由AIBP介导的胆固醇外流指导造血干细胞和原生细胞的命运
Qilin Gu1, Xiaojie Yang1, Jie Lv1,2
1Center for Cardiovascular Regeneration, Houston Methodist, 6550 Fannin Street, Houston, TX 77030, USA.
Science (New York, N.Y.)
|February 2, 2019
概括
高胆固醇会加速血液干细胞的扩张. AIBP蛋白调节胆固醇,激活Srebp2和Notch通路,这驱动了造血干细胞和原始细胞 (HSPC) 的出现和扩张.
科学领域:
- 心血管生物学
- 血液形成
- 分子生物学
背景情况:
- 高胆固醇血症是动脉样硬化的一个关键因素,已知可以增强造血干细胞和原生细胞 (HSPC) 的扩张和动员.
- 关联高胆固醇水平与血液形成变化的精确分子机制在很大程度上是未知的.
研究的目的:
- 阐明将高胆固醇血症与造血干细胞 (HSC) 的出现和扩张联系在一起的分子调节剂.
- 为了研究 AIBP 在这个过程中的作用.
主要方法:
- 使用全基因组ChIP-seq,RNA-seq和ATAC-seq来分析基因调节.
- 研究了AIBP,Srebp2和Notch信号在HSPC发展中的功能.
- 与人类高胆固醇血症数据相关的分子发现.
主要成果:
- 鉴定出 AIBP 是一种源自 somite 的线索,可以调节从血源性内皮中出现 HSPC.
- 证明AIBP介导的胆固醇流动激活了内皮Srebp2,从而提高了Notch信号的调节,促进了HSPC的出现.
- 显示Srebp2抑制可以抵消高胆固醇血症引起的HSPC扩张.
- 在高胆固醇的人群中观察到Srebp2激活和Notch上调.
结论:
- 建立了一个由AIBP调节的,依赖于Srebp2的途径,控制在发育过程中出现HSPC.
- 这种途径也与动脉样硬化心血管疾病相关的HSPC扩张有关.
- 这些发现在疾病背景下提供了胆固醇代谢和血液形成之间的分子联系.
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