触发AHR可以解决TGF-β1诱导的纤维细胞激活,并促进AT1细胞在膜器官中的再生
Andrew S Hagan1, Scott Williams1, Casey J N Mathison1
1Novartis Biomedical Research, San Diego, CA, USA.
Communications biology
|July 9, 2025
概括
研究人员确定了一种化合物,该化合物在肺部疾病中促进膜上皮的再生. 这一发现提供了一种新的治疗策略,通过抵消纤维化信号通路并增强肺部修复能力.
科学领域:
- 肺部医学 肺部医学
- 再生医学是一种再生医学.
- 细胞生物学 细胞生物学
背景情况:
- 膜上皮质再生对于慢性肺部疾病 (如纤维化间歇性肺病) 的肺功能至关重要.
- 膜类型2 (AT2) 细胞分化为膜类型1 (AT1) 细胞用于上皮质修复,但在病理条件下,这一过程受到损害.
- 了解促进AT1细胞分化的机制对于治疗肺纤维化至关重要.
研究的目的:
- 在疾病模型中识别增强AT1细胞分化和再生的小分子.
- 调查已识别的化合物在抵消病理信号的治疗潜力.
主要方法:
- 使用3D有机体培养系统模拟TGF-β1诱导的AT1球形形成损伤.
- 对大约16800种化合物进行了高通量屏幕 (HTS) 检测,以确定AT1球形形成的调节器.
- 采用纵向单细胞RNA测序 (scRNA-seq) 来分析细胞反应和分子机制.
主要成果:
- 确定DB-11-BE87是一个小分子,显著增加AT1球形形成,表明增强AT1再生.
- 发现DB-11-BE87可以降低TGF-β1诱导的纤维细胞激活,这是一个关键的纤维化过程.
- 在用DB-11-BE87治疗的纤维细胞中观察到阿里尔碳化合物受体 (AHR) 的并发激活.
结论:
- 成功建立了一个HTS系统,以发现促进AT1差异化的因素.
- DB-11-BE87通过通过AHR激活减轻病态TGF-β1信号传递来促进AT1再生.
- 激活AHR是一个潜在的治疗途径,可以抵消肺部疾病中的纤维化信号.
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