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

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（申请人提供）：外周动脉疾病（PAD）是由年龄引起的主要血管疾病之一。严重 PAD 的金标准治疗是手术或血管内血运重建术。然而，三分之一的患者不适合手术，其中大多数会因并发症而死亡。基于细胞疗法或血管生成生长因子递送的治疗性血管生成策略在许多动物和临床研究中显示出治疗严重肢体缺血的巨大潜力。与三维生物启发结构相关的干细胞疗法代表了一种有前途的血管再生疗法。骨髓分离的成体多系诱导 (MIAMI) 细胞是一种高度同质的间充质基质细胞 (MSC) 亚群，在过去 15 年中我们的实验室已对其进行了广泛的表征。衍生的 MIAMI 细胞具有对营养因子作出反应的能力，并在体外和体内形成成熟血管内皮细胞的表型和功能特征。该提案的目的是开发具有独特结构和生物学线索的三维细胞结构，并确定其在体外和体内环境中的血管生成潜力。我们假设，通过控制接种在植入缺血区域的仿生聚合物结构上的 MIAMI 细胞的空间呈现，可以实现引导治疗性血管生成。我们推测移植的 MIAMI 细胞片将成功植入缺血组织中，刺激血运重建和成熟血管形成。我们将通过追求两个具体目标来检验我们的假设。在 AIM I 中，我们将设计具有明确的结构和生物信号的纳米纤维三维细胞片。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 MIAMI 细胞粘附的生物表位对构建体的纳米纤维表面进行功能化。 MIAMI 细胞片的血管生成活性将根据 3-D 体外血管生成测定中的制造参数进行评估。在 AIM II 中，将确定 MIAMI 细胞构建体促进体内血管形成、成熟和方向的能力。此外，我们将确定衰老对接种在三维结构上的 MIAMI 细胞的能力的影响，以促进严重肢体缺血的老年小鼠模型的血管修复。