Modulation of MSC Differentiation for Fibrocartilage Tissue Engineering

描述（由申请人提供）：纤维软骨组织见于整个肌肉骨骼系统中在功能负荷期间经历大量拉伸和压缩的区域。这些组织具有高度组织化的异质结构，非常适合其机械功能。像关节软骨一样，纤维软骨具有较差的内在修复能力，并且损伤或降解通常导致早期骨关节炎或关节功能障碍。组织工程提供了潜在的治疗损伤或患病的纤维软骨生物和机械功能的替代品。然而，为了使这种方法取得成功，必须制定策略，最终产生具有细胞表型和ECM组织的工程替代品，能够在天然组织复杂且要求严格的机械环境中生存和发挥作用。从纤维软骨发育的线索，我们认为，协调的生化和生物力学环境的操作可以作为一种策略的一部分，以指导形成纤维软骨替代适当的细胞和基质成分。具体而言，我们建议，振荡压缩将作为软骨形成刺激，而振荡张力将作为纤维形成刺激，并且每个都能够调节MSC分化。这些机械刺激与促进软骨形成或纤维形成分化的特定生化因子的组合将产生成纤维细胞、软骨细胞和纤维软骨细胞的一系列细胞表型特征。将测试以下三个假设：1）短持续时间振荡压缩和张力将差异性地调节分化中的人MSC的细胞活性。2)持续的振荡压缩和拉伸将差异性地改变人MSC分化、构建体组成和机械性质。3)机械刺激对人MSC的影响将在没有谱系特异性机械或生物化学刺激的情况下持续存在。成功完成这一建议将提供一个基本的理解的作用，在指导人类MSC分化的张力和压缩，并将允许开发新的策略，涉及空间变化的刺激，以产生工程化的纤维软骨替代控制的空间异质性。 公共卫生相关性：这些研究将增强我们对机械负荷如何影响软骨和半月板等组织发育的理解。这将有助于开发功能性组织工程替代品，并有助于理解为什么特定的软骨修复方法成功或失败。

DESCRIPTION (provided by applicant): Fibrocartilaginous tissues are found throughout the musculoskeletal system in regions experiencing substantial levels of both tension and compression during functional loading. These tissues have highly organized, heterogeneous structures that are well suited for their mechanical functions. Like articular cartilage, fibrocartilage has a poor intrinsic repair capacity, and damage or degradation often leads to early osteoarthritis or joint dysfunction. Tissue engineering offers the potential to treat damaged or diseased fibrocartilages with biologically and mechanically functional replacements. In order for such an approach to be successful, however, strategies must be developed that ultimately produce an engineered replacement with cell phenotypes and ECM organization capable of surviving and functioning in the complex and demanding mechanical environment of the native tissue. Taking cues from fibrocartilage development, we believe that coordinated manipulation of the biochemical and biomechanical environment can be employed as part of a strategy to guide the formation of fibrocartilage replacements with appropriate cell and matrix constituents. Specifically, we propose that oscillatory compression will act as a chondrogenic stimulus while oscillatory tension will act as a fibrogenic stimulus, and that each is capable of modulating MSC differentiation. Combinations of these mechanical stimuli with specific biochemical factors promoting chondrogenic or fibrogenic differentiation will produce a range of cell phenotypes characteristic of fibroblasts, chondrocytes, and fibrochondrocytes. The following three hypotheses will be tested: 1) Short duration oscillatory compression and tension will differentially modulate cellular activity of differentiating human MSCs. 2) Sustained oscillatory compression and tension will differentially alter human MSC differentiation, construct composition and mechanical properties. 3) Effects of mechanical stimulation on human MSCs will persist without lineage-specific mechanical or biochemical stimulation. Successful completion of this proposal will provide a fundamental understanding of the role for tension and compression in guiding human MSC differentiation, and will allow the development of novel strategies involving spatially varying stimuli to produce engineered fibrocartilage replacements controlled spatial heterogeneity. PUBLIC HEALTH RELEVANCE: These studies will enhance our understanding of how mechanical loading influences the development of tissues such as cartilage and meniscus. This will aid in the development of functional tissue engineered replacements and may aid in understanding why particular approaches to cartilage repair succeed or fail.