MIAMI cellular-based constructs for vessel regeneration in an aged mouse model of

MIAMI 基于细胞的衰老小鼠模型血管再生结构

基本信息

批准号：
8878148
负责人：
Gianluca D'Ippolito
金额：
$ 21.91万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878148
关键词：
20 year old 3-Dimensional Adhesions Adult Affect Age Aged, 80 and over Aging Animal Model Animals Antibodies Apoptosis Architecture Area Autologous Behavior Binding Biological Biological Assay Blood Vessels Cardiovascular system Cause of Death Cell Adhesion Cell Density Cell Therapy Cells Cellular Morphology Characteristics Clinical Research Cues Data Developed Countries Development Diffuse Donor person Elderly Ensure Epitopes Fiber Fibronectins Future Gelatin Gene Expression Profile Goals Gold Growth Factor Health Human Immobilization Implant In Vitro Individual Injury Intervention Investigation Investigational New Drug Application Ischemia Laboratories Ligands Limb structure Marrow Mesenchymal Modality Morbidity - disease rate Mus Muscle Fibers Natural regeneration Operative Surgical Procedures Patients Peptides Peripheral arterial disease Phase Play Population Preparation Process Property Recovery of Function Research Research Personnel Risk Role Safety Signal Transduction Stem cells Stromal Cells Structure Surface Techniques Testing Therapeutic Tissues Translations Transplantation Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor-2 Walking Work adult stem cell age effect aged aging population angiogenesis base cell type density design effective therapy extracellular improved in vivo mortality mouse model nanofiber novel therapeutics preclinical study repaired response scaffold standard care stem cell therapy therapeutic angiogenesis tissue repair

20 year old 3-Dimensional Adhesions Adult Affect Age Aged, 80 and over Aging Animal Model Animals Antibodies Apoptosis Architecture Area Autologous Behavior Binding Biological Biological Assay Blood Vessels Cardiovascular system Cause of Death Cell Adhesion Cell Density Cell Therapy Cells Cellular Morphology Characteristics Clinical Research Cues Data Developed Countries Development Diffuse Donor person Elderly Ensure Epitopes Fiber Fibronectins Future Gelatin Gene Expression Profile Goals Gold Growth Factor Health Human Immobilization Implant In Vitro Individual Injury Intervention Investigation Investigational New Drug Application Ischemia Laboratories Ligands Limb structure Marrow Mesenchymal Modality Morbidity - disease rate Mus Muscle Fibers Natural regeneration Operative Surgical Procedures Patients Peptides Peripheral arterial disease Phase Play Population Preparation Process Property Recovery of Function Research Research Personnel Risk Role Safety Signal Transduction Stem cells Stromal Cells Structure Surface Techniques Testing Therapeutic Tissues Translations Transplantation Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor-2 Walking Work adult stem cell age effect aged aging population angiogenesis base cell type density design effective therapy extracellular improved in vivo mortality mouse model nanofiber novel therapeutics preclinical study repaired response scaffold standard care stem cell therapy therapeutic angiogenesis tissue repair

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项目摘要

DESCRIPTION (provided by applicant): Peripheral arterial disease (PAD) represents one of the major vascular diseases induced by age. The gold- standard treatment for severe PAD is surgery or endovascular revascularization. However, a third of patients are not suitable for surgery and most of them will die due to complications. Therapeutic angiogenesis strategies that are based on cell therapy or the delivery of angiogenic growth factors have shown great potential for the treatment of critical limb ischemia in a number of animal and clinical studies. Stem cell therapy associated with three-dimensional, biologically inspired constructs represents a promising therapy for vascular regeneration. Marrow-isolated adult multilineage inducible (MIAMI) cells, a highly homogeneous sub- population of mesenchymal stromal cells (MSCs), have been extensively characterized in our lab for the past 15 years. MIAMI cells derived have the capacity to respond to trophic factors and develop phenotypic and functional characteristic of mature vascular endothelial cells in vitro and in vivo. The objective of this proposal is to develop three-dimensional cellular constructs with distinct architectural and biological cues and determine their angiogenic potential in an in vitro and in vivo setting. We hypothesize that guided therapeutic angiogenesis could be attained by controlling the spatial presentation of MIAMI cells seeded on bioinspired polymeric constructs that are implanted in regions of ischemia. We conjecture that the transplanted MIAMI cellular sheets will be successfully engrafted into the ischemic tissue stimulate revascularization and mature vessel formation. We will test our hypothesis by pursuing two specific aims. In AIM I we will design nanofibrous three-dimensional cellular sheets with defined architectural and biological signals. We will use a state-of-the- art fabrication process to prepare electrospun gelatin constructs and will functionalize th surface of the construct's nanofibers with biological epitopes that promote MIAMI cell adhesion. The angiogenic activity of the MIAMI cellular sheets will be assessed as a function of fabrication parameters in a 3-D in vitro angiogenesis assay. In AIM II will determine the capacity of the MIAMI cellular constructs to promote vessel formation, maturation and direction in vivo. Furthermore, we will determine the effect of aging on the ability of MIAMI cells, seeded on three dimensional constructs, to promote vascular repair in an aged mouse model of critical limb ischemia.

描述（由申请人提供）：周围动脉疾病（PAD）代表了年龄引起的主要血管疾病之一。严重垫的金标准治疗方法是手术或血管内血运重建。但是，三分之一的患者不适合手术，大多数患者会因并发症而死亡。基于细胞疗法或血管生成因子的递送的治疗性血管生成策略在许多动物和临床研究中都表明了治疗临界肢体缺血的巨大潜力。与三维生物学启发的构建体相关的干细胞疗法代表了血管再生的一种有希望的疗法。在过去15年中，在我们的实验室中，在我们的实验室中广泛表征了骨髓分离的成年多素诱导（迈阿密）细胞，这是一种高均匀的间质基质细胞（MSC）。迈阿密细胞得出的能力有能力对营养因子反应，并在体外和体内发展成熟血管内皮细胞的表型和功能特征。该建议的目的是开发具有不同建筑和生物学提示的三维细胞构建体，并在体外和体内确定其血管生成潜力。我们假设可以通过控制植入在缺血区域的生物启发的聚合物构建体上的迈阿密细胞的空间表现来实现指导性的治疗性血管生成。我们推测，移植的迈阿密细胞片将成功植入缺血组织中刺激血运重建和成熟的血管形成。我们将通过追求两个具体目标来检验我们的假设。在目的中，我将设计具有定义的建筑和生物学信号的纳米纤维三维细胞板。我们将使用最先进的制造工艺来制备电纺明胶构建体，并使用促进迈阿密细胞粘附的生物表位来使构建体纳米纤维的表面功能化。迈阿密细胞片的血管生成活性将作为3-D体外血管生成测定法中制造参数的函数进行评估。在AIM II中将确定迈阿密细胞构建体的能力，以促进体内血管形成，成熟和方向。此外，我们将确定衰老对迈阿密细胞在三维结构上播种的迈阿密细胞能力的影响，以促进临界肢体缺血的老年小鼠模型中促进血管修复。