Abstract：
Transforming growth factor (TGF)-β1 is a multifunctional cytokine that plays important roles in health and disease. Previous studies have revealed that TGFβ1 activation, signaling, and downstream cell responses including epithelial-mesenchymal transition (EMT) and apoptosis are regulated by the elasticity or stiffness of the extracellular matrix. However, tissues within the body are not purely elastic, rather they are viscoelastic. How matrix viscoelasticity impacts cell fate decisions downstream of TGFβ1 remains unknown. Here, we synthesized polyacrylamide hydrogels that mimic the viscoelastic properties of breast tumor tissue. We found that increasing matrix viscous dissipation reduces TGFβ1-induced cell spreading, F-actin stress fiber formation, and EMT-associated gene expression changes, and promotes TGFβ1-induced apoptosis in mammary epithelial cells. Furthermore, TGFβ1-induced expression of integrin linked kinase (ILK) and colocalization of ILK with vinculin at cell adhesions is attenuated in mammary epithelial cells cultured on viscoelastic substrata in comparison to cells cultured on nearly elastic substrata. Overexpression of ILK promotes TGFβ1-induced EMT and reduces apoptosis in cells cultured on viscoelastic substrata, suggesting that ILK plays an important role in regulating cell fate downstream of TGFβ1 in response to matrix viscoelasticity.
摘要：
转化生长因子（TGF）-β1是一种多功能细胞因子，在健康和疾病中起重要作用。以前的研究表明，TGFβ1激活，信令,和下游细胞反应，包括上皮-间质转化（EMT）和细胞凋亡受细胞外基质的弹性或刚度调节。然而,体内的组织不是纯弹性的，相反，它们是粘弹性的。基质粘弹性如何影响TGFβ1下游的细胞命运决定仍然未知。这里,我们合成了模拟乳腺肿瘤组织粘弹性的聚丙烯酰胺水凝胶。我们发现，增加基质粘性耗散减少TGFβ1诱导的细胞扩散，F-肌动蛋白应力纤维形成，和EMT相关的基因表达变化，并促进TGFβ1诱导的乳腺上皮细胞凋亡。此外，与在几乎弹性的基质上培养的细胞相比，在粘弹性基质上培养的乳腺上皮细胞中，TGFβ1诱导的整合素连接激酶（ILK）的表达和ILK与黏带素在细胞粘附处的共定位减弱。ILK的过表达促进TGFβ1诱导的EMT并减少在粘弹性基质上培养的细胞中的凋亡，提示ILK在调节TGFβ1下游响应基质粘弹性的细胞命运中起重要作用。
