The Origin and Function of Macrophages in the Foreign Body Response

合成水凝胶是在三维支架中原位细胞输送的出色平台，其中 可以调整化学成分和性质，以促进和促进组织生长。然而，合成水凝胶，如 对于任何非生物物质，都会受到免疫系统对外来物质的正常反应。这个 异物反应(FBR)的特点是慢性炎症和形成致密的、无血管的 纤维性胶囊。这些事件会对嵌入在水凝胶中的细胞产生负面影响，并产生屏障 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，材料硬度、降解率等)，更好的 需要对FBR有所了解。虽然巨噬细胞是已知的协调FBR的细胞，但我们目前对 FBR中的巨噬细胞过于简单化。从根本上说，这些都是最近的范式转变， 可查看巨噬细胞。我们现在知道巨噬细胞来自截然不同的来源，“常驻”组织 巨噬细胞和从血液来源的单核细胞“招募”的巨噬细胞，对损伤区域有反应，但 完全不同的角色。“被招募的”单核细胞来源的巨噬细胞被认为是促进 损伤组织中的炎症和促纤维化反应。因此，可以合理地假设这些不同 巨噬细胞群可能参与了FBR。这一高级研究员的首要目标是 应用这一新的范式来研究FBR背景下的巨噬细胞。这个想法是巨噬细胞，它 在植入物的部位堆积，来自不同的来源以前在FBR中没有被考虑过。 这些研究是研究培训计划的核心，该计划将拓宽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的过渡以建立 肌肉骨骼研究用生物材料的免疫学研究新方向。最重要的是 该项目的假设是，从血液来源的单核细胞中“招募”的巨噬细胞主要是 对导致FBR慢性炎症和纤维化的事件负责。为了检验这一假设，有两个例子 提出了具体的目标：a)确定巨噬细胞的生物学效应及其在FBR中的功能状态 使用CCR2基因敲除小鼠模型和b)确定巨噬细胞的时间生物学效应及其 利用MAFIA转基因小鼠模型对FBR功能状态的影响。我们将使用新的技术和鼠标 防止单核细胞来源的巨噬细胞(即，CCR2基因敲除)和 这使我们能够以离散的时间间隔诱导性地耗尽所有巨噬细胞(即黑手党)。这些措施的结果 研究是在FBR的背景下重新定义巨噬细胞，并重要的是确定如何不同 巨噬细胞亚群对FBR有贡献。这种新的洞察力将被用来设计 针对时间和巨噬细胞亚群的免疫调节水凝胶(S) 联邦调查局。

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.