Progenitor Cells in Diabetes Impaired Wound Healing

摘要：糖尿病愈合障碍是一个主要的临床问题，导致延长 住院，失去工作时间，以及高昂的医疗费用。正常的伤口愈合是一个错综复杂的过程 涉及多种生长因子、细胞类型和信号相互作用的过程。在受损的糖尿病伤口中 愈合、生长因子产生的改变、细胞募集、血管生成、细胞外基质(ECM) 生产和伤口收缩都被证明起到了作用。基于细胞的治疗是一种新的疗法 糖尿病受损的伤口愈合的方法，因为有可能纠正许多这些缺陷。我们 最近发现基质祖细胞(SPC)可以纠正糖尿病创面愈合障碍， 糖尿病创面缺乏负责祖细胞募集的趋化因子。此外, 慢病毒过表达趋化因子SDF1-a也纠正了糖尿病上皮化的损害 和肉芽组织的生产。我们建议进行进一步的研究，以确定这种纠正的机制和 利用这一洞察力来改变糖尿病伤口愈合反应。具体目标1：描述 基质祖细胞治疗纠正糖尿病创面愈合的机制 减损。我们建议使用我们的糖尿病损伤创面愈合的db/db模型来表征 SPC治疗纠正糖尿病创面愈合损害的机制。具体地说，使用 激光捕获显微切割的新方法，我们将研究外源SPC的单独贡献 而内源性伤口细胞要：1)产生参与再上皮化、肉芽形成的生长因子 组织的产生和祖细胞的招募2)祖细胞的招募3)祖细胞的生产和 细胞外基质的质量和伤口的生物力学特性。具体目标2：描述 增加内源性祖细胞募集以纠正糖尿病伤口愈合的可能性 减损。我们建议使用我们的糖尿病损伤创面愈合的db/db模型来表征 慢病毒过表达SDF-1a纠正糖尿病创面愈合损害的机制。 具体地说，我们将检查：1)内皮祖细胞和基质前体细胞的募集，2)伤口 生长因子、趋化因子和细胞外基质分子的产生，3)生物力学特性 伤口，在Lenti-SDF1-a治疗后。此外，我们将研究受阻的释放的影响 骨髓来源的祖细胞对SDF-1a修复创面愈合缺陷的影响 纠正糖尿病伤口愈合障碍具有深远的后果，包括减少 住院，功能改善，手术程序减少，也许最重要的是， 降低伤口护理成本。顺利完成研究目标及落实我们建议的 新的干预措施将对医疗保健支出和功能结果产生巨大影响 糖尿病创面，并可能影响所有慢性创面的治疗。

Summary: Diabetic healing impairment represents a major clinical problem resulting in prolonged hospitalizations, lost time from work, and significant healthcare costs. Normal wound healing is an intricate process involving multiple growth factors, cell types, and signaling interactions. In impaired diabetic wound healing, alterations in growth factor production, cellular recruitment, angiogenesis, extracellular matrix (ECM) production, and wound contraction have all been shown to contribute. Cellular based therapy is a novel approach to diabetic impaired wound healing because of the potential to correct many of these deficits. We have recently shown that stromal progenitor cells (SPC) can correct the diabetic wound healing impairment, and that diabetic wounds are deficient in chemokines responsible for progenitor cell recruitment. In addition, lentiviral overexpression of the chemokine SDF1-a also corrects the diabetic impairments in re-epithelialization and granulation tissue production. We propose further studies to define the mechanisms of this correction and to use this insight to modify the diabetic wound healing response. Specific Aim 1: To characterize the mechanisms by which stromal progenitor cell treatment corrects the diabetic wound healing impairment. We propose to use our db/db model of diabetic impaired wound healing to characterize the mechanisms by which SPC treatment corrects the diabetic wound healing impairment. Specifically, using a novel approach of laser capture microdissection, we will examine the separate contribution of exogenous SPC and endogenous wound cells to; 1) The production of growth factors involved in re-epithelialization, granulation tissue production, and progenitor cell recruitment 2) The recruitment of progenitor cells 3) The production and quality of the extracellular matrix and wound biomechanical properties. Specific Aim 2: To characterize the potential for increased endogenous progenitor cell recruitment to correct diabetic wound healing impairment. We propose to use our db/db model of diabetic impaired wound healing to characterize the mechanism by which lentiviral overexpression of SDF-1a corrects the diabetic wound healing impairment. Specifically, we will examine; 1) The recruitment of endothelial and stromal progenitor cells, 2) The wound production of growth factors, chemokines, and ECM molecules, 3) The biomechanical properties of the wound, following lenti-SDF1-a treatment. In addition, we will examine the effect of impaired release of progenitor cells from the bone marrow on the correction of the wound healing defect with SDF-1a. Correction of the diabetic wound healing impairment has far-reaching consequences, including decreased hospitalizations, functional improvements, decreased surgical procedures, and perhaps most significantly, decrease wound care costs. Successful completion of the study aims and implementation of our proposed novel interventions would have an enormous impact on healthcare expenditures and functional outcomes in diabetic wounds and may impact the treatment of all chronic wounds.