Cell Recruitment Induced by ECM Scaffold Degradation

描述(申请人提供)：我们工作的长期目标是优化和更全面地了解细胞外基质(ECM)作为生物支架的方法，以促进损伤或缺失的组织和器官的结构和功能重建。细胞外基质为组织提供结构支持，作为生长因子的储存库，促进细胞与细胞之间的沟通。我们建议研究ECM以前未知的功能；具体地说，它通过释放新形成的生物活性多肽参与祖细胞的主动募集，这些生物活性多肽来自于组织损伤后完整的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)，具有不同的生物活性，包括对不同组织的祖细胞的化学吸引。我们提出了一个有效的假设，即每个组织的细胞外基质的降解产物对祖细胞具有组织特异性的趋化特性，这些祖细胞是特定组织或器官的谱系。我们提出了一系列互补性研究，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趋化性；多潜能祖细胞和谱系承诺(皮肤与肝脏)的祖细胞。其次，我们将确定阻止体内ECM降解是否影响(即阻止)前体细胞参与宿主重塑反应。最后，我们将从肝脏和皮肤ECM中分离和纯化趋化肽。这项建议在方法上是跨学科的，并寻求将生物学和伤口愈合的基本原理应用于新兴的再生医学领域。这项工作将由一个由组织工程师、生物化学家、干细胞生物学家、分子生物学家和医生组成的经验丰富的团队进行。研究的目标，实验设计所基于的假设，以及完成研究的时间表都被提出了。

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.