Calcium Signaling Regulates Valvular Interstitial Cell Alignment and Myofibroblast Activation in Fast-Relaxing Boronate Hydrogels.
Calcium Signaling Regulates Valvular Interstitial Cell Alignment and Myofibroblast Activation in Fast-Relaxing Boronate Hydrogels.
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DOI：
10.1002/mabi.202000268
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发表时间：
2020-12
影响因子：
4.6
通讯作者：
Anseth KS
中科院分区：
文献类型：
--
作者：
Ma H;Macdougall LJ;GonzalezRodriguez A;Schroeder ME;Batan D;Weiss RM;Anseth KS
粘弹性在纤维化疾病进展中所起的作用是一个新兴的研究领域。在这里，一个快速松弛的水凝胶系统被用来研究钙信号和机械转导之间的潜在串扰。合成了含有硼酸酯和三氮唑交联剂的聚乙二醇水凝胶，通过改变硼酸酯和三氮唑交联剂的比例来系统地改变最终水凝胶配方中的应力松弛程度。将瓣膜间质细胞(VIC)包裹在这些快速松弛支架中，研究粘弹性在VIC排列和肌成纤维细胞激活中的作用。在应力松弛程度最高的水凝胶中培养的VIC(90%)在第1天表现出铺展的形态，到第5天高度排列(80±2%)。关键的肌成纤维细胞标志，包括α-平滑肌肌动蛋白(α)和胶原1A1(COLL1A1)也显著升高。通过抑制机械转导，VIC的肌成纤维细胞活性降低了42±18%，与VIC的形态和排列无关。通过瞬时受体电位香草素4(TRPV4)的钙信号被发现以时间依赖的方式调节VIC的扩散、排列和肌成纤维细胞的激活。在早期抑制钙信号会导致细胞排列紊乱，机械转导减少，肌成纤维细胞活性减弱，而在以后的时间点抑制只会部分降低肌成纤维细胞的活性。这些结果表明，钙信号和机械转导之间存在潜在的串扰机制，其中钙信号作用于机械感觉的上游，有趣的是，钙信号还可以独立于机械转导调节VIC肌成纤维细胞的激活。在具有可调节粘弹性的三维快速松弛水凝胶支架中，研究了瓣膜间质细胞(VIC)的排列和肌成纤维细胞的激活。VIC的铺展和排列与基质粘弹性和激活钙通道的应力松弛程度较高相关。提出了粘弹性、钙信号和机械转导之间的潜在串扰，这为瓣膜组织纤维化治疗的潜在靶点提供了新的见解。
The role viscoelasticity plays 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 in the final hydrogel formulation. Valvular interstitial cells (VICs) are encapsulated in these fast-relaxing scaffolds, and the role that viscoelasticity plays on VIC alignment and myofibroblast activation is investigated. VICs cultured 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 (COLL1A1), are also 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 myofibroblast activation in a time dependent manner. Inhibition of calcium signaling at early time points results in disturbed cell alignment, decreased mechanotransduction, and diminished myofibroblast activation, while inhibition at later time points only causes partially reduced myofibroblast activation. These results suggest a potential crosstalk mechanism between calcium signaling and mechanotransduction, where calcium signaling acts upstream of mechanosensing and can interestingly also regulate VIC myofibroblast activation independently of mechanotransduction. Valvular interstitial cell (VIC) alignment and myofibroblast activation was investigated in a 3D fast-relaxing hydrogel scaffold with tunable viscoelasticity. VIC spreading and alignment correlated with higher extents of matrix viscoelasticity and stress relaxation via activating calcium channels. A potential crosstalk between viscoelasticity, calcium signaling, and mechanotransduction was proposed, which provides new insights into potential targets for valvular tissue fibrosis treatment.
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影响因子：
5
作者：
Adapala RK;Thoppil RJ;Luther DJ;Paruchuri S;Meszaros JG;Chilian WM;Thodeti CK
通讯作者：
Thodeti CK
影响因子：
16.6
作者：
Chaudhuri O;Gu L;Darnell M;Klumpers D;Bencherif SA;Weaver JC;Huebsch N;Mooney DJ
通讯作者：
Mooney DJ
影响因子：
41.2
作者：
Chaudhuri O;Gu L;Klumpers D;Darnell M;Bencherif SA;Weaver JC;Huebsch N;Lee HP;Lippens E;Duda GN;Mooney DJ
通讯作者：
Mooney DJ
影响因子：
7.3
作者：
Grove, Lisa M.;Mohan, Maradumane L.;Olman, Mitchell A.
通讯作者：
Olman, Mitchell A.
影响因子：
10
作者：
Hushka, Ella A.;Yavitt, F. Max;Anseth, Kristi S.
通讯作者：
Anseth, Kristi S.