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: 10512428
• 负责人: Wei Tan
• 金额: $ 3.81万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10512428
• 关键词: 3-Dimensional; Antioxidants; Arteriovenous fistula; Award; Blood; Blood Vessels; Blood flow; Cell Adhesion; Cells; Clinical; Complex; Dialysis procedure; End stage renal failure; Environment; Extracellular Matrix; Failure; Fiber; Functional disorder; Goals; Health; Hemodialysis; Hydrogels; Hydrogen Sulfide; In Vitro; Inflammatory; Knowledge; Lead; Matrix Metalloproteinases; Mesenchymal Stem Cells; Modeling; Morbidity - disease rate; Pathologic; Patients; Phenotype; Physiological; Property; Signal Transduction; Smooth Muscle Myocytes; Testing; Toxin; Translating; Vascular Graft; Vascular Smooth Muscle; arteriovenous graft; base; crosslink; cytokine; design; economic cost; improved; in vivo; innovation; insight; mimetics; model design; mortality; novel; parent project; peptidomimetics; preservation; prevent; regenerative; three-dimensional modeling

Hemodialysis vascular access dysfunction is currently considered to be one of the most challenging forms of clinical vascular grafting. The high failure rates associated with all types of dialysis vascular access that include arteriovenous fistulae (AVFs) and arteriovenous grafts (AVGs), lead to substantial morbidity, mortality, and economic cost. No effective solutions exist. End-stage renal disease and other health conditions of hemodialysis patients present a hostile environment that includes uremic toxins and inflammatory cytokines. The maturation failure of AVFs and AVGs is related to unresponsive or dysfunctional vascular cells, which can be attributed in part to this hostile milieu in the blood and in part to the dysfunctional matrix that alters the local strains during blood flow. For AVFs and AVGs to be successful, they must maintain a healthy vascular cell phenotype despite these hostile conditions. The central hypothesis for the parent project (5R01HL119371) is that precision cell niches, developed under hemodialysis-relevant conditions and when applied to the clinical setting of dialysis vascular access, prevent dialysis access failure. The goal for this supplement award is to create a physiologically- relevant three-dimensional (3D) model of the media layer of a blood vessel that would allow for a more accurate study of vascular smooth muscle cells (vSMCs) in vitro. The key attributes of the model will be a 3D media- mimetic that recapitulates: (1) the extracellular matrix (ECM) of the native media layer and (2) the complex strain environment that arises during pulsatile blood flow. The model will be based on an innovative embedded fiber hydrogel model developed by the team, but which will be adapted to recapitulate the native 3D environment of vSMCs. The hydrogel model will consist of a fiber (that mimics the ECM of the intima) seeded with vSMCs and embedded within a bulk hydrogel matrix comprised of matrix metalloproteinase-sensitive crosslinks and cell adhesion peptides that mimic the media layer. Importantly, the structural design of the model allows for control over the integration bond between the intima-like fiber and the media matrix to determine how much strain is transferred to the cells. This bond allows for the local strain to be varied (e.g., pathophysiological to normal) without altering the properties of the fiber or hydrogel matrix. By creating a more physiologically accurate model of the media layer, the information gained from in vitro studies should better translate to in vivo studies. This project will test the overarching hypothesis that abnormally high tensile strains contribute to a pathological phenotype in vSMCs, which is exacerbated under uremic conditions, but a cell protective and regenerative signal released from the fibers prevents a dysfunctional vSMC phenotype. To test this hypothesis two specific aims are proposed. AIM 1 will determine the effect of local strains on vSMC phenotype under uremic conditions. AIM 2 will assess the effect of antioxidants (i.e., hydrogen sulfide) on preserving the vSMC phenotype under uremic conditions. Taken together, this project will provide deeper insights into the synergistic effect of tensie strain and the hostile milieu on vSMC dysfunction through a novel 3D media-mimetic hydrogel model.

血液透析血管通路功能障碍目前被认为是最具挑战性的形式之一， 临床血管移植与所有类型的透析血管通路相关的高失败率，包括 动静脉瘘（AVF）和动静脉移植物（AVG）会导致大量发病率、死亡率和 经济成本。没有有效的解决办法。终末期肾病和其他血液透析健康状况 患者呈现出包括尿毒症毒素和炎性细胞因子的不利环境。成熟 AVF和AVG的失败与无反应或功能障碍的血管细胞有关，这可归因于 部分原因是血液中的这种敌对环境，部分原因是功能失调的基质改变了局部菌株， 血流AVF和AVG要成功，它们必须保持健康的血管细胞表型， 这些敌对的条件。母项目（5 R 01 HL 119371）的中心假设是精密度单元 在血液透析相关条件下以及应用于透析临床环境时开发的小生境 血管通路，防止透析通路失败。这个奖项的目标是创造一个生理上的- 血管的介质层的相关三维（3D）模型，其将允许更准确的测量。 血管平滑肌细胞（vSMC）的体外研究。模型的关键属性将是3D媒体- 一种模拟物，概括了：（1）天然培养基层的细胞外基质（ECM）和（2）复合菌株 在脉动血流期间产生的环境。该模型将基于一种创新的嵌入式光纤 水凝胶模型由团队开发，但它将被调整，以概括原生的3D环境， vSMC。水凝胶模型将由接种有vSMC的纤维（模拟内膜的ECM）组成， 包埋在由基质金属蛋白酶敏感性交联和细胞组成的大块水凝胶基质中， 模拟介质层的粘附肽。重要的是，模型的结构设计允许控制 在内膜样纤维和介质基质之间的整合结合上， 转移到细胞。这种结合允许局部应变变化（例如，病理生理至正常） 而不改变纤维或水凝胶基质的性质。通过建立一个更精确的生理模型 对于介质层，从体外研究中获得的信息应更好地转化为体内研究。这 该项目将测试总体假设，即异常高的拉伸应变有助于病理性 vSMC中的表型，其在尿毒症条件下加重，但细胞保护和再生信号 从纤维中释放的这些药物防止了功能失调的vSMC表型。为了检验这一假设，有两个具体目标， 提出了目的1将确定尿毒症条件下当地菌株对vSMC表型的影响。目的2 将评估抗氧化剂的效果（即，硫化氢）对维持尿毒症下vSMC表型的影响 条件总的来说，这个项目将提供更深入的了解张力应变和 通过一种新的三维介质模拟水凝胶模型对vSMC功能障碍的不利环境。