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机械硬性通过Piezo1-Wnt2/Wnt11-CCL24正反循环促进皮肤纤维化

Jiahao He¹, Xinwei Cheng¹, Bin Fang²

¹Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China.

Cell death & disease

|January 24, 2024

概括

皮肤纤维化进展是由一个积极的反循环驱动的,涉及机械敏感离子通道Piezo1和增加的组织度. 准Piezo1提供了治疗纤维化皮肤疾病的潜在策略.

科学领域:

生物医学工程生物医学工程
皮肤病学皮肤病学
机械生物学机械生物学

背景情况:

皮肤纤维化涉及过度的细胞外基质积累,并受到组织机械特性的影响.
增加细胞外矩阵 (ECM) 刚度是促进纤维细胞激活并驱动皮肤纤维化进展的关键机械暗示.
机械度影响皮肤纤维化中的纤维细胞激活的确切机制尚不清楚.

研究的目的:

阐明机械敏感离子通道Piezo1在调解组织硬性对纤维细胞激活和皮肤纤维化影响中的作用.
研究皮肤纤维化中的Piezo1介导机械传导所涉及的分子通路.
评估Piezo1作为改善皮肤纤维化的治疗标.

主要方法:

在人类和小鼠纤维化皮肤样本中研究了Piezo1表达.
在不同硬度基板上培养的皮肤纤维细胞中利用Piezo1敲击.
研究了Wnt2/Wnt11通路和CCL24分泌的参与.
在皮肤纤维化小鼠模型中采用腺相关病毒 (AAV) 介导的Piezo1 Knockdown.

主要成果:

在纤维化皮肤中,Piezo1的上调.
在硬基质上的纤维细胞中,Piezo1倒置废除了纤维增殖表型.
通过Wnt2/Wnt11通路,Piezo1通过机械诱导C-C动机化学因联体24 (CCL24) 的分泌.
通过AAV介导的Piezo1 knockdown可减少小鼠皮肤纤维化进展和皮肤硬.

结论:

一个积极的反循环存在,其中增加的矩阵刚度通过Piezo1-Wnt2/Wnt11-CCL24炎症途径促进皮肤纤维化.
皮肤硬度升高会增强Piezo1的表达,从而加剧纤维化.
准Piezo1是一个有希望的治疗策略,可以破坏这种反循环并治疗皮肤纤维化.

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