Developing Biomaterial Scaffolds That Delay Senescence in Mesenchymal Stem Cells

开发延迟间充质干细胞衰老的生物材料支架

• 批准号: 7675417
• 负责人: Amanda R Murphy
• 金额: $ 0.72万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675417
• 关键词: Address; Adhesions; Adult; Age; Aging-Related Process; Amino Acids; Ascorbic Acid; Biocompatible Materials; Bone Marrow; Cartilage; Cell Adhesion; Cell Communication; Cell Culture Techniques; Cell Therapy; Cell division; Cell physiology; Cells; Chemicals; Clinical; Collagen; Devices; Extracellular Matrix; Extracellular Matrix Proteins; Fibroins; Frequencies; Generations; Glutamic Acid; Goals; Growth; In Vitro; Integrins; Ligaments; Ligand Binding; Longevity; Mechanics; Mesenchymal Stem Cells; Methods; Modification; Monitor; Morphology; Muscle; Peptides; Process; Production; Property; Proteins; Public Health; Reaction; Role; Scaffolding Protein; Signal Transduction; Signaling Molecule; Silk; Site-Directed Mutagenesis; Spatial Distribution; Stem cells; Structure; Telomerase; Tissue Engineering; Tissue Expansion; Translating; Tyrosine; Work; biomaterial compatibility; bone; cell behavior; clinical efficacy; density; design; embryonic stem cell; osteogenic; prevent; regenerative therapy; scaffold; senescence; stem cell therapy; telomere; three dimensional structure

DESCRIPTION (provided by applicant): Adult mesenchymal stem cells (MSCs) offer enormous potential for regenerative therapies, but occur in low frequency in bone marrow, lack the ability to continuously divide under traditional ex vivo tissue expansion methods and eventually lose their differentiation potential. These factors limit the clinical efficacy of MSC therapies. The most promising approach to extend the expansion potential of MSCs in vitro is the cultivation of cells on extracellular matrix (ECM) proteins, where integrin-ligand binding between cells and the ECM are known to activate cellular processes such as proliferation, differentiation, and survival. Our objectives are to translate what is known about the role of ECM/MSC interactions in the aging process into a new generation of scaffold designs containing the appropriate chemical signals and physical features capable of regulating stem cell behavior. For this work, silk fibroin proteins will be used as a biomaterial scaffold onto which a variety of signaling molecules will be incorporated. Specific targets include cell adhesion peptides derived from collagen, and factors that activate telomerase to extend telomeres during cell division thus prolonging the life span of the cell. The chemical signaling identity and density of the peptide displays on the 3D silk scaffolds will be optimized independently in order to decouple and isolate the effects on aging of MSCs. In depth chemical and physical characterization of these modified scaffolds, and the morphology, growth rate, differentiation potential, and production of ECM proteins by the MSCs expanded on these modified 3D scaffolds will be studied and quantified along with appropriate controls. Osteogenic markers of MSCs expanded on these scaffolds will be monitored and compared to ascribe changes in cell behavior to the matrix composition. The goal of developing cell culture scaffolds that can delay senescence of MSCs to prolong their proliferative lifetimes would allow for long-term expansion of the cells ex vivo, enabling clinical use of MSCs in a broad range of cell therapies and tissue-engineered devices. Relevance to public health: Adult mesenchymal stem cells (MSCs) offer enormous potential for bone, cartilage, muscle and ligament regenerative therapies, and are easily obtained from adult bone marrow which avoids the embryonic stem cell controversy. Therefore, this project aims to address some of the clinical limitations of MSCs that currently prevent their use in cell therapies and tissue-engineered devices. Specifically, our goals are to delay the aging process in MSCs cultured ex vivo.

描述（由申请人提供）：成体间充质干细胞（MSC）为再生疗法提供了巨大的潜力，但在骨髓中出现频率低，在传统的离体组织扩张方法下缺乏连续分裂的能力，最终失去其分化潜力。这些因素限制了MSC疗法的临床疗效。在体外扩展MSC的扩增潜力的最有希望的方法是在细胞外基质（ECM）蛋白上培养细胞，其中已知细胞和ECM之间的整合素-配体结合激活细胞过程，如增殖、分化和存活。我们的目标是将已知的ECM/MSC相互作用在衰老过程中的作用转化为新一代支架设计，其中包含能够调节干细胞行为的适当化学信号和物理特征。在这项工作中，丝素蛋白将被用作生物材料支架，在其上将掺入各种信号分子。特异性靶点包括来源于胶原蛋白的细胞粘附肽，以及在细胞分裂期间激活端粒酶以延长端粒从而延长细胞寿命的因子。在3D丝支架上展示的肽的化学信号传导特性和密度将被独立地优化，以解耦和隔离对MSC老化的影响。将深入研究这些修饰的支架的化学和物理表征，以及在这些修饰的3D支架上扩增的MSC的形态、生长速率、分化潜力和ECM蛋白的产生，并与适当的对照一起沿着定量。将监测并比较在这些支架上扩增的MSC的成骨标志物，以将细胞行为的变化归因于基质组成。开发可以延迟MSC衰老以延长其增殖寿命的细胞培养支架的目标将允许细胞的离体长期扩增，使得MSC能够在广泛的细胞疗法和组织工程化装置中临床使用。与公共卫生的相关性：成体间充质干细胞（MSC）为骨、软骨、肌肉和韧带再生治疗提供了巨大的潜力，并且容易从成体骨髓中获得，避免了胚胎干细胞的争议。因此，该项目旨在解决目前阻止其用于细胞疗法和组织工程装置的MSC的一些临床局限性。具体来说，我们的目标是延缓离体培养的MSC的衰老过程。