Cbl 和 Cbl-b 泛素酶对于肠道上皮干细胞的维护至关重要
Neha Zutshi1,2, Bhopal C Mohapatra1,3, Pinaki Mondal4
1Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
iScience
|July 8, 2024
概括
卡西塔斯B系淋巴瘤 (CBL) 连接酶对于维持肠干细胞 (ISC) 至关重要. 损失CBL/CBLB通过破坏Akt-mTOR通路,损害ISC功能和器官生长.
科学领域:
- 细胞生物学 细胞生物学
- 干细胞生物学 干细胞生物学
- 分子生物学分子生物学
背景情况:
- 受体氨酸激酶 (RTKs) 调节干细胞的命运.
- 卡西塔斯B系淋巴瘤 (CBL) 家庭的乌比奎丁连接酶负面调节RTKs.
- 在干细胞调节中CBL连接酶的作用在很大程度上是未知的.
研究的目的:
- 研究CBL/CBLB在肠干细胞 (ISC) 维护和分化中的作用.
- 阐明ISC中CBL/CBLB功能背后的分子机制.
主要方法:
- 产生一种可诱导的ISC特定的Cbl/Cblb双淘汰 (iDKO) 鼠标模型.
- 通过 LacZ 血统追踪来追踪细胞命运.
- 肠道有机体培养和辐射伤害模型.
- 单细胞RNA测序 (scRNA-seq) 和Akt-mTOR路径分析.
主要成果:
- 特定于ISC的Cbl/Cblb淘汰导致Lgr5+ISC的快速丧失,并改变了分化.
- 放射后Cbl/Cblb缺乏导致肠道上皮质修复受损.
- 来自iDKO小鼠的器官培养物未能维持干细胞种群.
- scRNA-seq显示了iDKO有机体中的Akt-mTOR通路过活化.
- 药理上抑制Akt-mTOR可以挽救iDKO的缺陷.
结论:
- CBL/CBLB对于维持肠道干细胞种群至关重要.
- CBL/CBLB功能对于肠上皮质平衡和修复至关重要.
- 在ISC维护中,Akt-mTOR通路是CBL/CBLB的关键下游调解器.
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