Endothelial Progenitor Cells in Ischemic Wound Healing

描述(由申请人提供)： 多达200万美国人患有无法愈合的腿部创伤，每年有16.25万人住院治疗，10万人接受截肢手术，每年的医疗费用高达10亿美元。这些创伤通常是由动脉供血不足引起的，或者与糖尿病和标准可用的治疗方法相结合，只有30%-40%的成功率。这项拟议工作的长期目标是通过恢复成熟的微血管系统来识别导致缺血伤口闭合的分子。我们的总体假设是，这种分子在伤口底部的细胞特异性过度表达可以产生有利于恢复新生血管和皮肤结构的细胞因子环境。这些分子可以通过收获的骨髓来源的细胞前体潜在地输送到不可愈合的伤口上。创面新生血管的活化内皮细胞来自两个独立的池，一个是邻近组织内的常驻细胞池，另一个是来自骨髓的前体细胞池。我们的工作假设是，缺血性伤口的功能修复功能障碍可能是由于刺激内皮细胞的基质细胞(如成纤维细胞)来源的因子和/或来自骨髓的前体细胞在伤口床上的招募、分化或存活不足之间的失衡。具体地说，我们将(1)确定骨髓来源的内皮祖细胞在缺血伤口的新生血管和愈合中的作用；(2)研究成纤维细胞和成纤维细胞衍生的生长因子，如胰岛素样生长因子-1(IGF-1)和血小板衍生生长因子B(PDGF-B)在骨髓来源的内皮细胞前体的激活和毛细血管紊乱以及这些前体在缺血伤口的募集中的作用。我们将使用非糖尿病和糖尿病小鼠模型，通过手术创造动脉！不足，因为它们在模仿伤口愈合方面相辅相成，在倾向于发展为无法愈合的肢体缺血性伤口的患者中。此外，我们将使用活体人/鼠嵌合模型和体外人类血管生成模型来添加更多针对人类细胞的信息。

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.