Biologic scaffolds composed of extracellular matrix (ECM) have been successfully used as inductive templates for the constructive remodeling of many tissues including the lower urinary tract, skin, musculotendinous tissues and esophagus, among others in both preclinical animal studies and in human clinical applications. However, the mechanisms by which this constructive remodeling process occurs in diverse tissues is largely unknown. The source of cells that populate and participate in the ECM remodeling process is a source of controversy and the ability to control such a cell population would represent a significant technical advance in the field of regenerative medicine. The proposed work will address a very focused aspect of the cellular remodeling process. Specifically, we will examine the temporal and spatial patterns of ECM remodeling by two populations of cells: ciculating fibrocytes and local tissue fibroblasts. Circulating fibrocytes are a population of marrow derived cells of hematopoietic origin that have been shown to participate in wound healing, angiogenesis, antigen presentation, and tissue remodeling. To date, these cells have not been examined for their role in tissue reconstruction with an ECM based scaffold approach. We will examine both the bone marrow and surrounding soft tissue as potential sources of both circulating fibrocytes and local tissue fibroblasts during the remodeling process. Using chimeric and transgenic mouse models we will track selected cell populations during studies to accomplish two specific aims. The first specific aim will determine the involvement of bone marrow derived fibrocytes in the remodeling process of ECM biologic scaffolds. The second specific aim will determine the role of local tissue fibroblasts in the remodeling process. We have assembled a highly interdisciplinary team with expertise in medicine, surgery, tissue engineering, ECM biology, stem cell biology, and cellular differentiation. We have identified clearly defined specific aims with quantifiable end points and an efficient three year timeline to conduct this work.
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