在基因毒性损伤后,有机体生存需要Lgr5 +肠道干细胞
Joseph Lee1, Antoine Gleizes1, Nicolas V Janto2
1Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, GA 30322, USA.
Development (Cambridge, England)
|November 6, 2024
概括
活性肠干细胞 (aISC) 在多克索鲁比 (DXR) 损伤后对肠道器官的生存至关重要. 虽然自主性肠干细胞 (fISCs) 激活,但aISC的存活对于完整的有机体再生至关重要.
科学领域:
- 胃肠病学 胃肠病学
- 干细胞生物学 干细胞生物学
- 发展生物学 发展生物学
背景情况:
- 肠上皮依赖于活性干细胞 (aISC) 和选择性干细胞 (fISC) 来进行修复.
- 多克索鲁比 (DXR) 是一种化学疗法药物,会损害肠道干细胞.
研究的目的:
- 在小鼠肠道有机体中模拟DXR诱导的损伤.
- 调查aISCs和fISCs在DXR处理后有机体存活中的作用.
- 为了比较小鼠和人类肠道器官之间的体外DXR反应.
主要方法:
- 用不同剂量的多克索鲁比 (DXR) 治疗小鼠肠道器官.
- 在DXR后评估fISC基因激活和aISC存活率.
- 使用Lgr52A-DTR等位基来在DXR暴露后消去残留的aISCs.
- 在人类肠道有机体中比较DXR诱导的生存率和LGR5下调.
主要成果:
- 在有机体中,DXR治疗诱导了fISC基因激活,但功能干性取决于aISC的存活.
- 在DXR后的整体器官存活需要初始基因毒性侮辱的aISC存活率.
- 鼠标肠道器官显示剂量依赖的aISC损失,需要aISC存活才能再生.
- 与小鼠器官相比,人类肠道器官需要更高的DXR剂量来减少生存率和LGR5下调.
结论:
- 在DXR引起的器官损伤后,功能性肠干细胞严重依赖于活性干细胞池.
- 肠道器官中DXR诱导的损伤提供了一个可复制的模型来研究干细胞反应.
- 在小鼠和人类肠道器官之间对DXR的体外反应存在显著差异,突出了特定物种的反应.
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