Role of matrix shear stress in annulus fibrosus cell mechanobiology

基质剪切应力在纤维环细胞力学生物学中的作用

• 批准号: 8230610
• 负责人: Adam H. Hsieh
• 金额: $ 16.41万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-17 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230610
• 关键词: Anatomy; Animal Model; Animals; Architecture; Cell Culture Techniques; Cell physiology; Cells; Collagen; Collagen Fibril; Collagen Type I; Complex; Computer Simulation; Confocal Microscopy; Cues; Development; Disease; Elements; Embryo; Environment; Exhibits; Exposure to; Extracellular Matrix; Fibrillar Collagen; Film; Gel; Gene Expression; General Population; Homeostasis; Human; Imaging Techniques; In Situ; In Vitro; Injury; Intervertebral disc structure; Knowledge; Literature; Maintenance; Maps; Mechanical Stress; Mechanics; Microscopy; Modeling; Molecular; Molecular Profiling; Motion; Optical Coherence Tomography; Outcome; Phenotype; Physiological; Play; Population; Prevention therapy; Publishing; Radial; Regulation; Relative (related person); Reporting; Research; Resolution; Role; Simulate; Slide; Stimulus; Stress; Structure; System; Testing; Tissues; Translating; United States; Variant; base; cell growth regulation; experience; in vivo; insight; interfacial; intervertebral disk degeneration; novel; progenitor; programs; public health relevance; regenerative; repaired; response; scaffold; shear stress; spatial temporal variation

DESCRIPTION (provided by applicant): Degenerative disc disease (DDD) continues to be a burden on the general population and economy both in the United States and worldwide. There is strong evidence from the literature that indicate that mechanical stress plays a role in the progression of DDD. However, the complex lamellar architecture of the disc and the zonal variation in cell phenotype have made it difficult to translate tissue level mechanics to the cellular micromechanical environment, which governs intervertebral disc (IVD) cell function. Understanding how cells respond to stimuli that can be characterized in detail is important for developing repair strategies where scaffolds can be tailored to provide the appropriate micromechanical cues. Based on observations from our previous animal studies and recently reported descriptions of the interlamellar (IL) matrix in normal and degenerate annulus fibrosus (AF), we have developed an hypothesis on the regulation of the IL space by mechanical stress. This central hypothesis states that radial and shear stress coordinately modulate the IL matrix through mechanoregulation of AF cells. In order to provide cells with both radial and shear stimuli in a uniform micromechanical environment, we propose to implement a novel collagen interface cell culture model. Cells will be cultured and deformed between a fibrillar collagen thin film (CTF) that mimics the microfibrillar structure of the IL matrix and its type-matched collagen gel. Using this interface culture model, Aim 1 will determine how AF cells respond to macrostructural shear. Specifically, it will characterize zonal- and substrate-dependent deformation of inner and outer AF cells, and investigate whether intrinsic or structural factors dominate their responses. In Aim 2, our hypothetical mechanobiologic model of AF cell regulation by radial and shear stress will be tested using the interface culture model. A range of tension-compression stress and shear strain will be studied in the context of the healthy IL compartment. In parallel, a novel finite element model that explicitly incorporates an IL compartment will be developed, validated using optical coherence tomography, and implemented to predict the shear environment for IL cells. The mechanobiologic response obtained experimentally can then be spatially "mapped" to corresponding shear regions. PUBLIC HEALTH RELEVANCE: There is substantial evidence that matrix shear stresses are generated in the intervertebral disc, related to injury and degeneration. Results of this project will provide detailed insight into the effects of mechanical shear stresses on cell function. Such knowledge can aid the development of regenerative strategies against disorders such as degenerative disc disease.

描述(由申请人提供)：退行性间盘疾病(DDD)在美国和世界范围内仍然是普通人口和经济的负担。从文献中有强有力的证据表明，机械应力在DDD的进展中起着作用。然而，椎间盘的复杂板层结构和细胞表型的带状变化使得将组织水平的力学转化为细胞微机械环境变得困难，而细胞微机械环境控制着椎间盘(IVD)的细胞功能。了解细胞对可以详细描述的刺激的反应对于制定修复策略非常重要，在修复策略中，可以定制支架以提供适当的微机械线索。根据我们以前的动物研究和最近报道的对正常和退变纤维环中板层间基质(IL)基质的描述，我们提出了一个关于机械应力对IL间隙的调节的假说。这一中心假设认为，径向应力和剪切力通过对房颤细胞的机械调节来协调调节IL基质。为了在均匀的微观力学环境中为细胞提供径向和剪切刺激，我们提出了一种新的胶原界面细胞培养模型。细胞将在模仿IL基质微纤维结构的纤维状胶原薄膜(CTF)及其类型匹配的胶原凝胶之间进行培养和变形。使用这个界面培养模型，Aim 1将确定房颤细胞如何对宏观结构剪切做出反应。具体地说，它将表征内、外房颤细胞的带状和底物相关的变形，并研究内在因素或结构因素是否主导它们的反应。在目标2中，我们假设的径向和剪切应力调节房颤细胞的机制生物学模型将使用界面培养模型进行验证。一系列的拉伸-压缩应力和剪切应变将在健康的IL间隔室中进行研究。同时，将开发一种新的有限元模型，该模型明确包含一个IL隔室，使用光学相干断层扫描进行验证，并用于预测IL细胞的剪切环境。然后，通过实验获得的机械生物响应可以被空间“映射”到相应的剪切区。 与公众健康相关：有大量证据表明，基质剪应力在椎间盘中产生，与损伤和退变有关。该项目的结果将为深入了解机械剪切应力对细胞功能的影响提供详细的见解。这些知识可以帮助制定针对退行性腰椎间盘疾病等疾病的再生策略。

项目成果

Three dimensional mesoscale analysis of translamellar cross-bridge morphologies in the annulus fibrosus using optical coherence tomography.

• DOI: 10.1002/jor.22778
• 发表时间: 2015-03
• 期刊: JOURNAL OF ORTHOPAEDIC RESEARCH
• 影响因子: 2.8
• 作者: Han, Sang Kuy;Chen, Chao-Wei;Wierwille, Jerry;Chen, Yu;Hsieh, Adam H.
• 通讯作者: Hsieh, Adam H.