Mechanical Conditioning of Mesenchymal Stem Cells for Enhanced Recellularized Vascular Grafts

间充质干细胞的机械调理以增强再细胞化血管移植物

• 批准号: 9895844
• 负责人: Aaron Blair Baker
• 金额: $ 39.13万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895844
• 关键词: Adult; Anastomosis - action; Animals; Arterial Fatty Streak; Arteries; Atherosclerosis; Autologous; Autologous Transplantation; Biochemical; Biological Assay; Blood; Blood Vessels; Blood flow; Bone Marrow; Bypass; Caliber; Cardiovascular Diseases; Cause of Death; Cell Differentiation process; Cell physiology; Cells; Clinical; Cone; Coronary; Coronary Artery Bypass; Detergents; Development; Disease; Endothelial Cells; Endothelium; Evaluation; Exposure to; Failure; Family suidae; Financial Hardship; Frequencies; Generations; Goals; Harvest; Healthcare Systems; Heart; Homeostasis; Human; Injury; Intervention; Limb structure; Mechanics; Mediating; Medical; Mesenchymal Differentiation; Mesenchymal Stem Cells; Modeling; Mus; Myocardial Infarction; Operative Surgical Procedures; Oryctolagus cuniculus; Patients; Peripheral; Peripheral Vascular Diseases; Pharmacology; Phenotype; Play; Proteins; Research; Risk; Role; Route; Saphenous Vein; Signal Transduction; Smooth Muscle Myocytes; Source; Stimulus; Stretching; Stroke; Syndrome; System; Testing; Thrombosis; Tissue Engineering; Tissues; United States; Vascular Diseases; Vascular Graft; Vascular Smooth Muscle; Vascular System; Vascular remodeling; Veins; Venous; cell type; combinatorial; conditioning; cost; experimental study; graft failure; immunoreactivity; improved; inhibitor/antagonist; insight; mechanical force; mechanical load; mechanical properties; next generation sequencing; pluripotency; public health relevance; restenosis; restoration; scaffold; shear stress; small molecule inhibitor; social; stem cell biology; stem cell differentiation; stem cell niche; stem cell therapy; stem cells; synergism; vascular tissue engineering; vasculogenesis

Cardiovascular diseases are the most common cause of death worldwide and exert a massive social and financial burden on the healthcare system of the United States. The formation of occlusive vascular disease in the coronary and peripheral vascular often necessitates bypass graft surgery to provide a conduit for flow around the blockages. While this surgery can provide restoration of flow for the patient, there is only a limited amount of autologous arteries or veins in the patients that can be harvested for use in these surgeries. Often these vessels also have the presence of vascular disease and in many cases fail relatively rapidly due to accelerated occlusion by restenosis. Small diameter synthetic vascular grafts have proven extremely challenging to develop due to thrombosis and graft failure. A promising approach to this problem is to use tissue engineered vascular grafts to create new conduits to be used in bypass surgeries. Decellularized arteries are a very appealing approach for creating tissue engineered scaffolds that have mechanical properties similar to native vessels, are not immunogenic and can be seeded with cells harvested from the patient. Mechanical forces are an essential part of vascular homeostasis and provide needed stimuli to maintain blood vessel function. In addition, the mechanical microenvironment is key in regulating the remodeling of the vascular system during embryological development and during injury. Here, we will use mechanical forces in combination with biochemical signals and pharmacological inhibitors to optimize the generation of vascular smooth muscle cells (vSMCs) and endothelial cells from bone marrow mesenchymal stem cells (MSCs). Bone marrow MSCs are easily obtainable from patients and consequently are very appealing for providing autologous source of cells. These mechanically conditioned MSCs will be seeded into tissue engineered grafts created by decellularizing arteries. Our major goals are to identify optimal conditions to differentiate MSCs into vSMC and endothelial cell phenotype, and test whether mechanically conditioned MSCs are superior to non-conditioned MSCs when used in recellularized vascular grafts. We will approach this objective through the following specific aims: (1) Use high throughput, combinatorial experiments to find synergistic biochemical, pharmacological and mechanical conditions for robust differentiation of bone marrow MSCs into endothelial cells. (2) Perform an extensive evaluation of the synergistic role of mechanical stretch and biochemical stimulation in differentiating bone marrow MSCs into vascular smooth muscle cells (vSMCs). (3) Test the functionality and long-term differentiation of mechanically conditioned MSCs in enhancing recellularized grafts for bypass surgeries. Together these studies will provide new insights into mechanically mediated stem cell biology and provide optimized conditions for enhancing small diameter recellularized vascular grafts.

心血管疾病是全球死亡的最常见原因，并发挥巨大的社会性和 美国医疗保健系统的财务负担。在 冠状动脉和外围血管通常需要旁路移植手术才能提供流动管道 在障碍物附近。虽然该手术可以为患者提供流量的恢复，但只有有限的 可以收集用于这些手术的患者的自体动脉或静脉。经常 这些血管也存在血管疾病，在许多情况下，由于 再狭窄加速闭塞。小直径合成血管移植已被证明非常 由于血栓形成和移植失败而导致的挑战。解决这个问题的一种有希望的方法是使用 组织工程的血管移植物可创建用于旁路手术的新导管。脱细胞 动脉是一种非常吸引人的方法，用于创建具有机械的组织工程脚手架 与天然血管相似的特性不是免疫原性的，可以用从从那里收获的细胞中播种 病人。机械力是血管稳态的重要组成部分，并为 保持血管功能。另外，机械微环境是调节的关键 在胚胎发育期间和受伤期间对血管系统的重塑。在这里，我们将使用 机械力与生化信号和药理学抑制剂结合使用，以优化 产生血管平滑肌细胞（VSMC）和骨髓间充质的内皮细胞 干细胞（MSC）。骨髓MSC很容易从患者那里获得，因此非常 呼吁提供自体细胞来源。这些机械条件的MSC将被种植到 组织工程的移植物是通过脱细胞产生的。我们的主要目标是确定最佳条件 将MSC区分为VSMC和内皮细胞表型，并测试是否机械条件 当用于延细的血管移植物中时，MSC优于非条件MSC。我们将处理这个 通过以下特定目的进行目标：（1）使用高吞吐量，组合实验查找 骨髓的鲁棒分化的协同生化，药理和机械条件 MSC进入内皮细胞。 （2）对机械拉伸的协同作用进行广泛评估 将骨髓MSC分为血管平滑肌细胞（VSMC）的生化刺激。 （3）测试机械条件MSC的功能和长期分化以增强 用于旁路手术的卷积移植物。这些研究将共同​​提供对机械的新见解 介导的干细胞生物学，并提供了优化的条件，以增强小直径较细胞化 血管移植物。