ECM Scaffolds and Macrophage Polarization-Induced Tissue Remodeling

描述（由申请人提供）：细胞外基质（ECM）由排列在三维结构中的结构和功能组分组成。来自ECM的无细胞、非交联支架已显示出一致地调节瘢痕组织形成的默认哺乳动物愈合反应，使其朝向更具重建性的宿主反应类型。ECM支架调节宿主对建设性重塑而不是瘢痕组织形成的反应的机制知之甚少;然而，越来越清楚的是，单核细胞与植入的ECM支架的相互作用在组织重塑结果中起着重要和决定性的作用。本提案旨在研究两个变量对巨噬细胞（吞噬单核细胞的重要子集）极化（M1/M2）的影响，以响应植入的ECM支架：（1）材料内细胞组分的存在和（2）支架快速降解的能力。提出了三个具体目标：（1）建立并比较宿主巨噬细胞对四种不同支架的反应的M1/M2曲线，（2）确定支架降解对所得M1/M2曲线的影响;和（3）确定参与宿主应答的巨噬细胞的M1/M2谱与下游组织之间的关系-与ECM支架植入相关的重塑结果。这些特定的目标将通过在大鼠体壁模型中植入ECM支架来实现，每个ECM支架的制备方法和/或来源的物种和器官不同，并通过组织学、免疫组织化学和基因表达方法评估宿主巨噬细胞反应和下游组织重塑结果。然后，这些结果将用于确定M1/M2曲线与下游组织重塑结果之间的关系。迄今为止，ECM支架已被植入1，000，000多名患者，应用包括治疗部分和全层伤口、烧伤、软组织修复、脊柱和颅骨修复、骨盆重建以及治疗尿失禁等。因此，为了更好地理解宿主对ECM支架的反应的机制以及生产方法对这种反应的影响，所提出的工作的结果将具有直接的临床意义。这项研究也将有助于理解巨噬细胞极化在整个组织重塑范式中的作用。这项工作将在两年的时间里在一个强烈的智力刺激和跨学科活动的环境中进行。

DESCRIPTION (provided by applicant): The extracellular matrix (ECM) is composed of structural and functional components arranged in a three dimensional architecture. Acellular, noncross-linked scaffolds derived from the ECM have been shown to consistently modulate the default mammalian healing response of scar tissue formation towards a more reconstructive type of host response. The mechanisms by which ECM scaffolds modulate the host response towards constructive remodeling as opposed to scar tissue formation are poorly understood; however, it is becoming increasingly clear that mononuclear cell interactions with implanted ECM scaffolds play an important and determinant role in the tissue-remodeling outcome. The present proposal seeks to study the effects of two variables upon the polarization (M1/M2) of macrophages, an important subset of phagocytic mononuclear cells, in response to an implanted ECM scaffold: (1) the presence of a cellular component within the material and (2) the ability of the scaffold to degrade rapidly. Three specific aims are proposed: (1) establish and compare the M1/M2 profile of the host macrophage response to four different scaffolds in a rat body wall model; (2) determine the effect of scaffold degradation upon the resultant M1/M2 profile; and (3) determine the relationship between the M1/M2 profile of the macrophages participating in the host response and the downstream tissue-remodeling outcome associated with the implantation of an ECM scaffold. These specific aims will be achieved by implanting ECM scaffolds, each differing in method of preparation and/or species and organ of origin, in a rat body wall model and assessing both the host macrophage response and the downstream tissue-remodeling outcome via histological, immunohistochemical, and gene expression methods. These results will then be used to determine the relationship between an M1/M2 profile and the downstream tissue-remodeling outcome. ECM scaffolds have been implanted in 1,000,000+ patients to date in applications that include the treatment of partial and full thickness wounds, burns, soft tissue repair, spinal and cranial repair, pelvic reconstruction, and the treatment of urinary incontinence, among others. Therefore, the results of the proposed work to better understand the mechanisms underlying the host response to an ECM scaffold, and the effects that production methods can have on this response, will have immediate clinical relevance. This research will also contribute to the understanding of the role of macrophage polarization within the tissue remodeling paradigm as a whole. The work will be conducted over the course of two years in an environment of strong intellectual stimulation and interdisciplinary activity.