PDF(Pubmed)
Abstract：
The switching of the fibroblast phenotype to myofibroblast is a hallmark of a wide variety of tissue pathologies. This phenotypical switch is known to be influenced not only by humoral factors such as TGF-β, but also by mechanical and physical cues in the cellular environment, and is accompanied by distinctive changes in cell morphology. However, the causative link between these cues, the concomitant morphological changes, and the resulting phenotypic switch remain elusive. Here, we use protein micropatterning to spatially control dermal fibroblast adhesion without invoking exogenous mechanical changes and demonstrate that varying the spatial configuration of focal adhesions (FAs) is sufficient to direct fibroblast phenotype. We further developed an automated morphometry analysis pipeline, which revealed FA eccentricity as the primary determinant of cell-state positioning along the spectrum of fibroblast phenotype. Moreover, linear fibronectin patterns that constrain the FAs were found to promote a further phenotype transition, characterized by dispersed expression of alpha-smooth muscle actin, pointing to an interesting possibility of controlling fibroblast phenotype beyond the canonical fibroblast-myofibroblast axis. Together, our study reveals that the spatial configuration of adhesion to the cellular microenvironment is a key factor governing fibroblast morphotype and phenotype, shedding new light on fibroblast phenotype regulation.
摘要：
成纤维细胞表型转变为肌成纤维细胞是多种组织病理学的标志。已知这种表型转换不仅受体液因子如TGF-β的影响,而且还通过细胞环境中的机械和物理线索，并伴随着细胞形态的独特变化。然而,这些线索之间的因果关系，伴随的形态变化，并且所产生的表型转换仍然难以捉摸。这里,我们使用蛋白质微模式在空间上控制真皮成纤维细胞粘附，而不引起外源性机械变化，并证明改变局灶性粘附（FAs）的空间构型足以指导成纤维细胞表型。我们进一步开发了一个自动形态分析管道，这表明FA偏心率是成纤维细胞表型谱中细胞状态定位的主要决定因素。此外，发现限制FAs的线性纤连蛋白模式促进进一步的表型转变，以α-平滑肌肌动蛋白的分散表达为特征，指出控制成纤维细胞表型超出经典成纤维细胞-肌成纤维细胞轴的有趣可能性。一起,我们的研究表明，粘附到细胞微环境的空间构型是控制成纤维细胞形态和表型的关键因素，为成纤维细胞表型调节提供新的思路。
