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：
7618520
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/7618520
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 Immunologic Markers 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 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）：由于世界各地的心血管疾病的增加，对小直径血管的需求增加了，作为替代移植物。尽管静脉移植物目前是黄金标准，但十年失败率却接近35％。生物工程的血管移植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法。最近，我们表明，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，可承受置于羔羊颈静脉静脉的插入式植入。在实验期间（15周），植入的TEV保留了专利，其血液流量与天然静脉的程度相同，并表现出显着的基质重塑。尽管在生物材料设计血管组织工程的设计方面取得了重大进展，但细胞的来源仍然是一个主要问题。从患者中分离自体细胞需要侵入性手术并伤害供体部位。最重要的是，血管平滑肌细胞的增殖能力和功能特性受到限制，尤其是当它们起源于年长的供体时，人口主要需要血管假体。为了应对这一挑战，我们建议使用我们在实验室中开发的新方法来将平滑肌细胞与年轻（6个月至1岁）和旧（年龄> 6岁）动物的骨髓（BM）分离。将通过一系列分子和功能分析研究来自Young（YBM-TEV）和年龄（ABM-TEV）平滑肌祖细胞的组织工程血管。将评估BM-TEV对生化和物理刺激的反应，以建立最佳的培养条件，以改善细胞外基质和机械强度的沉积。将获得基因表达谱，以识别可能导致由于衰老而导致功能丧失的分子。此外，纤维蛋白水凝胶将用生长因子融合蛋白进行装饰，以改善信号传导和增强BM-TEV的功能特性。最后，我们将在年轻卵巢接受者的静脉系统中植入ABM-TEV和YBM-TEV，并在植入后长达一年的静脉系统中评估通畅和长期改建。提出的工作将阐明衰老对BM衍生的平滑肌细胞的潜力，作为血管组织工程的来源，并将确定增强BM-TEV功能特性的生化和生物物理因子。公共卫生相关性：由于全世界心血管疾病的增加，对小直径血管的需求增加，因为替代移植物。为了应对这一健康挑战，我们将评估骨髓的潜力，作为工程小直径血管移植的自体干细胞来源，用于治疗心血管疾病。相同的细胞也可以应用于工程其他心脏组织，例如心脏瓣膜和心脏斑块，从而进一步增加了这项工作的潜在临床影响。