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

基本信息

批准号：
9306175
负责人：
Wei Tan
金额：
$ 37.08万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306175
关键词：
Address Anisotropy Arteries Atherosclerosis Biochemical Biocompatible Materials Biological Blood Vessels Cell Adhesion Cell Adhesion Molecules Cell Differentiation process Cell Therapy Cell secretion Cell-Matrix Junction Cells Chemicals Chemistry Clinic Coculture Techniques Disease Environment Environmental Risk Factor Evaluation Feedback Fibrinogen Fibrosis Future Gel Goals Growth Factor Hydrogels In Vitro Individual Interdisciplinary Study Ischemia Knowledge Lead Ligands Mechanics Mesenchymal Differentiation Mesenchymal Stem Cells Modeling Morbidity - disease rate Names Natural regeneration Peptides Peripheral arterial disease Phenotype Physiological Population Proteins Receptor Cell Regulation Reporting Sheep Signal Transduction Signaling Molecule Specificity Stenosis System Technology Tissue Engineering Tissues Translations Treatment Efficacy Vascular Diseases Vascular Graft base blood perfusion clinical translation cytokine density design functional loss improved in vivo innovation loss of function mechanotransduction mimetics mortality nanofiber paracrine public health relevance scaffold spatiotemporal stem cell therapy synergism therapy outcome

项目摘要

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）：由于动脉粥样硬化，外周动脉疾病或缺血等疾病而导致动脉或微瘤功能的丧失，这导致了美国的高发病率和高死亡率，这是一种新兴的溶液是间质干细胞（MSC）疗法（MSC）疗法，其潜在的治疗症治疗了血液和疾病的可能性。但是，基于MSC的血管疗法的结果并不一致，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未定义的细胞环境，这最终在治疗过程中调节了MSC的命运。为了实现成功的基于MSC的血管疗法，必须解决几个未解决的问题：（a）次优MSC环境，导致具有低血管特异性或信号传导的混合细胞群体；（b）缺乏关于多因素环境如何确定体内MSC命运的理解；（c）有限的平台技术可用于将体外细胞区分环境转换为体内血管疗法。为了解决这些知识差距，该提案的总体目标是建立一个全面的平台，该平台概括了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血管治疗。我们的假设是，血管模仿机械和生化环境为MSC提供了协同信号，在体外和体内生理条件下的血管再生延续。为了提出我们的假设，我们将通过开发具有独立调制的微环境因素的3D纳米纤维壁ni，即基质刚度，配体和细胞因子，以优化血管细胞再生，并将这些独特的壁细胞生成纳入与Spatiotal Emporal Control Incesluation Phromenticagiation frolperuation。这种方法建立在我们团队的生物材料能力上，该能力可生产具有刚性，各向异性和蛋白质时空释放以及配体掺入的纳米纤维材料。这里提出了三个目的：目标1的重点是3D合成小裂矩阵用于血管分化的理性设计的基础的MSC-Matrix相互作用机制； AIM 2旨在定义合成生态位，以收敛机械化学信号传导以进行最佳的血管再生； AIM 3将合成生态位与血管移植物相结合和评估，以证明可行性，并为将来的设计和临床翻译提供关键的反馈。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），将有助于实现我们设计应用特定的血管微生物生理系统的长期目标，这些系统可以预测，改善和优化基于细胞的血管治疗。