Biomimetic soft fibrous hydrogels for contractile and pharmacologically responsive smooth muscle
Biomimetic soft fibrous hydrogels for contractile and pharmacologically responsive smooth muscle
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DOI：
10.1016/j.actbio.2018.05.015
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发表时间：
2018-07-01
影响因子：
9.7
通讯作者：
Tan, Wei
中科院分区：
文献类型：
--
作者：
Ding, Yonghui;Xu, Xin;Tan, Wei
评估正常或病理相关血管组织环境中平滑肌收缩性和药理反应性变化的能力对于血管药物发现至关重要。然而，在捕捉体内血管重塑的复杂性和评估复杂的组织样环境中的细胞收缩性方面仍然存在重大挑战。在此，我们开发了一种仿生纤维水凝胶，其结构、硬度和成分可调节，类似于天然血管组织环境。该水凝胶平台进一步与组合蛋白质阵列技术以及测量细胞力学和收缩性的先进方法相结合，从而可以评估各种组织样微环境中的平滑肌功能。我们的结果表明，仿生纤维结构在平滑肌功能中起主导作用，而粘附蛋白的呈现在不同程度上对其进行共同调节。具体来说，与扁平水凝胶相比，纤维网络能够实现细胞浸润并上调肌动球蛋白的表达。值得注意的是，水凝胶的纤维结构和生理相关的硬度共同增强了单细胞和完整组织水平上的平滑肌收缩性和对血管活性药物的药理反应。总之，这项研究首次证明了细胞阵列平台在仿生柔软纤维环境中人类血管平滑肌收缩性和药理反应性的改变。这里产生的集成平台可以通过开发广泛的病理生理学相关的体外组织模型来进行病理学和药理学干预的研究。意义声明体外工程功能性平滑肌在患病组织替代和药物测试方面具有巨大的潜力。一个主要挑战是概括平滑肌收缩性和药理反应，因为其对环境变化的反应具有显着的表型可塑性。我们提出了一种具有可调节结构、刚度和成分的仿生纤维水凝胶，能够在类似天然的血管组织微环境中创建功能性平滑肌组织。这种纤维水凝胶进一步与组合蛋白阵列技术相结合，构建细胞阵列，用于评估平滑肌表型、收缩和细胞力学。这里产生的集成平台有望用于开发各种正常或患病的体外组织模型。 (C) 2018 Acta Materialia Inc. 由 Elsevier Ltd 出版。保留所有权利。
The ability to assess changes in smooth muscle contractility and pharmacological responsiveness in normal or pathological-relevant vascular tissue environments is critical to enable vascular drug discovery. However, major challenges remain in both capturing the complexity of in vivo vascular remodeling and evaluating cell contractility in complex, tissue-like environments. Herein, we developed a biomimetic fibrous hydrogel with tunable structure, stiffness, and composition to resemble the native vascular tissue environment. This hydrogel platform was further combined with the combinatory protein array technology as well as advanced approaches to measure cell mechanics and contractility, thus permitting evaluation of smooth muscle functions in a variety of tissue-like microenvironments. Our results demonstrated that biomimetic fibrous structure played a dominant role in smooth muscle function, while the presentation of adhesion proteins co-regulated it to various degrees. Specifically, fibre networks enabled cell infiltration and upregulated expression of actomyosin proteins in contrast to flat hydrogels. Remarkably, fibrous structure and physiologically relevant stiffness of hydrogels cooperatively enhanced smooth muscle contractility and pharmacological responses to vasoactive drugs at both the single cell and intact tissue levels. Together, this study is the first to demonstrate alterations of human vascular smooth muscle contractility and pharmacological responsiveness in biomimetic soft, fibrous environments with a cellular array platform. The integrated platform produced here could enable investigations for pathobiology and pharmacological interventions by developing a broad range of pathophysiologically relevant in vitro tissue models.Statement of SignificanceEngineering functional smooth muscle in vitro holds the great potential for diseased tissue replacement and drug testing. A central challenge is recapitulating the smooth muscle contractility and pharmacological responses given its significant phenotypic plasticity in response to changes in environment. We present a biomimetic fibrous hydrogel with tunable structure, stiffness, and composition that enables the creation of functional smooth muscle tissues in the native-like vascular tissue microenvironment. Such fibrous hydrogel is further combined with the combinatory protein array technology to construct a cellular array for evaluation of smooth muscle phenotype, contraction, and cell mechanics. The integrated platform produced here could be promising for developing a broad range of normal or diseased in vitro tissue models. (C) 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.