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肺介质中的过度活跃的mTORC1诱导了内皮细胞功能障碍和肺血管重塑

Susan M Lin^1,2, Ryan Rue¹, Alexander R Mukhitov¹

¹Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Perelman School of Medicine.

The Journal of clinical investigation

|December 21, 2023

概括

构成性活跃的mTORC1在肺介质细胞中驱动了内皮细胞功能障碍和肺血管改造在淋巴结膜炎 (LAM) 中. 这突出了在LAM病变发生过程中的一个关键的介质细胞-内皮细胞轴.

科学领域:

肺部医学肺部医学
细胞生物学细胞生物学
遗传学是一个遗传学.

背景情况:

淋巴细胞结核病 (LAM) 是一种进展性肺部疾病,与TSC1/2基因突变,mTORC1激活和潜在的肺高血压有关.
驱动血管重塑的LAM细胞和内皮细胞 (ECs) 之间的通信仍然不太清楚.
拉姆肺部扩展体显示EC功能障碍,包括增加增殖,迁移和血管生成受损.

研究的目的:

为了研究介质细胞-内皮细胞交叉在LAM相关的肺血管改造中的作用.
用小鼠模型来建模LAM,该小鼠模型具有介质细胞特异性TSC2缺陷和mtORC1激活.
确定介质细胞通过哪些分子机制影响LAM中的EC.

主要方法:

使用了一种Tbx4LME-Cre Tsc2fl/fl小鼠模型,模仿LAM中介质细胞特异性遗传变化.
从年轻和老年小鼠的内皮细胞 (ECs) 中分析了转录组变化.
在老年小鼠中使用单细胞RNA-Seq来识别介质细胞和动脉EC之间对膜信号传递.

主要成果:

在小鼠中,介质基因特异性 Tsc2 缺失导致 8 周大时 EC 发生转录基因变化.
一岁的突变小鼠发生了显著的肺血管重塑,中间厚度增加.
单细胞RNA-Seq揭示了 Tsc2 缺陷介质细胞向 EC 发出信号,改变血管重塑路径的对分泌体配体.

结论:

构成性活跃的mTORC1在肺介质细胞中协调了功能障碍的EC反应,有助于LAM中的肺血管重塑.
这项研究在LAM的病理生理学中确定了一个关键的介质细胞-内皮细胞轴.
这些发现对了解LAM和其他mTORC1驱动的血管疾病有影响.

关键词:

细胞生物学细胞生物学内皮细胞是内皮细胞.鼠标模型鼠标模型血管生物学血管生物学

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