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Matrix stiffness-modulated proliferation and secretory function of the airway smooth muscle cells

机译:气道平滑肌细胞的基质刚度调节的增殖和分泌功能

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摘要

Multiple pulmonary conditions are characterized by an abnormal misbalance between various tissue components, for example, an increase in the fibrous connective tissue and loss/increase in extracellular matrix proteins (ECM). Such tissue remodeling may adversely impact physiological function of airway smooth muscle cells (ASMCs) responsible for contraction of airways and release of a variety of bioactive molecules. However, few efforts have been made to understand the potentially significant impact of tissue remodeling on ASMCs. Therefore, this study reports how ASMCs respond to a change in mechanical stiffness of a matrix, to which ASMCs adhere because mechanical stiffness of the remodeled airways is often different from the physiological stiffness. Accordingly, using atomic force microscopy (AFM) measurements, we found that the elastic modulus of the mouse bronchus has an arithmetic mean of 23.1 ± 14 kPa (SD) (median 18.6 kPa). By culturing ASMCs on collagen-conjugated polyacrylamide hydrogels with controlled elastic moduli, we found that gels designed to be softer than average airway tissue significantly increased cellular secretion of vascular endothelial growth factor (VEGF). Conversely, gels stiffer than average airways stimulated cell proliferation, while reducing VEGF secretion and agonist-induced calcium responses of ASMCs. These dependencies of cellular activities on elastic modulus of the gel were correlated with changes in the expression of integ-rin-p! and integrin-linked kinase (ILK). Overall, the results of this study demonstrate that changes in matrix mechanics alter cell proliferation, calcium signaling, and proangiogenic functions in ASMCs.
机译:多种肺部条件的特征在于各种组织成分之间的异常不平衡,例如,纤维结缔组织和细胞外基质蛋白(ECM)的损失/增加的增加。这种组织重塑可能对负责气道的收缩和释放各种生物活性分子的气道平滑肌细胞(ASMC)产生不利地影响气道平滑肌细胞(ASMC)的生理功能。然而,已经努力了解组织重塑在ASMC上的潜在显着影响。因此,本研究报告了ASMCS如何响应矩阵的机械刚度的变化,因为改造的气道的机械刚度通常与生理刚度不同。因此,使用原子力显微镜(AFM)测量,发现小鼠支气管的弹性模量具有23.1±14kPa(SD)的算术平均值(中值18.6kPa)。通过用受控弹性模育培养胶原蛋白缀合的聚丙烯酰胺水凝胶上的ASMC,我们发现设计成比平均气道组织更软的凝胶显着增加了血管内皮生长因子(VEGF)的细胞分泌。相反,凝胶比平均航空刺激细胞增殖更硬,同时减少VEGF分泌和激动剂诱导的ASMC的钙应答。这些细胞活性对凝胶弹性模量的依赖性与Integ-rin-P表达的变化相关!和整合蛋白联系激酶(ILK)。总体而言,本研究结果表明,基质力学改变细胞增殖,钙信号传导和ASMS中的常规功能的变化。

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