Endothelial Progenitor Cells in Ischemic Wound Healing

描述（由申请人提供）： 多达200万美国人患有下肢伤口不愈合，每年有162，500人住院，100，000人截肢，每年的医疗保健费用为10亿美元。 这些伤口通常是由动脉功能不全单独或与糖尿病联合引起的，标准的治疗方法只有30-40%的成功率。 这项工作的长期目标是确定通过恢复成熟的微血管系统诱导缺血性伤口闭合的分子。 我们的总体假设是，这些分子的细胞特异性过表达的基础上的伤口可以产生一个细胞因子的环境，有利于恢复新血管形成和皮肤结构。 这些分子可以通过收获的骨髓来源的细胞前体潜在地递送到不愈合的伤口。 用于伤口新血管形成的活化内皮细胞来源于两个单独的池，一个是邻近组织内的驻留细胞池，另一个是来自骨髓的前体细胞池。 我们的工作假设是，缺血性伤口的功能障碍性愈合可能是由于刺激驻留内皮细胞的基质细胞（例如成纤维细胞）的因子之间的不平衡和/或前体细胞从骨髓到伤口床的募集、分化或存活不足。 具体而言，我们将（1）确定骨髓来源的内皮祖细胞在新生血管形成和缺血性伤口愈合中的作用;（2）研究成纤维细胞及其衍生生长因子胰岛素样生长因子（IGF-1）和血小板衍生生长因子B（PDGF-B）在骨髓基质细胞活化和毛细血管脱分化中的作用。衍生的内皮细胞前体和这些前体向缺血性伤口的募集。我们将使用非糖尿病和糖尿病小鼠模型与手术创建的动脉！因为它们在模拟倾向于发展不愈合的缺血性肢体伤口的患者中的伤口愈合中彼此互补。此外，我们将使用体内人/鼠嵌合模型和体外人血管生成模型来增加对人细胞更特异的信息。

DESCRIPTION (provided by applicant): Up to 2 million Americans suffer from non-healing lower extremity wounds, accounting for 162, 500 annual hospitalizations, 100,000 major limb amputations and one billion dollars per year in health care costs. These wounds usually result from arterial insufficiency alone, or in combination, with diabetes and standard available therapies carry only 30-40% success. The long-term objective of the proposed work is to identify molecules that induce closure of ischemic wounds by restoring a mature microvasculature. Our overall hypothesis is that the cell-specific overexpression of such molecules within the base of the wound can produce a cytokine milieu that is favorable for restoring neovascularization and skin architecture. These molecules could be potentially delivered to a non-healing wound by harvested bone marrow-derived cellular precursors. Activated endothelial cells for neovascularization of wounds are derived from two separate pools, a pool of resident cells within the adjacent tissue and a pool of precursor cells from the bone marrow. Our working hypothesis is that dysfunctional healing in ischemic wounds may be due to an imbalance between factors derived from stromal cells (e.g. fibroblasts) that stimulate the resident endothelial cells and/or insufficient recruitment, differentiation, or survival of precursor cells from the bone marrow into the wound bed. Specifically, we will (1) determine the role of bone marrow-derived endothelial progenitor cells in neovascularization and healing of ischemic wounds; (2) study the role of fibroblasts and fibroblast-derived growth factors like insulin-like growth factor-1 (IGF-1) and platelet derived growth factor B (PDGF-B) in the activation and capillary disorentiation of bone marrow-derived endothelial cell precursors and the recruitment of these precursors to ischemic wounds. We will use non-diabetic and diabetic murine models with surgically created arteria! insufficiency as they complement each other in mimicking wound healing in patients that tend to develop non-healing ischemic limb wounds. In addition, we will use in vivo human/murine chimeric models and models of human angiogenesis in vitro to add information more specific to human cells.