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Mitral valvular interstitial cell responses to substrate stiffness depend on age and anatomic region.

机译:二尖瓣间质细胞对基质硬度的反应取决于年龄和解剖区域。

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摘要

The material properties of heart valves depend on the subject's age, the state of the disease and the complex valvular microarchitecture. Furthermore, valvular interstitial cells (VICs) are mechanosensitive, and their synthesis of extracellular matrix not only determines the valve's material properties but also provides an adhesive substrate for VICs. However, the interrelationship between substrate stiffness and VIC phenotype and synthetic properties is poorly understood. Given that the local mechanical environment (substrate stiffness) surrounding VICs differs among different age groups and different anatomic regions of the valve, it was hypothesized that there may be an age- and valve-region-specific response of VICs to substrate stiffness. Therefore, 6-week-, 6-month- and 6-year-old porcine VICs from the center of the mitral valve anterior leaflet (MVAC) and posterior leaflet (PML) were seeded onto poly(ethylene) glycol hydrogels of different stiffnesses and stained for markers of VIC activation (smooth muscle alpha-actin (SMaA)) and collagen synthesis (heat shock protein-47 (HSP47), prolyl 4-hydroxylase (P4H)). Six-week-old MVAC demonstrated decreased SMaA, P4H and HSP47 on stiffer gels, while 6-week-old PML only demonstrated decreased HSP47. Six-month-old MVAC demonstrated no difference between substrates, while 6-month-old PML demonstrated decreased SMaA, P4H and HSP47. Six-year-old MVAC demonstrated decreased P4H and HSP47, while 6-year-old PML demonstrated decreased P4H and increased HSP47. In conclusion, the age-specific and valve-region-specific responses of VICs to substrate stiffness link VIC phenotype to the leaflet regional matrix in which the VICs reside. These data provide further rationale for investigating the role of substrate stiffness in VIC remodeling within diseased and tissue engineered valves.
机译:心脏瓣膜的材料特性取决于受试者的年龄,疾病状态和复杂的瓣膜微结构。此外,瓣膜间质细胞(VIC)具有机械敏感性,其细胞外基质的合成不仅决定了瓣膜的材料特性,而且还为VIC提供了粘性基质。但是,对底物刚度和VIC表型与合成性能之间的相互关系了解得很少。鉴于围绕VIC的局部机械环境(基底刚度)在不同年龄组和瓣膜的不同解剖区域之间是不同的,因此假设VIC对基底刚度可能存在特定于年龄和瓣膜区域的响应。因此,将来自二尖瓣前小叶(MVAC)和后小叶(PML)中心的6周,6个月和6岁的猪VIC接种到不同刚度和不同强度的聚乙二醇水凝胶上。对VIC活化(平滑肌α-肌动蛋白(SMaA))和胶原蛋白合成(热休克蛋白-47(HSP47),脯氨酰4-羟化酶(P4H))的标记进行染色。六周龄的MVAC在较硬的凝胶上显示SMaA,P4H和HSP47降低,而六周龄的PML仅显示HSP47下降。六个月大的MVAC显示底物之间没有差异,而六个月大的PML显示SMaA,P4H和HSP47降低。 6岁的MVAC显示P4H和HSP47降低,而6岁的PML显示P4H和HSP47降低。总之,VIC对基质刚度的年龄特异性和瓣膜区域特异性响应将VIC表型与VIC所在的小叶区域矩阵联系起来。这些数据为研究底物刚度在患病和组织工程瓣膜的VIC重塑中的作用提供了进一步的理论依据。

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