Mechanical stretch sustains myofibroblast phenotype and function in microtissues through latent TGF-β1 activation.

IF 1.5 4区 生物学 Q4 CELL BIOLOGY Integrative Biology Pub Date : 2020-09-07 DOI:10.1093/intbio/zyaa015
Matthew Walker, Michel Godin, Andrew E Pelling
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引用次数: 11

Abstract

Developing methods to study tissue mechanics and myofibroblast activation may lead to new targets for therapeutic treatments that are urgently needed for fibrotic disease. Microtissue arrays are a promising approach to conduct relatively high-throughput research into fibrosis as they recapitulate key biomechanical aspects of the disease through a relevant 3D extracellular environment. In early work, our group developed a device called the MVAS-force to stretch microtissues while enabling simultaneous assessment of their dynamic mechanical behavior. Here, we investigated TGF-β1-induced fibroblast to myofibroblast differentiation in microtissue cultures using our MVAS-force device through assessing α-SMA expression, contractility and stiffness. In doing so, we linked cell-level phenotypic changes to functional changes that characterize the clinical manifestation of fibrotic disease. As expected, TGF-β1 treatment promoted a myofibroblastic phenotype and microtissues became stiffer and possessed increased contractility. These changes were partially reversible upon TGF-β1 withdrawal under a static condition, while, in contrast, long-term cyclic stretching maintained myofibroblast activation. This pro-fibrotic effect of mechanical stretching was absent when TGF-β1 receptors were inhibited. Furthermore, stretching promoted myofibroblast differentiation when microtissues were given latent TGF-β1. Altogether, these results suggest that external mechanical stretch may activate latent TGF-β1 and, accordingly, might be a powerful stimulus for continued myofibroblast activation to progress fibrosis. Further exploration of this pathway with our approach may yield new insights into myofibroblast activation and more effective therapeutic treatments for fibrosis.

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机械拉伸通过潜在的TGF-β1激活维持微组织中肌成纤维细胞的表型和功能。
发展研究组织力学和肌成纤维细胞活化的方法可能会为纤维化疾病的治疗提供新的靶点。微组织阵列是一种很有前途的方法,可以进行相对高通量的纤维化研究,因为它们通过相关的3D细胞外环境概括了疾病的关键生物力学方面。在早期的工作中,我们的团队开发了一种称为MVAS-force的设备来拉伸微组织,同时能够同时评估其动态力学行为。在这里,我们利用我们的MVAS-force装置,通过评估α-SMA的表达、收缩性和刚度,研究TGF-β1诱导的微组织培养成纤维细胞向肌成纤维细胞的分化。在此过程中,我们将细胞水平的表型变化与纤维化疾病临床表现特征的功能变化联系起来。正如预期的那样,TGF-β1处理促进了肌成纤维细胞表型,显微组织变得更硬,收缩性增加。静态条件下,TGF-β1退出后,这些变化部分可逆,而长期循环拉伸则维持了肌成纤维细胞的激活。当TGF-β1受体被抑制时,机械拉伸的促纤维化作用不存在。此外,当微组织被给予潜伏的TGF-β1时,拉伸促进了肌成纤维细胞的分化。总之,这些结果表明,外部机械拉伸可能激活潜伏的TGF-β1,因此,可能是肌成纤维细胞持续激活以进展纤维化的强大刺激。通过我们的方法进一步探索这一途径可能会对肌成纤维细胞激活和更有效的纤维化治疗产生新的见解。
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来源期刊
Integrative Biology
Integrative Biology 生物-细胞生物学
CiteScore
4.90
自引率
0.00%
发文量
15
审稿时长
1 months
期刊介绍: Integrative Biology publishes original biological research based on innovative experimental and theoretical methodologies that answer biological questions. The journal is multi- and inter-disciplinary, calling upon expertise and technologies from the physical sciences, engineering, computation, imaging, and mathematics to address critical questions in biological systems. Research using experimental or computational quantitative technologies to characterise biological systems at the molecular, cellular, tissue and population levels is welcomed. Of particular interest are submissions contributing to quantitative understanding of how component properties at one level in the dimensional scale (nano to micro) determine system behaviour at a higher level of complexity. Studies of synthetic systems, whether used to elucidate fundamental principles of biological function or as the basis for novel applications are also of interest.
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