孤儿核受体NR4A1和NR4A2调节小鼠造血干细胞规范中的内皮细胞到造血细胞的转变
Diana Sá da Bandeira1, Chris D Nevitt1, Felipe Segato Dezem2
1Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Development (Cambridge, England)
|November 26, 2024
概括
NR4A核受体在胚胎发生过程中对造血干细胞 (HSC) 发育至关重要. 它们的缺席会通过破坏Notch信号来阻止HSC的成熟,从而影响终身造血.
科学领域:
- 发展生物学 发展生物学
- 血液形成 血液形成 血液形成
- 分子生物学分子生物学
背景情况:
- 造血干细胞 (HSC) 对于终身血液生产至关重要.
- 高血细胞源于血源性内皮细胞原体,通过内皮细胞转化为血质构造细胞 (EHT).
- EHT和HSC规范的分子调节者尚未完全理解,NR4A核受体家族以前没有与这个过程有关.
研究的目的:
- 在EHT期间调查NR4A亚家族的孤儿核受体在HSC规范中的作用.
- 阐明NR4A受体影响HSC发育的分子机制.
主要方法:
- 在EHT期间对血液内皮的Nr4a1和Nr4a2基因表达的分析.
- 使用Nr4a基因剂量的基因废除研究来评估对造血原体发育的影响.
- 在使用基因改造胚胎的细胞进行体内造血重组试验.
- 空间转录组分析以确定受NR4A基因切除影响的分子通路.
- 活体培养实验,以评估发育缺陷的救援.
主要成果:
- 在EHT期间,血源性内皮的Nr4a1和Nr4a2表达增加.
- 随着Nr4a基因剂量的逐渐丧失,造血原体的数量减少,并阻碍了HSC的成熟.
- Nr4a1-/-; Nr4a2-/- 胚胎细胞缺乏长期的造血重生潜力.
- Nr4a1和Nr4a2的基因切除阻止了Notch信号的下调,阻碍了亲HSC到HSC的成熟.
- 带有特定生长因子的ex vivo培养部分挽救了成熟缺陷,这表明绕过了依赖口的调节.
结论:
- 孤儿核受体的NR4A家族在内皮细胞转化为造血细胞的过程中发挥着重要作用.
- NR4A受体对于造血干细胞的适当成熟至关重要,部分是通过调节Notch信号.
- 这些发现揭示了NR4A受体在早期血液形成中的新功能.
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