TNF受体1调节结肠介质细胞多样性和上皮干细胞利基
bioRxiv : the preprint server for biology
|September 18, 2025
概括
瘤亡因子受体1 (TNFR1) 信号传递对于维持多样化的结肠介质细胞和支持干细胞位至关重要. 丧失TNFR1会损害炎症性肠病 (IBD) 中的粘膜愈合.
科学领域:
- 胃肠病学 胃肠病学
- 免疫学 免疫学 免疫学
- 干细胞生物学 干细胞生物学
背景情况:
- 抗瘤亡因子 (TNF) 疗法是炎症性肠病 (IBD) 的标准,但对许多患者的疗效有限.
- 矛盾的是,虽然TNF是促炎性的,但其受体TNFR1的枯竭会使慢性结肠炎恶化.
- 大肠炎诱导的介质细胞重塑会影响皮质干细胞利基,这对粘膜修复至关重要.
研究的目的:
- 调查TNFR1在结肠介质细胞多样性中的作用.
- 确定TNFR1信号如何影响IBD的干细胞和粘膜愈合.
- 测试TNFR1促进介质细胞多样性和干细胞利基功能的假设.
主要方法:
- 使用了TNFR1淘汰 (TNFR1-/-) 和条件淘汰 (PDGFRα-Cre;TNFR1fl/fl) 的小鼠模型.
- 在初级结肠肌纤维细胞 (CMFs) 上使用单细胞RNA-Seq来评估细胞多样性和基因功能.
- 通过共同培养和操纵的整体蛋白A6 (ITGA6) 和R-脊柱蛋白3 (RSPO3) 水平,研究了介质细胞-上皮相互作用.
主要成果:
- TNFR1-/-介质酶显示细胞多样性减少,特别是减少了专门的TNF和干扰素信号传递的密细胞.
- 危密细胞介质体中TNFR1的损失降低了PDGFRα+CMF和RSPO3,但增加了ITGA6.
- 抑制ITGA6拯救的TNFR1-/-CMF的扩散和迁移,恢复PDGFRα和RSPO3的表达. 在TNFR1-/- CMF共同培养中,RSPO3补充拯救了结肠状干细胞标志物表达.
结论:
- TNFR1信号传递对于指定和维护结肠介质细胞种群至关重要.
- TNFR1在维护结肠密室干细胞中发挥着至关重要的作用.
- 准TNFR1-介导的介质细胞信号可能为IBD和粘膜愈合提供新的治疗途径.
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