Stem Cells for Vascular Tissue Engineering

用于血管组织工程的干细胞

基本信息

批准号：
7797674
负责人：
Stelios Theoharis Andreadis
金额：
$ 38.73万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7797674
关键词：
1 year old 6 year old Activities of Daily Living Address Aged, 80 and over Aging Angiography Animal Model Animals Autologous Biochemical Biochemical Markers Biocompatible Materials Biological Assay Biomedical Engineering Blood Vessel Prosthesis Blood Vessel Tissue Blood Vessels Blood flow Bone Marrow Caliber Cardiac Cardiovascular Diseases Cardiovascular system Cells Chimeric Proteins Clinical Collagen Deposition Doppler Ultrasound Elastin Elastin Fiber Endothelial Cells Engineering Enzymes Exhibits Extracellular Matrix Factor XIII Failure Fibrin Gel Gene Chips Gene Expression Growth Factor Health Heart Valves Histologic Histology Hydrogels Immune Immunohistochemistry Immunosuppression Implant In Vitro Insulin Laboratories Legal patent Measures Mechanics Methodology Microscopic Modeling Molecular Molecular Profiling Molecular Target Operative Surgical Procedures Patients Peptides Physiological Plasma Population Property Protein-Lysine 6-Oxidase Reaction Sampling Series Signal Transduction Site Smooth Muscle Smooth Muscle Myocytes Source Stem cells Stimulus Structure of jugular vein System Technology Testing Time Tissue Engineering Tissues Vascular Graft Vasoconstrictor Agents Vasodilator Agents Veins Venous Venous system Western Blotting Work age effect aged alpha Actin animal old age base cell type clinical application controlled release crosslink design enhancing factor gene therapy immune activation immunocytochemistry implantation improved in vivo injured insight loss of function monolayer novel polymerization pressure progenitor promoter public health relevance research study response vascular tissue engineering

项目摘要

DESCRIPTION (provided by applicant): Due to rise in cardiovascular disease throughout the world, there is increasing demand for small diameter blood vessels as replacement grafts. Although venous grafts are currently the golden standard, the ten-year failure rate is approaching 35%. Bioengineered vascular grafts are capable of remodeling in response to host signals and offer a clear alternative to existing technologies. Recently we showed that fibrin-based small- diameter tissue engineered blood vessels (TEV) exhibited vascular reactivity and considerable mechanical strength to withstand interpositional implantation into the jugular veins of lambs. Implanted TEV remained patent for the duration of the experiment (15 weeks), supported blood flow to the same degree as native veins and exhibited remarkable matrix remodeling. Despite significant progress in design of biomaterials for vascular tissue engineering, the source of cells remains a major problem. Isolation of autologous cells from the patient requires invasive surgery and injures the donor site. Most important, the proliferative capacity and functional properties of vascular smooth muscle cells are limited, especially when they originate from older donors, the population mostly in need for vascular prostheses. To address this challenge, we propose to isolate smooth muscle cells from the bone marrow (BM) of young (6 months to 1year old) and old (aged, >6 years old) animals using a novel methodology that we developed in our laboratory. Tissue engineered vessels from young (yBM-TEV) and aged (aBM-TEV) smooth muscle progenitor cells will be studied with a series of molecular and functional assays. The response of BM-TEV to biochemical and physical stimuli will be evaluated in order to establish optimal culture conditions that improve deposition of extracellular matrix and mechanical strength. Gene expression profiles will be obtained to identify molecules that may be responsible for potential loss of function as a result of aging. In addition, fibrin hydrogels will be decorated with growth factor fusion proteins as a means of improving signaling and enhancing the functional properties of BM-TEV. Finally, we will implant aBM-TEV and yBM-TEV in the venous system of young ovine recipients and assess patency and long-term remodeling up to one year post-implantation. The proposed work will elucidate the effects of aging on the potential of BM-derived smooth muscle cells as a source for vascular tissue engineering and will determine the biochemical and biophysical factors that enhance the functional properties of BM-TEV. PUBLIC HEALTH RELEVANCE: Due to rise in cardiovascular disease throughout the world, there is increasing demand for small diameter blood vessels as replacement grafts. To address this health challenge, we will evaluate the potential of bone marrow as an autologous stem cell source for engineering small diameter vascular grafts for treatment of cardiovascular disease. The same cells may also be applied in engineering other cardiac tissues such as heart valves and cardiac patches further increasing the potential clinical impact of this work.

描述（由申请人提供）：由于全世界心血管疾病的增加，对小直径血管作为替代移植物的需求不断增加。尽管静脉移植是目前的金标准，但十年失败率接近35%。生物工程血管移植物能够响应宿主信号进行重塑，并为现有技术提供了明确的替代方案。最近，我们发现基于纤维蛋白的小直径组织工程血管（TEV）表现出血管反应性和相当大的机械强度，可以承受插入羔羊颈静脉中的植入。植入的 TEV 在实验期间（15 周）保持专利状态，支持与天然静脉相同程度的血流，并表现出显着的基质重塑。尽管血管组织工程生物材料的设计取得了重大进展，但细胞来源仍然是一个主要问题。从患者体内分离自体细胞需要进行侵入性手术，并且会损伤供体部位。最重要的是，血管平滑肌细胞的增殖能力和功能特性是有限的，特别是当它们来自老年供体时，这些人最需要血管假体。为了应对这一挑战，我们建议使用我们实验室开发的新方法从年轻（6 个月至 1 岁）和老年（6 岁以上）动物的骨髓 (BM) 中分离平滑肌细胞。来自年轻 (yBM-TEV) 和衰老 (aBM-TEV) 平滑肌祖细胞的组织工程血管将通过一系列分子和功能测定进行研究。将评估 BM-TEV 对生化和物理刺激的反应，以建立改善细胞外基质沉积和机械强度的最佳培养条件。将获得基因表达谱，以识别可能导致衰老导致的潜在功能丧失的分子。此外，纤维蛋白水凝胶将用生长因子融合蛋白装饰，作为改善信号传导和增强 BM-TEV 功能特性的手段。最后，我们将 aBM-TEV 和 yBM-TEV 植入年轻绵羊受体的静脉系统中，并评估植入后一年内的通畅性和长期重塑。拟议的工作将阐明衰老对 BM 来源的平滑肌细胞作为血管组织工程来源的潜力的影响，并将确定增强 BM-TEV 功能特性的生化和生物物理因素。公共卫生相关性：由于全世界心血管疾病的增加，对小直径血管作为替代移植物的需求不断增加。为了应对这一健康挑战，我们将评估骨髓作为自体干细胞来源用于工程小直径血管移植物以治疗心血管疾病的潜力。相同的细胞还可以应用于工程其他心脏组织，例如心脏瓣膜和心脏补片，进一步增加这项工作的潜在临床影响。