Cellular Remodeling of ECM Scaffolds

描述(申请人提供)：由细胞外基质(ECM)组成的生物支架已成功地作为诱导模板用于许多组织的结构性重建，包括下尿路、皮肤、肌腱组织和食道等，在临床前动物研究和人类临床应用中都是如此。然而，这种建设性重塑过程在不同组织中发生的机制在很大程度上是未知的。填充并参与ECM重塑过程的细胞的来源是一个争议的来源，控制这样的细胞数量的能力将代表着再生医学领域的重大技术进步。拟议的工作将解决细胞重塑过程中非常关注的一个方面。具体地说，我们将研究两类细胞的ECM重塑的时间和空间模式：环状纤维细胞和局部组织成纤维细胞。循环纤维细胞是一类起源于造血细胞的骨髓来源细胞，已被证明参与伤口愈合、血管生成、抗原提呈和组织重塑。到目前为止，这些细胞在以ECM为基础的支架方法的组织重建中的作用还没有得到检验。在重建过程中，我们将检查骨髓和周围软组织作为循环纤维细胞和局部组织成纤维细胞的潜在来源。使用嵌合和转基因小鼠模型，我们将在研究期间跟踪选定的细胞群体，以实现两个特定目标。第一个特定目标将确定骨髓来源的纤维细胞在ECM生物支架重建过程中的参与。第二个特定目标将确定局部组织成纤维细胞在重塑过程中的作用。我们组建了一支高度跨学科的团队，拥有医学、外科、组织工程、细胞外基质生物学、干细胞生物学和细胞分化方面的专业知识。我们已经确定了明确界定的具体目标和可量化的终点，并确定了开展这项工作的三年有效时间表。

DESCRIPTION (provided by applicant): Biologic scaffolds composed of extracellular matrix (ECM) have been successfully used as inductive templates for the constructive remodeling of many tissues including the lower urinary tract, skin, musculotendinous tissues and esophagus, among others in both preclinical animal studies and in human clinical applications. However, the mechanisms by which this constructive remodeling process occurs in diverse tissues is largely unknown. The source of cells that populate and participate in the ECM remodeling process is a source of controversy and the ability to control such a cell population would represent a significant technical advance in the field of regenerative medicine. The proposed work will address a very focused aspect of the cellular remodeling process. Specifically, we will examine the temporal and spatial patterns of ECM remodeling by two populations of cells: ciculating fibrocytes and local tissue fibroblasts. Circulating fibrocytes are a population of marrow derived cells of hematopoietic origin that have been shown to participate in wound healing, angiogenesis, antigen presentation, and tissue remodeling. To date, these cells have not been examined for their role in tissue reconstruction with an ECM based scaffold approach. We will examine both the bone marrow and surrounding soft tissue as potential sources of both circulating fibrocytes and local tissue fibroblasts during the remodeling process. Using chimeric and transgenic mouse models we will track selected cell populations during studies to accomplish two specific aims. The first specific aim will determine the involvement of bone marrow derived fibrocytes in the remodeling process of ECM biologic scaffolds. The second specific aim will determine the role of local tissue fibroblasts in the remodeling process. We have assembled a highly interdisciplinary team with expertise in medicine, surgery, tissue engineering, ECM biology, stem cell biology, and cellular differentiation. We have identified clearly defined specific aims with quantifiable end points and an efficient three year timeline to conduct this work.