免疫逃逸的人类岛屿类器官改善糖尿病
Eiji Yoshihara1,2,3, Carolyn O'Connor4, Emanuel Gasser1
1Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
Nature
|August 21, 2020
概括
来自干细胞的人类岛屿类器官 (HILO) 显示出糖尿病治疗的前景. 在糖尿病小鼠中,WNT4信号驱动成熟,PD-L1表达使免疫规避成功移植.
科学领域:
- 干细胞生物学
- 内分泌学
- 免疫学
背景情况:
- 干细胞衍生小岛为胰岛素依赖性糖尿病治疗提供了潜力.
- 在实现功能成熟和免疫兼容方面仍然存在挑战.
研究的目的:
- 从诱导的多能干细胞产生功能性人体岛屿类器官 (HILO).
- 研究WNT4信号在HILO代谢成熟中的作用.
- 在糖尿病模型中评估HILO的治疗潜力和免疫规避策略.
主要方法:
- 从诱导的多能干细胞生成HILO.
- 评估葡萄糖刺激的胰岛素分泌和代谢成熟.
- 将HILO移植到糖尿病小鼠模型中 (NOD/SCID和免疫能力).
- 对编程死亡配体1 (PD-L1) 过度表达和干扰素γ刺激进行免疫规避的评估.
主要成果:
- 确定非正规的WNT4信号对于HILO的代谢成熟至关重要.
- 在糖尿病小鼠中,功能成熟的HILO在移植后迅速恢复葡萄糖平衡.
- 在具有免疫能力的小鼠中,PD- L1 保护的HILO 异位细胞过度表达50天.
- 干扰素-γ诱导PD-L1,限制T细胞激活,并防止移植的排斥.
结论:
- 可以从干细胞产生对葡萄糖敏感的HILO,表现出强大的胰岛素分泌.
- PD-L1表达是一种可行的策略,以克服HILO异种移植的免疫排斥.
- 对于目前的糖尿病疗法来说, HILO 是一个有前途的,
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