Alpha5beta1 integrin-fibronectin interactions specify liquid to solid phase transition of 3D cellular aggregates.
Alpha5beta1 integrin-fibronectin interactions specify liquid to solid phase transition of 3D cellular aggregates.
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DOI：
10.1371/journal.pone.0011830
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发表时间：
2010-07-29
期刊：
影响因子：
3.7
通讯作者：
Foty RA
中科院分区：
文献类型：
--
作者：
Caicedo-Carvajal CE;Shinbrot T;Foty RA
胚胎发育和伤口愈合期间的组织组织化一方面取决于细胞在主动重排期间交换粘合键的能力，另一方面取决于细胞在达到组织稳态时固定在适当位置的能力。细胞通过调节由钙粘蛋白介导的细胞-细胞粘附键或由整合素调节的细胞-细胞外基质（ECM）连接来实现这些矛盾的任务。整合素α5β1和可溶性纤连蛋白（sFN）是细胞-ECM力产生和ECM聚合的关键参与者。在这里，我们探讨整合素α5β1和sFN之间的相互作用及其对组织力学性质和细胞分选行为的影响。我们产生了一系列α5β1受体密度不同的细胞系。然后，我们系统地探讨了不同的sFN浓度对聚集体的生物力学性能，使用组织表面张力测定法的影响。我们发现了以前未报道的复杂行为，包括观察到纤连蛋白和整合素α5β1之间的相互作用产生双相组织内聚特征。具体来说，我们表明，在恒定的sFn浓度下，随着α5β1受体密度从低水平增加到中等水平，聚集体凝聚力线性增加，产生从粘弹液体到伪粘弹固体行为的转变。然而，受体密度的进一步增加会导致组织凝聚力的突然下降，并转变回粘弹性液体性质。我们认为这可能是由于在高α5β1水平下聚集体微环境中sFn的耗竭低于临界值。我们还发现α5β1整合素的差异表达可以促进细胞间的相分离。α5-整联蛋白和sFn之间的相互作用显著促进组织凝聚力，并且取决于它们的表达水平，可以介导从液体行为到弹性行为的转变。这种相互作用代表了整合素和ECM之间的可调控制水平，其可以影响组织凝聚力和其他机械性质，这可以转化为组织结构和功能的规范。这些研究提供了重要的生物过程，如胚胎发育，伤口愈合和组织工程应用的见解。
Tissue organization during embryonic development and wound healing depends on the ability of cells on the one hand to exchange adhesive bonds during active rearrangement and on the other to become fixed in place as tissue homeostasis is reached. Cells achieve these contradictory tasks by regulating either cell-cell adhesive bonds, mediated by cadherins, or cell-extracellular matrix (ECM) connections, regulated by integrins. Integrin α5β1 and soluble fibronectin (sFN) are key players in cell-ECM force generation and in ECM polymerization. Here, we explore the interplay between integrin α5β1 and sFN and its influence on tissue mechanical properties and cell sorting behavior. We generated a series of cell lines varying in α5β1 receptor density. We then systematically explored the effects of different sFN concentrations on aggregate biomechanical properties using tissue surface tensiometry. We found previously unreported complex behaviors including the observation that interactions between fibronectin and integrin α5β1 generates biphasic tissue cohesion profiles. Specifically, we show that at constant sFn concentration, aggregate cohesion increases linearly as α5β1 receptor density is increased from low to moderate levels, producing a transition from viscoelastic-liquid to pseudo viscoelastic-solid behavior. However, further increase in receptor density causes an abrupt drop in tissue cohesion and a transition back to viscoelastic-liquid properties. We propose that this may be due to depletion of sFn below a critical value in the aggregate microenvironment at high α5β1 levels. We also show that differential expression of α5β1 integrin can promote phase-separation between cells. The interplay between α5-integrin and sFn contributes significantly to tissue cohesion and, depending on their level of expression, can mediate a shift from liquid to elastic behavior. This interplay represents a tunable level of control between integrins and the ECM that can influence tissue cohesion and other mechanical properties, which may translate to the specification of tissue structure and function. These studies provide insights into important biological processes such as embryonic development, wound healing, and for tissue engineering applications.
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