ECM Scaffolds and Macrophage Polarization-Induced Tissue Remodeling

描述(申请人提供)：细胞外基质(ECM)由三维结构中排列的结构和功能成分组成。从ECM衍生的无细胞、非交联型支架已被证明一致地调节瘢痕组织形成的默认哺乳动物愈合反应，转向更重建类型的宿主反应。ECM支架调节宿主对建设性重塑的反应而不是瘢痕组织形成的机制尚不清楚；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极化(M1/M2)的影响：(1)材料中细胞成分的存在和(2)支架快速降解的能力。巨噬细胞是吞噬单核细胞的重要亚群。本研究提出了三个具体目标：(1)在大鼠体壁模型中建立并比较宿主巨噬细胞对四种不同支架的M1/M2图谱；(2)确定支架降解对所产生的M1/M2图谱的影响；以及(3)确定参与宿主反应的巨噬细胞的M1/M2图谱与植入细胞外基质支架相关的下游组织重建结果之间的关系。这些特定的目标将通过在大鼠体壁模型中植入不同制备方法和/或来源的ECM支架，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来实现。这些结果将被用来确定M1/M2曲线和下游组织重塑结果之间的关系。到目前为止，ECM支架已经在1,000,000多名患者中植入，应用领域包括治疗部分和全部伤口、烧伤、软组织修复、脊柱和颅骨修复、骨盆重建和尿失禁治疗等。因此，更好地了解宿主对ECM支架反应的潜在机制以及生产方法对这种反应的影响的拟议工作的结果，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.