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一个分子电路调节新兴和成年AT2细胞的命运可塑性

Amitoj S Sawhney¹, Brian J Deskin², Junming Cai¹

¹Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.

Nature communications

|October 14, 2025

概括

胚胎肺中的单胞膜细胞 (AT2s) 获得可塑性,直到C/EBPα抑制了Notch信号. 这种机制涉及PRC2和"脉冲发生器",决定AT1/AT2细胞的命运. 在成人肺部,CHOP调解AT2可塑性恢复.

科学领域:

细胞生物学细胞生物学
发育生物学是发展生物学.
肺部医学肺部医学

背景情况:

气膜1型 (AT1) 和2型 (AT2) 细胞对于肺功能和气体交换至关重要.
它们在肺部发育和疾病中的分化和命运可塑性尚未完全理解.

研究的目的:

阐明控制AT2细胞出现,命运可塑性和胚胎肺中的分化机制.
研究转录因子和信号通路在调节AT1/AT2细胞命运中的作用.
在受伤的成年肺部探索AT2细胞的可塑性.

主要方法:

胚胎肺部发育的分析.
对bZIP转录因子C/EBPα和Notch信号的研究.
在基因调节中多镇压复合体 (PRC2) 的作用.
在成年肺损伤模型中对CHOP的研究.

主要成果:

单个AT2细胞在中间区域出现,并与相邻的上皮连接.
C/EBPα抑制了Dlk1增强器的Notch信号,通过PRC2控制的"脉冲发生器"电路调节AT1/AT2命运.
在受伤的成年肺部中,CHOP调节了C/EBPα的下调,重新访问AT2命运可塑性.
Cebpa损失引发了一个独特的"捍卫者"AT2状态,与补偿状态分开.

结论:

一个涉及C/EBPα,DLK1和PRC2的新型"脉冲发生器"电路精确地乘以Notch激活,以建立AT1和AT2细胞的"盐和胡"模式.
在成年肺部,AT2细胞命运可塑性可以通过C/EBPα降低调节重新被投入,这由CHOP促进.
存在"捍卫者"AT2状态,这表明AT2细胞在感染后可以在保护和修复作用之间交替.

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