Calcium Signaling Regulates Valvular Interstitial Cell Alignment and Myofibroblast Activation in Fast-Relaxing Boronate Hydrogels.,Macromolecular Bioscience

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Calcium Signaling Regulates Valvular Interstitial Cell Alignment and Myofibroblast Activation in Fast-Relaxing Boronate Hydrogels.
Macromolecular Bioscience ( IF 4.4 ) Pub Date : 2020-09-13 , DOI: 10.1002/mabi.202000268
Hao Ma _{1,

2} , Laura J Macdougall _{1,

2} , Andrea GonzalezRodriguez _{1,

2} , Megan E Schroeder _{2,

3} , Dilara Batan _{2,

4} , Robert M Weiss ₅ , Kristi S Anseth _{1,

2}

Affiliation

The role viscoelasticity in fibrotic disease progression is an emerging area of interest. Here, a fast‐relaxing hydrogel system is exploited to investigate potential crosstalk between calcium signaling and mechanotransduction. Poly(ethylene glycol) (PEG) hydrogels containing boronate and triazole crosslinkers are synthesized, with varying ratios of boronate to triazole crosslinks to systematically vary the extent of stress relaxation. Valvular interstitial cells (VICs) encapsulated in hydrogels with the highest levels of stress relaxation (90%) exhibit a spread morphology by day 1 and are highly aligned (80 ± 2%) by day 5. Key myofibroblast markers, including α‐smooth muscle actin (αSMA) and collagen 1a1 (COL1A1), are significantly elevated. VIC myofibroblast activation decreases by 42 ± 18% through inhibition of mechanotransduction, independently of VIC morphology and alignment. Calcium signaling through a transient receptor potential vanilloid 4 (TRPV4) is found to regulate VIC spreading, alignment, and activation in a time dependent manner. Inhibition of calcium signaling at early time points results in disturbed cell alignment, decreased mechanotransduction, and diminished activation, while inhibition at later time points only causes partially reduced myofibroblast activation. These results suggest a potential crosstalk mechanism, where calcium signaling acts upstream of mechanosensing and can regulate VIC myofibroblast activation independently of mechanotransduction.

中文翻译：

钙信号调节快速松弛硼酸盐水凝胶中的瓣膜间质细胞排列和肌成纤维细胞激活。

粘弹性在纤维化疾病进展中的作用是一个新兴的研究领域。在这里，利用快速松弛的水凝胶系统来研究钙信号传导和机械转导之间的潜在串扰。合成了含有硼酸酯和三唑交联剂的聚乙二醇（PEG）水凝胶，通过改变硼酸酯与三唑交联的比例来系统地改变应力松弛程度。封装在具有最高应力松弛水平 (90%) 的水凝胶中的瓣膜间质细胞 (VIC) 在第 1 天时表现出扩散形态，并在第 5 天时高度对齐 (80 ± 2%)。关键的肌成纤维细胞标记物，包括 α-平滑肌肌动蛋白 (αSMA) 和胶原蛋白 1a1 (COL1A1) 显着升高。通过抑制机械转导，VIC 肌成纤维细胞活化降低 42 ± 18%，与 VIC 形态和排列无关。研究发现，通过瞬时受体电位香草酸 4 (TRPV4) 的钙信号传导能够以时间依赖性方式调节 VIC 的扩散、排列和激活。在早期时间点抑制钙信号传导会导致细胞排列紊乱、机械转导减少和活化减少，而在后期时间点抑制仅导致肌成纤维细胞活化部分减少。这些结果表明了一种潜在的串扰机制，其中钙信号传导作用于机械传感的上游，并且可以独立于机械转导来调节 VIC 肌成纤维细胞活化。

更新日期：2020-09-13

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