Fibrogenic fibroblasts increase intercellular adhesion strength by reinforcing individual OB-cadherin bonds
Fibrogenic fibroblasts increase intercellular adhesion strength by reinforcing individual OB-cadherin bonds
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DOI：
10.1242/jcs.024877
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发表时间：
2008-03-15
影响因子：
4
通讯作者：
Hinz, Boris
中科院分区：
文献类型：
--
作者：
Pittet, Philippe;Lee, Kyumin;Hinz, Boris
我们之前已经证明，在成纤维细胞从迁移表型向纤维化表型转变的过程中，从N-钙粘附素到OB-钙粘附素的表达转换增加了成纤维细胞之间的细胞间黏附。使用原子力显微镜，我们在这里表明，这种更强的粘附力的一部分是因为OB-钙粘附素键抵抗类似于N-钙粘附素连接的两倍高的力。通过评估重组钙粘附素二聚体之间和扩散成纤维细胞膜上天然钙粘附素之间的粘附力，我们证明了随着时间的推移，钙粘附素结合会随着两种不同的力的增加而增强。通过调节钙粘蛋白的横向扩散和F-肌动蛋白的组织程度，我们可以将由此产生的三种力态归因于单分子键，而不是钙粘附素簇的形成。值得注意的是，与肌动蛋白细丝的结合使钙粘蛋白在单分子水平上的粘附力提高了三倍；肌动蛋白解聚将单键强度降低到缺少细胞质结构域的钙粘附素结构的水平。因此，成纤维细胞通过以下方式加强细胞间的联系：(1)从N-钙粘蛋白表达转换为OB-钙粘蛋白表达；(2)分三个不同的步骤增加单分子键的强度；(3)肌动蛋白促进钙粘附素细胞外结合的内在激活。我们认为，这种可塑性使成纤维细胞的黏附适应于重塑下组织不断变化的力学微环境。
We have previously shown that the switch from N-cadherin to OB-cadherin expression increases intercellular adhesion between fibroblasts during their transition from a migratory to a fibrogenic phenotype. Using atomic force microscopy we here show that part of this stronger adhesion is accomplished because OB-cadherin bonds resist similar to twofold higher forces compared with N-cadherin junctions. By assessing the adhesion force between recombinant cadherin dimers and between native cadherins in the membrane of spread fibroblasts, we demonstrate that cadherin bonds are reinforced over time with two distinct force increments. By modulating the degree of lateral cadherin diffusion and F-actin organization we can attribute the resulting three force states to the single-molecule bond rather than to cadherin cluster formation. Notably, association with actin filaments enhances cadherin adhesion strength on the single-molecule level up to threefold; actin depolymerization reduces single-bond strength to the level of cadherin constructs missing the cytoplasmic domain. Hence, fibroblasts reinforce intercellular contacts by: (1) switching from N- to OB-cadherin expression; (2) increasing the strength of single-molecule bonds in three distinct steps; and (3) actin-promoted intrinsic activation of cadherin extracellular binding. We propose that this plasticity adapts fibroblast adhesions to the changing mechanical microenvironment of tissue under remodeling.