The Origin and Function of Macrophages in the Foreign Body Response

巨噬细胞在异物反应中的起源和功能

• 批准号: 9611776
• 负责人: Stephanie J Bryant
• 金额: $ 6.96万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9611776
• 关键词: Area; Attenuated; Biocompatible Materials; Biological; Biology; Blood; Cells; Chemistry; Chronic; Dimensions; Embryonic Development; Event; Exhibits; Fellowship; Fibrosis; Flow Cytometry; Foreign Bodies; Genes; Goals; Growth; Health; Hydrogels; Immune signaling; Immune system; Immunology; Implant; In Situ; Inflammation; Inflammatory; Injury; Knock-out; Knockout Mice; Knowledge; Lead; Learning; Mediating; Mus; Musculoskeletal; Myeloid Cells; Outcome Study; Phenotype; Physicians; Population; Proliferating; Property; Regulation; Research; Research Training; Role; Scientist; Signal Pathway; Site; Source; Surface; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Transgenic Mice; Work; capsule; design; discrete time; experimental study; follower of religion Jewish; healing; immunoregulation; improved; improved outcome; injured; insight; macrophage; monocyte; mouse model; negative affect; novel; novel strategies; novel therapeutics; prevent; recruit; response; sabbatical; scaffold; self-renewal; time interval

Synthetic hydrogels are remarkable platforms for in situ cell delivery in a three-dimensional scaffold where the chemistry and properties can be tuned to promote and facilitate tissue growth. Synthetic hydrogels, however, as with any non-biological material, suffer from the immune system’s normal response to foreign materials. The foreign body response (FBR) is characterized by chronic inflammation and the formation of a dense, avascular fibrous capsule. These events can negatively affect cells embedded within a hydrogel and create a barrier between the scaffold and the host tissue that prevents integration. Given that synthetic hydrogels offer numerous advantages for designing tunable scaffolds (e.g., material stiffness, degradation rates, etc.), a better understanding of the FBR is needed. While macrophages are known to orchestrate the FBR, our current view of macrophages in the FBR is oversimplified. Fundamentally, these has been a recent paradigm shift in how macrophages are viewed. We now know that macrophages from distinctly different origins, “resident” tissue macrophages and “recruited” macrophages from blood-derived monocytes, respond to areas of injury, but with distinctly different roles. “Recruited” monocyte-derived macrophages are thought to be the main drivers of pro- inflammatory and pro-fibrotic responses in injured tissue. Thus, it is reasonable to postulate that these different macrophage populations may be involved in the FBR. The overarching goal of this senior fellowship is to apply this new paradigm to study the macrophage in the context of the FBR. This idea that macrophages, which accumulate at the site of an implant, arrive from different origins has not been considered previously in the FBR. These studies are central to the research training plan that will broaden the PI’s knowledge in immunology, enable her to learn state-of-the-art techniques to study macrophages, and facilitate the PI’s transition to establish a new research direction in immunology of biomaterials for musculoskeletal research. The overarching hypothesis for this project is that “recruited” macrophages from blood-derived monocytes are primarily responsible for the events that lead to chronic inflammation and fibrosis in the FBR. To test this hypothesis two specific aims are proposed: a) identify the biological effect of macrophages and their functional state on the FBR using CCR2 knockout mouse models and b) identify the temporal biological effect of macrophages and their functional state on the FBR using MaFIA transgenic mouse models. We will employ novel techniques and mouse models that prevent recruitment of monocyte-derived (i.e., “recruited”) macrophages (i.e., CCR2 knockouts) and that allow us to inducibly deplete all macrophages at discrete time intervals (i.e., MaFIA). The outcome of these studies is to re-define the macrophage in the context of the FBR and importantly identify how different macrophage subpopulations contribute to the FBR. This new insight will be leveraged to design immunomodulatory hydrogels that target the timing and the macrophage subpopulation(s) that is responsible for the FBR.

合成水凝胶是用于在三维支架中原位细胞递送的显著平台， 可以调节化学和性质以促进和促进组织生长。然而，合成水凝胶，如 与任何非生物材料接触时，免疫系统对外来物质的正常反应会受到影响。的 异物反应（FBR）的特征是慢性炎症和形成致密的无血管的 纤维囊这些事件会对嵌入水凝胶中的细胞产生负面影响，并形成屏障 在支架和宿主组织之间阻止整合。鉴于合成水凝胶提供了许多 设计可调支架的优点（例如，材料刚度、降解速率等），更好的 需要对FBR进行了解。虽然巨噬细胞是已知的编排FBR，我们目前的看法， FBR中的巨噬细胞被过分简化了。从根本上说，这些都是最近的范式转变， 巨噬细胞被观察到。我们现在知道，巨噬细胞从明显不同的起源，“居民”组织， 巨噬细胞和来自血液来源的单核细胞的“募集的”巨噬细胞对损伤区域有反应，但 截然不同的角色。“募集的”单核细胞衍生的巨噬细胞被认为是促细胞增殖的主要驱动力。 损伤组织中的炎症和促纤维化反应。因此，有理由假设这些不同的 巨噬细胞群可能参与FBR。这个高级奖学金的首要目标是 应用这种新的范例来研究FBR背景下的巨噬细胞。巨噬细胞， 在FBR中，以前未考虑过在植入部位累积来自不同来源。 这些研究是研究培训计划的核心，将扩大PI在免疫学方面的知识， 使她能够学习最先进的技术来研究巨噬细胞，并促进PI的过渡， 一个新的研究方向，在免疫学的生物材料的肌肉骨骼研究。总体 该项目的假设是，来自血液来源的单核细胞的“募集”巨噬细胞主要是 导致FBR中慢性炎症和纤维化的事件。为了验证这一假设， 提出了具体的目标：a）确定巨噬细胞的生物学效应及其功能状态对FBR的影响 使用CCR2敲除小鼠模型，和B）鉴定巨噬细胞的时间生物学效应及其 使用MaFIA转基因小鼠模型对FBR的功能状态进行研究。我们将采用新的技术和鼠标 防止单核细胞来源的募集的模型（即，“募集的”）巨噬细胞（即，CCR2敲除）和 其允许我们以离散的时间间隔诱导性地耗尽所有巨噬细胞（即，MaFIA）。成果的 研究的目的是在FBR的背景下重新定义巨噬细胞，重要的是确定 巨噬细胞亚群有助于FBR。这种新的洞察力将被用来设计 免疫调节水凝胶靶向时间和巨噬细胞亚群， FBR。