Synthetic Mesenchymal Stem Cell Niches for Vascular Therapy

描述(申请人提供)：动脉或微血管功能的丧失，由于疾病，如动脉粥样硬化、外周动脉疾病或缺血，在美国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)治疗，它具有再生血管的潜力，并使血管疾病的治疗发生革命性变化。然而，基于MSC的血管治疗结果并不一致，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定义不明确的细胞环境，这最终决定了治疗过程中MSC的命运。为了实现成功的基于MSC的血管治疗，必须解决几个悬而未决的问题：(A)亚优化的MSC环境导致混合细胞群体的血管特异性或信号转导低；(B)对于多因素环境如何决定MSC在体内的命运缺乏机械性了解；以及(C)可用于将体外细胞分化为体内血管治疗的平台技术有限。为了解决这些知识空白，这项建议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，以便使MSCs在血管治疗中保持高度特异和成熟的血管分化。我们的假设是，模拟血管的机械和生化环境为MSCs提供协同信号，在体外和体内的生理条件下维持血管再生。为了实现我们的假设，我们将采取一种创新的方法，开发具有独立调节的微环境因素的3D纳米纤维壁龛，即基质刚性、配体和细胞因子，以优化血管细胞再生，并将这些不同的壁龛整合到具有时空控制的移植物支架中，以在生理流动下进行评估。这种方法建立在我们团队的生物材料能力的基础上，即生产具有受控刚性、蛋白质的各向异性和时空释放以及配体掺入的纳米纤维材料。这里提出了三个目标：目标1专注于合理设计用于血管分化的3D合成生态位矩阵的MSC-基质相互作用机制；目的2试图定义融合机械力化学信号以优化血管再生的合成生态位；以及目的3整合和评估合成生态位与血管移植，以证明可行性并为未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、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特定用途的血管微生理系统的长期目标，该系统可以预测、改进和优化基于细胞的血管治疗。

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.