA损伤标记物 (γH2AX) 和酸酶活性 (PP4c).
- 对核糖体DNA (rDNA) 基因表达和核糖体生物发生的评估.
主要成果:
- 循环衰老的HSC表现出增加的复制应激,细胞周期缺陷和与降低MCM酶表达相关的DNA断裂.
- 衰老的高细胞耐受复制压力,但由于PP4c酸酶活性受损,在静止时显示持续的核细胞γH2AX信号.
- 持久的γH2AX标记了转录沉默的rDNA基因,减少了静止年龄的HSC中的核糖体生物发生.
- 复制应激被认为是老年HSC功能衰退的关键因素.
结论:
- 由MCM基酶功能障碍驱动的复制应激是老年HSC功能衰退的主要原因.
- 由于酸酶局部错误导致的持久核细胞 γH2AX 损害了静止年龄的 HSC 中的 rDNA 转录和核糖体生产.
- 准MCM DNA螺旋酶可能提供一个治疗策略,以使老年HSC复苏.
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