ORIGIN OF CELLS THAT REPOPULATE RESORBABLE ECM SCAFFOLDS

本申请是为了响应项目公告99-024：组织工程研究。我们组织工程努力的总体目标是开发安全有效的支架，以支持受伤或受损组织的修复。具体而言，该研究将研究无细胞可吸收支架/基质与植入哺乳动物宿主后重新填充此类支架的细胞之间的相互作用。该应用的中心假设是，从自然发生的细胞外基质（ECM）发展而来的支架可以招募居住在支架上的循环祖细胞，增殖并分化成特定部位的功能组织。提出了两项对照动物研究；每种方法都使用两种不同的小鼠模型，以选择性地识别源自骨髓的细胞。这些研究旨在成功地实现三个特定目标：(1)确定当自然产生的ecm用作组织修复的可吸收支架时，循环祖细胞对重塑组织的贡献；(2)确定参与ECM支架新生血管形成的内皮细胞来源；(3)确定在多孔合成聚合物支架中添加ECM材料对新生血管的影响和内皮细胞的来源，内皮细胞有助于重塑。参与ECM支架重构的细胞的起源（来源）将与参与其他脱细胞可吸收支架重构的细胞的起源进行比较；特别是I型胶原，异体真皮和聚L-乙醇酸（PLGA）。这三个具体目标的完成将为未来各种组织工程应用中支架的智能化设计提供重要和必要的信息；特别是那些新生血管是成功的关键决定因素的应用。提出的研究的基本原理是基于广泛的初步研究，祖细胞生物学的最新发现，由一位共同研究者开发的创新动物模型，并将由一个经验丰富的跨学科研究团队及时进行。

This application is in response to Program Announcement 99-024: Research on Tissue Engineering. The overall goal of our tissue engineering efforts is to develop safe and effective scaffolds that support the restoration of injured or damaged tissues. Specifically, the proposed research will investigate the interaction between acellular, resorbable scaffold/matrices and the cells which repopulate such scaffolds following implantation in mammalian hosts. The central hypothesis of this application is that scaffolds developed from naturally-occurring extracellular matrix (ECM) can recruit circulating progenitor cells which inhabit the scaffold, proliferate, and differentiate into site-specific functional tissues. Two controlled animal studies are proposed; each of which uses two separate mouse models that allow for selective identification of cells which originate in the bone marrow. These studies are designed to successfully accomplish three specific aims: (1) to determine the contribution of circulating progenitor cells to remodeled tissue when naturally-occurring ECMs are used as resorbable scaffolds for tissue repair; (2) to determine the source of endothelial cells which participate in neovascularization of ECM scaffolds; and (3) to determine the effect of adding ECM materials to porous synthetic polymer scaffolds upon neovascularization and the source of endothelial cells which contribute to remodeling. The origin (source) of cells which participate in ECM scaffold remodeling will be compared against the origin of cells which contribute to the remodeling of other acellular resorbable scaffolds; specifically Type I collagen, Alloderm , and poly(L- glycolic acid) (PLGA). Completion of these 3 specific aims will provide important and necessary information for the future intelligent design of scaffolds in a variety of tissue engineering applications; especially those applications where neovascularization is a critical determinant for success. The rationale for the proposed research is based upon extensive preliminary studies, recent findings in progenitor cell biology, an innovative animal model developed by one of the co- investigators, and will be conducted by an experienced interdisciplinary research team in a timely fashion.