Modulation of MSC Differentiation for Fibrocartilage Tissue Engineering

纤维软骨组织工程中 MSC 分化的调节

基本信息

批准号：
7895815
负责人：
MARC Elliot LEVENSTON
金额：
$ 36万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895815
关键词：
Address Biochemical Biomechanics Cartilage Cell Differentiation process Cells Cellular Morphology Characteristics Chondrocytes Chondrogenesis Collagen Collagen Gene Collagen Type I Complex Core Protein Cues Degenerative polyarthritis Development Dexamethasone Engineering Environment Excision Extracellular Matrix Fetal Movement Fibrin Fibroblasts Fibrocartilages Functional disorder Future Gene Expression Genes Goals Heterogeneity Hour Human In Vitro Investigation Joints Ligaments Measurement Mechanical Stimulation Mechanics Meniscus structure of joint Mesenchymal Stem Cells Messenger RNA Musculoskeletal System Outcome Outcome Measure Pattern Phenotype Production Property Protein Biosynthesis Proteins Role Serum Stem cells Stimulus Structure Structure of articular disc of temporomandibular joint Tendon structure Testing Time Tissue Engineering Tissues Work aggrecan articular cartilage biglycan cartilage repair cell behavior cell type decorin experience fetal bovine serum fibrogenesis improved in vivo novel strategies polysulfated glycosaminoglycan preconditioning public health relevance repaired response stem cell differentiation versican

项目摘要

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.

描述（由申请人提供）：在功能载荷期间，在整个肌肉骨骼系统中都发现了纤维状软骨组织。这些组织具有高度组织的异质结构，非常适合其机械功能。像关节软骨一样，纤维球杆菌的内在修复能力较差，损害或降解通常会导致早期的骨关节炎或关节功能障碍。组织工程提供了通过生物学和机械功能替代品治疗受损或患病的纤维球固醇的潜力。但是，为了使这种成功的方法成功，必须制定策略，以最终通过细胞表型和ECM组织产生工程替代，能够在天然组织的复杂且苛刻的机械环境中生存和运作。从纤维球发展中获取线索，我们认为，可以将生化和生物力学环境的协调操作作为指导使用适当的细胞和基质成分形成纤维球纤维替代物的策略的一部分。具体而言，我们建议振荡性压缩将充当软骨刺激，而振荡性张力将充当纤维化刺激，并且每个刺激都可以调节MSC分化。这些机械刺激与促进软骨形成或纤维化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。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地调节分化人类MSC的细胞活性。 2）持续的振荡压缩和张力将差异改变人类MSC分化，构建组成和机械性能。 3）机械刺激对人MSC的影响将持续存在，而无需谱系特异性的机械或生化刺激。该提案的成功完成将提供对指导人类MSC分化的张力和压缩作用的基本理解，并允许制定涉及空间变化的刺激的新型策略，以产生工程的纤维电替代原替换剂控制的空间异质性。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拟象等组织发展的理解。这将有助于开发功能性组织工程的替代品，并可能有助于理解为什么特定的软骨修复方法成功或失败。