Understanding and Controlling Macrophage Behavior in Angiogenesis

了解和控制血管生成中的巨噬细胞行为

• 批准号: 10629777
• 负责人: Kara Lorraine Spiller
• 金额: $ 7.74万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629777
• 关键词: Adoptive Transfer; Behavior; Biocompatible Materials; Cells; Cues; Data; Goals; Heart; Hindlimb; Hydrogels; In Vitro; Inflammatory; Inflammatory Response; Injury; Ischemia; Modeling; Mus; Phase; Phenotype; Population; Process; Site; T-Lymphocyte; Testing; Time; Tissues; Vascularization; Work; angiogenesis; bioscaffold; cell type; directed differentiation; healing; macrophage; monocyte; response; response to injury; scaffold; wound healing

Project summary At the heart of angiogenesis and biomaterial vascularization lies the inflammatory response, orchestrated primarily by macrophages, which dramatically shift phenotype over time in response to microenvironmental cues. In the normal response to injury, macrophages are initially pro-inflammatory (aka M1), and at later stages they are replaced by a mixed population referred to collectively as M2 that upregulate factors associated with resolution of the wound healing process. Previously we showed that M1 macrophages are critical for the initiation of angiogenesis, but they must switch to M2 for stable angiogenesis and wound healing. The extent of the diversity of this M2 population, and how they regulate angiogenic processes, is still unknown. At later stages of angiogenesis and biomaterial vascularization, M2 macrophages are generated 1) via transition from M1 macrophages, or 2) from direct differentiation of newly arriving monocytes. The differences between the M2 macrophages arising from each population have not been investigated. Preliminary data suggest that M1-derived M2 macrophages possess enhanced angiogenic functionality, and that biomaterials that transiently stimulate the initial M1 phase may enhance the subsequent response to M2-promoting biomaterials to achieve enhanced vascularization and healing. The overarching hypothesis of this project is that biomaterials that promote sequential M1 and M2 activation of the same population of macrophages will enhance vascularization. We recently found that adoptively transferred macrophages and M2-promoting microparticles are synergistic in promoting tissue revascularization in a murine hindlimb ischemia model. However, the macrophages were rapidly cleared from the site of injury (within 2 days), making it difficult to study the phenotype changes in adoptively transferred macrophages. Therefore, the goal of this project is to adoptively transfer macrophages using biomaterial scaffolds as a cell carrier, so that the macrophages are retained at the site of injury for long enough to track their phenotype changes and to observe their interactions with other cell types involved in angiogenesis. We will use porous scaffolds (as opposed to hydrogels) because other work in our lab has shown using in vitro studies that macrophage-T cell crosstalk is important for the M1-to-M2 transition of macrophages, so it is important that T cells are able to inflitrate the biomaterial carrier. In the current project, we will administer pro-inflammatory M1 macrophages to the site of injury using porous scaffolds in order to test the hypothesis that M1 macrophage crosstalk with T cells promotes Th2 differentiation in T cells, the M1-to-M2 transition in macrophages, and enhanced angiogenesis. The hypothesis is that adoptively transferred M1 macrophages will transition into a distinct M2 phenotype with enhanced angiogenic functions (compared to M0 macrophages) via crosstalk with endogenous T cells.

项目摘要 血管生成和生物材料血管的核心是炎症反应，精心策划 主要是由巨噬细胞响应微环境提示的巨噬细胞，随着时间的流逝而显着转移表型。 在对损伤的正常反应中，巨噬细胞最初是促炎（又称M1），在后来的阶段 被共同称为M2的混合种群所取代，该群体上调了与 解决伤口愈合过程。以前我们表明M1巨噬细胞对于开始至关重要 血管生成，但必须切换到M2进行稳定的血管生成和伤口愈合。范围 M2人群的多样性及其调节血管生成过程的多样性仍然未知。在以后的阶段 血管生成和生物材料血管形成，M2巨噬细胞1）通过M1过渡 巨噬细胞，或2）直接分化新到达的单核细胞。 M2之间的差异 尚未研究由每个人群产生的巨噬细胞。初步数据表明M1衍生 M2巨噬细胞具有增强的血管生成功能，并且瞬时刺激的生物材料 初始M1相可能会增强对M2促进生物材料的后续反应，以增强 血管化和治愈。该项目的总体假设是促进的生物材料 同一巨噬细胞的顺序M1和M2激活将增强血管形成。 我们最近发现，采用转移的巨噬细胞和M2促进微粒是 在鼠类后肢缺血模型中促进组织血运重建方面的协同作用。但是， 巨噬细胞从受伤部位迅速清除（在2天内），因此很难研究表型 收养转移的巨噬细胞的变化。因此，该项目的目的是采用转移 使用生物材料支架作为细胞载体的巨噬细胞，以便将巨噬细胞保留在 损伤足够长以跟踪其表型的变化并观察他们与其他细胞类型的相互作用 参与血管生成。我们将使用多孔脚手架（与水凝胶相反），因为我们实验室中的其他工作 使用体外研究表明，巨噬细胞-T细胞串扰对于M1至M2的转变很重要 巨噬细胞，因此重要的是T细胞能够使生物材料载体及易得到膨胀。在当前项目中，我们 将使用多孔支架对损伤部位进行促炎的M1巨噬细胞，以测试 M1巨噬细胞与T细胞串扰的假设促进了T细胞中的Th2分化，M1至M2 巨噬细胞的过渡和增强的血管生成。 假设是，采用转移的M1巨噬细胞将过渡到独特的M2 具有增强血管生成功能（与M0巨噬细胞相比）的表型通过串扰 内源性T细胞。