Therapeutic Microvascular Pericytes

治疗性微血管周细胞

• 批准号: 7361098
• 负责人: Shayn Peirce-Cottler
• 金额: $ 18.34万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7361098
• 关键词: 3-Dimensional; Address; Adipose tissue; Adult; Applaud; Behavior; Biological Assay; Biomedical Engineering; Blocking Antibodies; Blood Vessels; Blood capillaries; Blood flow; Budgets; Capillary Endothelial Cell; Cell Maintenance; Cell Therapy; Cell surface; Cells; Cellular Morphology; Characteristics; Coculture Techniques; Computational Biology; Computer Simulation; Coronary; Data; Endothelial Cells; Endothelium; Engineering; Funding; Funding Mechanisms; Goals; Grant; Growth; Harvest; Hindlimb; Human; Imagery; In Vitro; Invasive; Ischemia; Label; Length; Limb Salvage; Literature; Longevity; Maintenance; Membrane; Mesentery; Modeling; Molecular; Morphology; Multipotent Stem Cells; Muscle; Numbers; Operative Surgical Procedures; Perfusion; Pericytes; Peripheral Vascular Diseases; Phenotype; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Population; Procedures; Process; Publishing; Recruitment Activity; Role; SCID Mice; Science; Side; Signal Transduction; Skeletal Muscle; Smooth Muscle Myocytes; Sorting - Cell Movement; Source; Stromal Cells; Study Section; Suction Lipectomy; Surface; System; Techniques; Technology; Testing; Therapeutic; Time; TimeLine; Tissue Engineering; Tissues; Vascularization; Work; base; capillary; cell behavior; density; design; human migration; in vivo; injured; innovation; migration; novel; platelet-derived growth factor BB; receptor function; response

DESCRIPTION (provided by applicant): A major challenge in both in vivo therapeutic (re)vascularization and in engineering vascularized tissue constructs ex vivo is establishing new capillary channels and maintaining them for extended periods of time. In the native microvasculature a unique cell population, termed "pericytes," is responsible for providing support signals to capillary endothelial cells and maintaining newly formed microvessels. Therefore, a prudent approach in "microvascular tissue engineering" and revascularization strategies is to identify a pericyte 'precursor' population that is easily obtainable, can be expanded ex vivo, is capable of being recruited to the ablumenal surface of the endothelium, and promotes and microvessel viability and longevity through recognized molecular mechanisms. Stromal cells obtained from adult human adipose tissue are readily available and easily harvested through minimally invasive liposuction and lipoectomy procedures. New data suggests that human adipose tissue contains a sub-population of self-renewing, multipotent stem cells (hASCs) that possess vast differentiation potential and an ability to augment microvascular growth in vivo in injured tissues. We have identified a pericyte-precursor sub-population of hASCs, and we have collected preliminary data to support that they behave like pericytes when injected in vivo, meaning that they express pericyte markers, migrate to the ablumenal surface of microvessels and alter their morphologies to conform to the curvatures of vessels, and enhance vascular length density. The goal of the proposed work is to understand the molecular mechanisms and cellular behaviors by which these hASCperiytes contribute to vascular growth in a pericyte-like manner so that this readily available source of therapeutic cells may be most effectively exploited in microvascular engineering and revascularization strategies following ischemic insult. Specifically, we propose to test the hypothesis that hASC-pericytes enhance microvascular maintenance during ischemia through pericyte-like mechanisms, and specifically PDGF-BB signaling, in the following specific aims: AIM 1: Quantify the migratory behaviors of hASCs in response to PDGF-BB signaling in vitro. AIM 2-Develop a multi-cell agent-based computational model, based on an established published model, to facilitate a systems-level interrogation molecular signals (in addition to PDGF-BB) modulating hASCparticipation in microvascular remodeling. AIM 3: In a novel whole mount model of muscle ischemia, inject GFP-labeled hASCs and track their behaviors in vivo.

描述（由申请人提供）：体内治疗性（再）血管化和离体工程血管化组织构建体的主要挑战是建立新的毛细血管通道并长时间维持它们。在天然微血管系统中，一种独特的细胞群，称为“周细胞”，负责向毛细血管内皮细胞提供支持信号并维持新形成的微血管。因此，“微血管组织工程”和血运重建策略中的审慎方法是确定易于获得、可以离体扩增、能够募集到内皮细胞外表面并促进和促进血管再生的周细胞“前体”群体。通过公认的分子机制实现微血管的活力和寿命。从成人脂肪组织中获得的基质细胞很容易获得，并且可以通过微创吸脂和脂肪切除术轻松收获。新数据表明，人类脂肪组织含有自我更新的多能干细胞 (hASC) 亚群，它们具有巨大的分化潜力，并且能够增强受损组织体内微血管的生长。我们已经鉴定了 hASC 的周细胞前体亚群，并且我们收集了初步数据来支持它们在体内注射时表现得像周细胞，这意味着它们表达周细胞标记，迁移到微血管的体表面并改变其形态顺应血管曲率，增强血管长度密度。拟议工作的目标是了解这些 hASC 周细胞以类似周细胞的方式促进血管生长的分子机制和细胞行为，以便在微血管工程和血运重建策略中最有效地利用这种现成的治疗细胞来源缺血性损伤。具体来说，我们建议测试 hASC 周细胞通过类周细胞机制，特别是 PDGF-BB 信号传导增强缺血期间微血管维持的假设，具体目标如下： 目标 1：量化 hASC 响应 PDGF 的迁移行为体外 BB 信号传导。目标 2-基于已建立的已发表模型，开发基于多细胞代理的计算模型，以促进系统级询问分子信号（除 PDGF-BB 外）调节 hASC 参与微血管重塑。 目标 3：在新型肌肉缺血整体模型中，注射 GFP 标记的 hASC 并跟踪其体内行为。