Synthetic Mesenchymal Stem Cell Niches for Vascular Therapy

用于血管治疗的合成间充质干细胞生态位

• 批准号: 8883699
• 负责人: Wei Tan
• 金额: $ 36.03万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883699
• 关键词: Accounting; Address; Anisotropy; Arteries; Atherosclerosis; Biochemical; Biocompatible Materials; Biological; Blood Vessels; Cell Adhesion; Cell Adhesion Molecules; Cell Differentiation process; Cell secretion; Cell-Matrix Junction; Cells; Chemicals; Chemistry; Clinic; Clinical; Coculture Techniques; Disease; Environment; Environmental Risk Factor; Evaluation; Feedback; Fibrosis; Figs - dietary; Future; Gel; Goals; Growth Factor; Health; Hydrogels; In Vitro; Individual; Interdisciplinary Study; Ischemia; Knowledge; Lead; Ligands; Mechanics; Mesenchymal Stem Cells; Modeling; Morbidity - disease rate; Names; Natural regeneration; Outcome; Peptides; Peripheral arterial disease; Phenotype; Physiological; Population; Proteins; Receptor Cell; Regulation; Reporting; Sheep; Signal Transduction; Signaling Molecule; Solutions; Specificity; Stenosis; System; Technology; Therapeutic; Tissue Engineering; Tissues; Translations; Treatment Efficacy; Vascular Diseases; Vascular Graft; base; blood perfusion; cytokine; density; design; functional loss; improved; in vivo; innovation; loss of function; mimetics; mortality; nanofiber; paracrine; scaffold; spatiotemporal; stem cell differentiation; stem cell fate; stem cell niche; stem cell therapy; synergism

DESCRIPTION (provided by applicant): Loss of function to arteries or the microvasculature, due to diseases such as atherosclerosis, peripheral artery diseases or ischemia, contributes to high morbidity and high mortality in the U.S. An emerging solution is mesenchymal stem cell (MSC) therapy, which has the potential to regenerate blood vessels and revolutionize the treatment of vascular diseases. However, results from MSC-based vascular therapies have been inconsistent, and worse, some studies have reported vascular dysfunction. These therapeutic outcomes are, at least in part, attributable to an ill-defined cell environment, which ultimately regulates MSC fate during therapy. To achieve successful MSC-based vascular therapy, several unresolved issues must be addressed: (a) suboptimal MSC environments that result in a mixed cell populations with low vascular specificity or signaling; (b) lack of mechanistic understandings as to how multifactorial environments determine MSC fate in vivo; and (c) limited platform technologies available for the translation of in vitro cell differentiatio environments to in vivo vascular therapies. To address these knowledge gaps, the overall goal of this proposal is to establish a comprehensive platform that recapitulates the synergism of the physical and biochemical environments in normal vascular tissues in order to perpetuate highly specific and mature vascular differentiation of MSCs for vascular therapy. Our hypothesis is that vessel-mimetic mechanical and biochemical environments provide synergistic signaling to MSCs, perpetuating vascular regeneration under physiological conditions in vitro and in vivo. To pursue our hypothesis, we will take an innovative approach by developing 3D nanofibrous niches with independently modulated microenvironment factors, i.e. matrix rigidity, ligand and cytokine, to optimize vascular cell regeneration, and incorporating these distinct niches into a graft scaffold with spatiotemporal control for evaluation under physiological flow. This approach is built on our team's biomaterial capabilities of producing nanofibrous materials with controlled rigidity, anisotropy and spatiotemporal release of proteins, and ligand incorporation. Three aims are proposed here: AIM 1 focuses on MSC-matrix interaction mechanisms underlying the rational design of 3D synthetic niche matrices for vascular differentiation; AIM 2 seeks to define synthetic niches that converge mechano-chemical signaling for optimal vascular regeneration; and AIM 3 integrates and evaluates synthetic niches with vascular grafts to demonstrate feasibility and provide critical feedback for future design and clinical translation. This new interdisciplinary study, combining biomaterials, cell signaling, vascular mechanobiology and tissue engineering, if successful, will help to accomplish our long-term goal of designing application-specific vascular microphysiological systems that can predict, improve and optimize cell-based vascular therapy.

描述（由申请人提供）：在美国，由于诸如动脉粥样硬化、外周动脉疾病或缺血的疾病导致的动脉或微血管系统功能的丧失导致高发病率和高死亡率。一种新兴的解决方案是间充质干细胞（MSC）疗法，其具有再生血管和彻底改变血管疾病治疗的潜力。然而，基于MSC的血管治疗的结果并不一致，更糟糕的是，一些研究报告了血管功能障碍。这些治疗结果至少部分归因于不明确的细胞环境，其最终在治疗期间调节MSC的命运。为了实现成功的基于MSC的血管治疗，必须解决几个未解决的问题：（a）次优的MSC环境，其导致具有低血管特异性或信号传导的混合细胞群;（B）缺乏关于多因素环境如何决定MSC在体内命运的机制理解;以及（c）有限的平台技术可用于将体外细胞分化环境转化为体内血管治疗。为了解决这些知识差距，本提案的总体目标是建立一个全面的平台，概括正常血管组织中物理和生化环境的协同作用，以使MSC的高度特异性和成熟的血管分化永久化，用于血管治疗。我们的假设是，血管模拟的机械和生物化学环境提供协同信号的MSC，在体外和体内的生理条件下，永久的血管再生。为了实现我们的假设，我们将采取一种创新的方法，通过开发具有独立调节的微环境因素（即基质刚性，配体和细胞因子）的3D纳米纤维壁龛来优化血管细胞再生，并将这些不同的壁龛纳入具有时空控制的移植物支架中，以在生理流动下进行评估。这种方法是建立在我们团队的生物材料能力，生产纳米纤维材料与控制刚度，各向异性和时空释放的蛋白质，配体掺入。在此提出三个目标：AIM 1侧重于MSC-基质相互作用机制，这些机制是用于血管分化的3D合成生态位基质的合理设计的基础; AIM 2旨在定义聚合机械化学信号以实现最佳血管再生的合成生态位; AIM 3整合并评估合成生态位与血管移植物，以证明可行性并为未来设计和临床转化提供关键反馈。这项新的跨学科研究结合了生物材料、细胞信号传导、血管机械生物学和组织工程，如果成功，将有助于实现我们的长期目标，即设计能够预测、改善和优化基于细胞的血管治疗的应用特定的血管微生理系统。