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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(申请人提供)：纤维软骨组织遍布肌肉骨骼系统，在功能性负荷过程中承受相当程度的拉伸和压缩。这些组织具有高度组织化的异质结构，非常适合它们的机械功能。与关节软骨一样，纤维软骨的固有修复能力较差，损伤或退化往往会导致早期骨关节炎或关节功能障碍。组织工程学为治疗受损或疾病的纤维软骨提供了生物和机械功能替代的可能性。然而，为了使这种方法成功，必须制定策略，最终产生具有细胞表型和ECM组织的工程化替代材料，能够在复杂和苛刻的自然组织机械环境中生存和发挥作用。以纤维软骨发育为线索，我们认为，生物化学和生物力学环境的协调操作可以作为指导具有适当细胞和基质成分的纤维软骨替代物形成的策略的一部分。具体地说，我们认为振荡压缩将作为软骨源性刺激，而振荡张力将作为纤维化刺激，并且两者都能够调节MSC的分化。这些机械刺激与促进成软骨或成纤维分化的特定生化因素相结合，将产生成纤维细胞、软骨细胞和纤维软骨细胞特有的一系列细胞表型。将检验以下三个假说：1)短时间振荡压缩和拉伸将不同程度地调节分化为人MSCs的细胞活性。2)持续的振荡压缩和拉伸将不同程度地改变人MSC的分化、结构组成和力学性能。3)机械刺激对人MSCs的影响在没有谱系特异性机械刺激或生化刺激的情况下将持续存在。该提案的成功完成将使我们对拉伸和压缩在引导人类MSC分化中的作用有一个基本的了解，并将允许开发涉及空间变化刺激的新策略，以生产可控制空间异质性的工程化纤维软骨替代物。公共卫生相关性：这些研究将加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。这将有助于功能性组织工程化替代物的开发，并可能有助于理解软骨修复的特定方法成功或失败的原因。