Cell Recruitment Induced by ECM Scaffold Degradation

描述（由申请人提供）：我们工作的长期目标是优化和更充分地了解细胞外基质（ECM）作为生物支架用于促进受伤或缺失组织和器官的结构和功能重建的方法。ECM为组织提供结构支持，作为生长因子的储存库，并促进细胞间的通信。我们建议研究以前未被认识到的ECM功能；具体来说，它通过释放新形成的生物活性肽参与祖细胞的积极募集，这些肽来源于组织损伤后完整ECM的降解。我们的初步研究表明，细胞外基质的化学和酶降解导致低分子量组分（约5-16 kDa）具有多种生物活性，包括对来自各种组织的祖细胞的化学吸引力。我们已经提出了一个可行的假设，即每个组织的细胞外基质的降解产物对特定组织或器官的祖细胞具有组织特异性的化学引诱性。我们提出了一系列补充性研究，以解决三个具体目标。首先，我们将确定从真皮或肝脏获取的细胞外基质的降解产物是否对祖细胞具有化学吸引作用；多能祖细胞和具有谱系的（皮肤或肝脏）祖细胞。其次，我们将确定体内ECM降解的预防是否会影响（即阻止）祖细胞参与宿主重塑反应。最后，我们将分离和纯化来自肝脏和真皮ECM的化学引诱肽。本提案的方法是跨学科的，并寻求将生物学和伤口愈合的基本原理应用于再生医学的新兴领域。这项工作将由经验丰富的组织工程师、生物化学家、干细胞生物学家、分子生物学家和医生组成的团队进行。提出了研究的目标、实验设计所依据的假设以及完成研究的时间表。

DESCRIPTION (provided by applicant): The long term objective of our work is to optimize and more fully understand the methods by which the extracellular matrix (ECM) can be used as a biologic scaffold to promote the structural and functional reconstitution of injured or missing tissues and organs. The ECM provides structural support for tissues, serves as a storage depot for growth factors, and facilitates cell: cell communication. We propose to investigate a previously unrecognized function of the ECM; specifically, that it participates in the active recruitment of progenitor cells via the release of newly formed bioactive peptides derived from the degradation of intact ECM following tissue injury. Our preliminary studies show that chemical and enzymatic degradation of the extracellular matrix results in low molecular weight fractions (approximately 5-16 kDa) that possess diverse biologic activities including chemoattraction for progenitor cells from various tissues. We have-developed a working hypothesis that degradation products of the extracellular matrix of each tissue have tissue-specific chemoattractant properties for progenitor cells that are lineage committed for that particular tissue or organ. We propose a series of complementary studies that will address three Specific Aims. First, we will determine if degradation products of extracellular matrix harvested from either the dermis or the liver are chemoattractant for progenitor cells; both multipotential progenitor cells and lineage- committed (skin vs. liver) progenitor cells. Second, we will determine if prevention of ECM degradation in vivo affects (i.e., prevents) the participation of progenitor cells in the host remodeling response. Finally, we will isolate and purify chemoattractant peptides derived from hepatic and dermal ECM. This proposal is interdisciplinary in its approach and seeks to apply fundamental principles of biology and wound healing to the emerging field of regenerative medicine. The work will be conducted by an experienced team of tissue engineers, biochemists, stem cell biologists, molecular biologists, and physicians. The objectives of the studies, the hypothesis upon which the experimental design is based, and a timeline for completion of the studies are presented.