波浪狀細胞中的YAP機械傳導

Abstract

彈性結締組織如韌帶和動脈，含有波浪狀排列的組織纖維結構，這些結構會隨著疾病、損傷和老化而改變。我們先前研究發現，這類波浪結構影響細胞形狀與表型，促進韌帶成纖維細胞膠原蛋白生成，以及血管平滑肌細胞收縮蛋白表現。結合微製成技術與牽引力顯微鏡（TFM），我們亦觀察到波浪形細胞隨曲率增加展現更大的牽引力與細胞核變形。然而，細胞如何感知這些波浪狀結構並對壓力做出反應的機制仍不清楚。研究表明，細胞形狀透過與細胞骨架的相互作用來影響細胞核形狀與基因表現。YAP（Yes-associated protein）作為關鍵的機械敏感轉錄因子，其核定位已被廣泛應用於評估細胞張力與機械訊號的變化。 本研究以微接觸列印技術模擬波浪狀微環境，並探討肌球蛋白II與Arp2/3在波浪形細胞中對YAP活性的調控作用。我們觀察到波浪狀細胞表現出較大的細胞核變形程度與YAP核定位，並在拉伸刺激下增強。肌球蛋白II介導細胞張力形成與拉伸下的細胞核變形；而Arp2/3則影響軸向張力與動態機械轉導路徑，影響細胞對外力的整體反應。

Elastic connective tissues, such as ligaments and arteries, contain wavy arrangements of tissue fibers that change with disease, injury, and aging. Our previous studies have shown that these wavy structures affect cell shape and phenotype, promoting collagen production in ligamentous fibroblasts and contractile protein expression in vascular smooth muscle cells. Combining microfabrication with traction force microscopy (TFM), we have also observed that wavy cells exhibit greater traction and nuclear deformation with increasing curvature. However, the mechanism of how cells perceive these wavy structures and respond to stress remains unclear. Studies have shown that cell shape affects nuclear shape and gene expression through interactions with the cytoskeleton. YAP-associated protein, as a key mechanosensitive transcription factor, has been widely used to assess changes in cell tension and mechanical signals due to its nuclear localization. In this study, we used a microcontact printing to simulate a wavy microenvironment and investigated the role of myosin II and Arp2/3 in the regulation of YAP activity in wavy cells. We observed that wavy cells exhibited a greater degree of nuclear deformation and localization of YAP nuclei, which was enhanced under tensile stimulation. Myosin II mediates cellular tension formation and nuclear deformation under stretch, whereas Arp2/3 affects axial tension and dynamic mechanotransduction pathways, influencing the overall cellular response to external forces. Our findings emphasize the importance of cytoskeletal coordination in integrating external and geometric signals into nuclear signals.