ORIGIN OF CELLS THAT REPOPULATE RESORBABLE ECM SCAFFOLDS

本申请是响应计划公告99-024：组织工程研究。 我们组织工程工作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，拟议的研究将调查无细胞的，可吸收的支架/基质和细胞之间的相互作用，这些细胞在植入哺乳动物宿主后重新填充这种支架。 本申请的中心假设是，从天然存在的细胞外基质（ECM）开发的支架可以募集循环祖细胞，所述循环祖细胞占据支架、增殖并分化成位点特异性功能组织。 提出了两项对照动物研究;每项研究使用两种单独的小鼠模型，允许选择性鉴定源自骨髓的细胞。 这些研究旨在成功地实现三个特定目标：（1）确定当天然存在的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支架的新血管形成的内皮细胞的来源;和（3）确定将ECM材料添加到多孔合成聚合物支架中对新血管形成和有助于重塑的内皮细胞来源的影响。 将参与ECM支架重塑的细胞的起源（来源）与有助于其他无细胞可吸收支架重塑的细胞的起源进行比较;特别是I型胶原蛋白、Alloderm和聚（L-乙醇酸）（PLGA）。 这3个具体目标的完成将提供重要的和必要的信息，为未来的智能设计的支架在各种组织工程应用，特别是那些应用中的新血管形成是一个关键的决定因素成功。 拟议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，由一名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.