Synthetic Mesenchymal Stem Cell Niches for Vascular Therapy

描述（由申请人提供）：动脉粥样硬化、外周动脉疾病或缺血等疾病导致的动脉或微血管功能丧失，是美国高发病率和高死亡率的原因之一。一种新兴的解决方案是间充质干细胞（MSC）治疗，它有可能再生血管，并彻底改变血管疾病的治疗。然而，基于msc的血管治疗结果不一致，更糟糕的是，一些研究报道了血管功能障碍。这些治疗结果至少部分归因于不明确的细胞环境，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，必须解决几个尚未解决的问题：(a)次优的MSC环境导致混合细胞群与低血管特异性或信号；(b)缺乏对体内多因子环境如何决定MSC命运的机制理解；(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。为了解决这些知识空白，本提案的总体目标是建立一个综合平台，概括正常血管组织中物理和生化环境的协同作用，以使MSCs的高度特异性和成熟的血管分化永续用于血管治疗。我们的假设是，血管模拟的机械和生化环境为MSCs提供了协同信号，使体外和体内生理条件下的血管再生永续。为了实现我们的假设，我们将采用一种创新的方法，通过开发具有独立调节微环境因素（即基质刚度、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，以进行生理流动下的评估。这种方法是建立在我们团队的生物材料能力上的，即生产具有可控刚性、各向异性、蛋白质时空释放和配体结合的纳米纤维材料。本文提出了三个目标：AIM 1侧重于msc -基质相互作用机制，为血管分化的三维合成生态位基质的合理设计奠定基础；AIM 2旨在定义聚合机械化学信号的合成壁龛，以实现最佳的血管再生；AIM 3整合和评估血管移植的合成壁龛，以证明可行性，并为未来的设计和临床翻译提供关键反馈。这项新的跨学科研究，结合了生物材料、细胞信号、血管力学生物学和组织工程，如果成功，将有助于实现我们设计应用特异性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.