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.

心血管疾病是全世界最常见的死亡原因，对社会和社会造成巨大影响。 美国医疗保健系统的财政负担。闭塞性血管疾病的形成 冠状动脉和周围血管通常需要进行旁路移植手术以提供血流管道 堵塞物周围。虽然这种手术可以为患者恢复血流，但效果有限。 可采集患者体内用于这些手术的自体动脉或静脉的数量。经常 这些血管也存在血管疾病，并且在许多情况下由于以下原因相对较快地衰竭： 再狭窄加速闭塞。小直径人造血管移植物已被证明非常 由于血栓形成和移植失败，发展具有挑战性。解决这个问题的一个有前途的方法是使用 组织工程血管移植物创建用于搭桥手术的新导管。脱细胞 动脉是一种非常有吸引力的方法来创建具有机械性能的组织工程支架 与天然血管相似的特性，不具有免疫原性，可以用从血管中收获的细胞进行接种 病人。机械力是血管稳态的重要组成部分，并提供所需的刺激 维持血管功能。此外，机械微环境是调节的关键。 胚胎发育和损伤期间血管系统的重塑。在这里，我们将使用 机械力与生化信号和药理学抑制剂相结合，以优化 从骨髓间充质产生血管平滑肌细胞 (vSMC) 和内皮细胞 干细胞（MSC）。骨髓间充质干细胞很容易从患者身上获得，因此非常有用 呼吁提供自体细胞来源。这些经过机械调节的 MSC 将被播种到 由动脉脱细胞产生的组织工程移植物。我们的主要目标是确定最佳条件 将 MSC 分化为 vSMC 和内皮细胞表型，并测试是否经过机械条件处理 当用于再细胞化血管移植物时，MSC 优于非条件化 MSC。我们将接近这个 通过以下具体目标来实现目标：（1）使用高通量、组合实验来寻找 用于骨髓稳健分化的协同生化、药理学和机械条件 间充质干细胞转化为内皮细胞。 (2) 对机械拉伸的协同作用进行广泛评估 以及生化刺激将骨髓间充质干细胞分化为血管平滑肌细胞（vSMC）。 (3) 测试机械条件下MSCs增强功能和长期分化能力 用于搭桥手术的再细胞移植物。这些研究将为机械领域提供新的见解 介导的干细胞生物学并为增强小直径再细胞化提供优化条件 血管移植物。