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，并造成巨大的社会和经济损失。 美国医疗保健系统的财政负担。闭塞性血管病的形成 冠状和外周血管通常需要旁路移植手术来提供流动管道 绕过封锁线虽然该手术可以为患者提供血流恢复，但仅存在有限的血流恢复。 患者体内可以采集用于这些手术的自体动脉或静脉的量。经常 这些血管也存在血管疾病 再狭窄加速闭塞。小直径人造血管移植物已被证明是非常 由于血栓形成和移植失败而难以发展。解决这个问题的一个有希望的方法是使用 组织工程血管移植物，以创建用于旁路手术的新管道。脱细胞 动脉是一种非常有吸引力的方法， 与天然血管相似的性质，没有免疫原性，并且可以用从血管中收获的细胞接种。 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 在胚胎发育期间和损伤期间重塑血管系统。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， 从骨髓间充质干细胞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获得，因此是非常重要的。 呼吁提供自体来源的细胞。将这些机械条件化的MSC接种到 通过去除动脉细胞制造的组织工程移植物。我们的主要目标是确定最佳条件 使MSC分化为vSMC和内皮细胞表型，并测试是否机械条件化 当用于再细胞化血管移植物时，MSC上级非条件MSC。我们会处理这个问题 目的通过以下具体目标：（1）使用高通量，组合实验，以发现 用于骨髓稳健分化的协同生物化学、药理学和机械条件 MSC转化为内皮细胞。(2)对机械拉伸的协同作用进行广泛评估 和生物化学刺激在骨髓MSC分化为血管平滑肌细胞（vSMC）中的作用。 (3)测试机械条件化的MSC在增强细胞增殖中的功能性和长期分化。 再细胞化移植物用于搭桥手术。这些研究将为机械地 介导的干细胞生物学，并为增强小直径再细胞化提供优化的条件。 血管移植物