Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, China.
Cell Death Dis. 2024 Jan 24;15(1):84. doi: 10.1038/s41419-024-06466-3.
Skin fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) caused by fibrotic disorders of the skin. In recent years, ECM stiffness has emerged as a prominent mechanical cue that precedes skin fibrosis and drives its progression by promoting fibroblasts activation. However, how stiffness influences fibroblasts activation for skin fibrosis progression remains unknown. Here, we report a positive feedback loop mediated by the mechanosensitive ion channel Piezo1 and aberrant tissue mechanics in driving skin fibrosis. Piezo1 is upregulated in fibrotic skin in both humans and mice. Piezo1 knockdown dermal fibroblasts lose their fibroproliferative phenotypes despite being grown on a stiffer substrate. We show that Piezo1 acts through the Wnt2/Wnt11 pathway to mechanically induce secretion of C-C motif chemokine ligand 24 (CCL24, also known as eotaxin-2), a potent cytokine associated with fibrotic disorders. Importantly, adeno-associated virus (AAV)-mediated Piezo1 knockdown ameliorated the progression of skin fibrosis and skin stiffness in mice. Overall, increased matrix stiffness promotes skin fibrosis through the inflammatory Piezo1-Wnt2/Wnt11-CCL24 pathway. In turn, a stiffer skin microenvironment increases Piezo1 expression to exacerbate skin fibrosis aggression. Therefore, targeting Piezo1 represents a strategy to break the positive feedback loop between fibroblasts mechanotransduction and aberrant tissue mechanics in skin fibrosis.
皮肤纤维化的特征是细胞外基质（ECM）的过度积累，这是由皮肤纤维化障碍引起的。近年来，ECM 硬度作为一个突出的机械线索出现，它通过促进成纤维细胞的激活，在皮肤纤维化发生之前驱动其进展。然而，硬度如何影响成纤维细胞激活以促进皮肤纤维化进展尚不清楚。在这里，我们报告了一个由机械敏感离子通道 Piezo1 和异常组织力学介导的正反馈回路，该回路驱动皮肤纤维化。Piezo1 在人类和小鼠的纤维化皮肤中均上调。尽管在更硬的基质上生长，Piezo1 敲低的真皮成纤维细胞失去了它们的成纤维增殖表型。我们表明 Piezo1 通过 Wnt2/Wnt11 途径发挥作用，通过机械诱导 C-C 基序趋化因子配体 24（CCL24，也称为嗜酸性粒细胞趋化因子-2）的分泌，CCL24 是一种与纤维化疾病相关的强效细胞因子。重要的是，腺相关病毒（AAV）介导的 Piezo1 敲低可改善小鼠皮肤纤维化和皮肤硬度的进展。总的来说，基质硬度的增加通过炎症性 Piezo1-Wnt2/Wnt11-CCL24 途径促进皮肤纤维化。反过来，更硬的皮肤微环境增加 Piezo1 的表达，从而加剧皮肤纤维化的侵袭性。因此，靶向 Piezo1 代表了打破皮肤纤维化中成纤维细胞机械转导和异常组织力学之间正反馈循环的一种策略。
