Valve interstitial cell tensional homeostasis directs calcification and extracellular matrix remodeling processes via RhoA signaling.
Valve interstitial cell tensional homeostasis directs calcification and extracellular matrix remodeling processes via RhoA signaling.
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DOI：
10.1016/j.biomaterials.2016.07.034
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发表时间：
2016-10
期刊：
影响因子：
14
通讯作者：
Butcher, Jonathan T.
中科院分区：
文献类型：
--
作者：
Farrar, Emily J.;Pramil, Varsha;Richards, Jennifer M.;Mosher, Christopher Z.;Butcher, Jonathan T.
关键词：
主动脉瓣间质细胞在主动脉瓣钙化过程中具有活跃和侵袭性，但其在机械诱导的钙化重构中的动态调节作用尚不清楚。本研究的目的是利用一种新的三维培养系统阐明瓣膜间质细胞和钙化力学之间的反馈回路，该系统允许研究细胞、疾病和机械瓣膜环境之间的积极相互作用。我们设计并表征了一种新的生物反应器系统，用于在对照和成骨条件下量化主动脉瓣间质细胞在3-D水凝胶中的收缩能力。间质细胞表现出对其环境施加收缩力的显著能力，并使胶原纤维与张力方向对齐。成骨环境破坏了间质细胞的收缩性，导致胶原基质的紊乱，同时α - sma、TGF-β、Runx2和钙化结节的形成增加。有趣的是，RhoA在成骨状态下也增加，这表明疾病中瓣膜间质细胞机械活性异常亢进。RhoA抑制实验证实了这一点。在成骨治疗的同时抑制RhoA可减少促成骨信号和钙化结节的形成。时间过程相关分析显示胶原纤维间质细胞重构与钙化事件有显著相关性。间质细胞收缩调节内应力状态和主动脉瓣细胞外基质的组织。成骨破坏间质细胞的机械表型，并通过rhoa依赖机制驱动组织紊乱、结节形成和促钙化信号。
Valve interstitial cells are active and aggressive players in aortic valve calcification, but their dynamic mediation of mechanically-induced calcific remodeling is not well understood. The goal of this study was to elucidate the feedback loop between valve interstitial cell and calcification mechanics using a novel three-dimensional culture system that allows investigation of the active interplay between cells, disease, and the mechanical valve environment. We designed and characterized a novel bioreactor system for quantifying aortic valve interstitial cell contractility in 3-D hydrogels in control and osteogenic conditions over 14 days. Interstitial cells demonstrated a marked ability to exert contractile force on their environment and to align collagen fibers with the direction of tension. Osteogenic environment disrupted interstitial cell contractility and led to disorganization of the collagen matrix, concurrent with increased αSMA, TGF-β, Runx2 and calcific nodule formation. Interestingly, RhoA was also increased in osteogenic condition, pointing to an aberrant hyperactivation of valve interstitial cells mechanical activity in disease. This was confirmed by inhibition of RhoA experiments. Inhibition of RhoA concurrent with osteogenic treatment reduced pro-osteogenic signaling and calcific nodule formation. Time-course correlation analysis indicated a significant correlation between interstitial cell remodeling of collagen fibers and calcification events. Interstitial cell contractility mediates internal stress state and organization of the aortic valve extracellular matrix. Osteogenesis disrupts interstitial cell mechanical phenotype and drives disorganization, nodule formation, and pro-calcific signaling via a RhoA-dependent mechanism.
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