Epigenetic regulation of macrophage response to biomaterial implants

项目摘要/摘要 创面愈合受损是一个主要的临床问题，目前可供选择的治疗方法 往往不能完全修复组织。负压创伤疗法(NPWT)是一种临床应用 应用生物材料支架和负压进行机械刺激的治疗 皮肤上的伤口。然而，NPWT背后的机制仍然知之甚少，而且 治疗仍然有相当大比例的患者失败。我们之前的工作已经确立了 生物材料的地形特性调节巨噬细胞的功能，巨噬细胞是必不可少的天然细胞 免疫细胞同时参与推进和消退炎症，并促进 组织修复。更具体地说，导致巨噬细胞伸长的表面增强了它们的 对伤口愈合细胞因子的反应，并保护细胞免受炎症。有趣的是，细胞 伸长已经被证明导致几个细胞的表观遗传状态的深刻变化 包括干细胞和成体间充质细胞，但表观遗传学在生物材料中的作用- 诱导巨噬细胞极化仍是完全未知的。在这项研究中，我们建议 研究巨噬细胞对生物材料结构的表观遗传调控 NPWT。我们假设生物材料支架的结构调节巨噬细胞 通过表观基因组的变化作出反应。我们建议通过以下方法来检验这一假设：(1) 生物材料结构对创面细胞因子及细胞浸润的影响 接受NPWT的患者，并描述细胞转录和表观基因组学特征 以及(2)生物材料结构对人巨噬细胞的影响 极化和表观基因组，并筛选表观遗传修饰物文库对 生物材料诱导的巨噬细胞反应。拟议工作的长期目标是 更好地了解生物材料结构对巨噬细胞的调控，以便开发 促进伤口愈合和组织再生的新策略。

PROJECT SUMMARY / ABSTRACT Impaired wound healing is a major clinical problem, and currently available treatment options often fail to fully repair tissue. Negative pressure wound therapy (NPWT) is a clinically used treatment that applies a biomaterial scaffold and negative pressure to mechanically stimulate dermal wounds. However, the mechanisms underlying NPWT remain poorly understood, and treatment still fails in a significant percentage of patients. Our previous work has established that topographical properties of biomaterials modulate the function of macrophages, essential innate immune cells that are involved in both advancing and resolving inflammation, and promoting tissue repair. More specifically, surfaces that cause macrophage elongation potentiate their response to wound healing cytokines, and protect cells from inflammation. Interestingly, cell elongation has been shown to cause profound changes in the epigenetic state of several cell types including stem cells and adult mesenchymal cells, but the role of epigenetics in biomaterial- induced macrophage polarization remains completely unknown. In this study, we propose to investigate the epigenetic regulation of macrophages in response to biomaterials structure during NPWT. We hypothesize that the structure of the biomaterial scaffold modulates the macrophage response through changes in the epigenome. We propose to test this hypothesis by: (1) investigating the effect of biomaterial structure on wound cytokines and cellular infiltrate in patients undergoing NPWT, and characterize the cellular transcriptomic and epigenomic landscapes, and (2) examine the effect of biomaterial structure on human macrophage polarization and epigenome in vitro, and screen the effects of a library of epigenetic modifiers on the biomaterial-induced macrophage response. The long-term goal of the proposed work is to better understand regulation of macrophages by the structure of biomaterials, in order to develop new strategies to promote wound healing and tissue regeneration.