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.
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