Merryman W David, Liao Jun, Parekh Aron, Candiello Joseph E, Lin Hai, Sacks Michael S
Engineered Tissue Mechanics and Mechanobiology Laboratory, Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
Tissue Eng. 2007 Sep;13(9):2281-9. doi: 10.1089/ten.2006.0324.
Heart valve interstitial cells (VICs) appear to have a dynamic and reversible phenotype, an attribute speculated to be necessary for valve tissue remodeling during times of development and repair. Therefore, we hypothesized that the cytoskeletal (CSK) remodeling capability of the aortic and pulmonary VICs (AVICs and PVICs, respectively), which are dominated by smooth muscle alpha-actin, would exhibit unique contractile behaviors when seeded on collagen gels. Using a porcine cell source, we observed that VIC populations did not contract the gels at early time points (2 and 4 hours) as dermal fibroblasts did, but formed a central cluster of cells prior to contraction. After clustering, VICs appeared to radiate out from the center of the gels, whereas fibroblasts did not migrate but contracted the gels locally. VIC gels treated with transforming growth factor beta1 contracted the gels rapidly, revealing similar sensitivity to the cytokine. Moreover, we evaluated the initial mechanical state of the underlying CSK by comparing AVIC and PVIC stiffness with atomic force microscopy. Not only were AVICs significantly stiffer (p < 0.001) than the PVICs, but they also contracted the gels significantly more at 24 and 48 hours (p < 0.001). Taken together, these findings suggest that the AVICs are capable of inducing greater extra cellular matrix contraction, possibly manifesting in a more pronounced ability to remodel valvular tissues. Moreover, significant mechanobiological differences between AVICs and PVICs exist, and may have implications for understanding native valvular tissue remodeling. Elucidating these differences will also define important functional endpoints in the development of tissue engineering approaches for heart valve repair and replacement.
心脏瓣膜间质细胞（VICs）似乎具有动态且可逆的表型，据推测这一特性对于发育和修复期间的瓣膜组织重塑是必要的。因此，我们假设以平滑肌α - 肌动蛋白为主的主动脉和肺动脉VICs（分别为AVICs和PVICs）的细胞骨架（CSK）重塑能力，在接种于胶原凝胶时会表现出独特的收缩行为。使用猪细胞来源，我们观察到VIC群体在早期时间点（2小时和4小时）不像真皮成纤维细胞那样使凝胶收缩，而是在收缩前形成细胞中央簇。聚集后，VICs似乎从凝胶中心向外辐射，而成纤维细胞不迁移但在局部使凝胶收缩。用转化生长因子β1处理的VIC凝胶迅速使凝胶收缩，显示出对该细胞因子的类似敏感性。此外，我们通过原子力显微镜比较AVIC和PVIC的硬度来评估潜在CSK的初始机械状态。不仅AVICs比PVICs明显更硬（p < 0.001），而且它们在24小时和48小时时使凝胶收缩得也明显更多（p < 0.001）。综上所述，这些发现表明AVICs能够诱导更大程度的细胞外基质收缩，可能表现为更显著的瓣膜组织重塑能力。此外，AVICs和PVICs之间存在显著的机械生物学差异，这可能对理解天然瓣膜组织重塑有影响。阐明这些差异也将为心脏瓣膜修复和置换的组织工程方法的开发确定重要的功能终点。
