Vascular and Neuronal Repair with Adipose Stromal cells in Retinopathy

描述（由申请人提供）：糖尿病视网膜病变（DR）是长期糖尿病患者最常见的血管并发症，也是导致工作年龄成年人失明的主要原因。据估计，美国的糖尿病患病率为3.4%（近410万人），约40%的糖尿病患者会出现威胁视力的视网膜病变。未来的预测表明，随着老龄化人口的增加以及糖尿病患病率的增加，糖尿病将成为一个更大的公共卫生问题。在DR的早期阶段，周细胞丢失、基底膜增厚和内皮功能障碍导致血液-视网膜屏障完整性丧失，导致严重的黄斑水肿。在随后的阶段，进行性毛细血管和神经变性导致明显的视力丧失。近年来，利用细胞基础疗法修复终末分化器官的概念不断发展。来源于人脂肪组织基质部分的细胞（ASC，脂肪干细胞/基质细胞）可能被用作dr的治疗策略。在本研究中，我们假设脂肪组织可能提供一种新的自体干细胞来源，具有显著的糖尿病损伤组织修复和拯救潜力。在链脲佐菌素（STZ）诱导的糖尿病大鼠模型和缺血再灌注（I/R）损伤模型中，ASC治疗显著改善了血管病理，增强了视觉功能。基于这些初步数据，本项目的主要目标是探讨ASC治疗通过减少缺血/炎症诱导的细胞死亡和通过形成血管周围周细胞稳定血管系统来挽救糖尿病引起的血管和神经元损伤的假设。我们建议通过以下具体目的来研究我们的假设：具体目的1：评估ASC在体外抵抗高血糖应激以保护视网膜细胞并促进血管完整性的潜在机制。目的2：观察ASC移植玻璃体对stz诱导的糖尿病和I/R损伤大鼠模型的治疗效果。总的来说，我们期望通过特定目标的研究结果将描述1)ASC对视网膜神经元和内皮细胞产生有益作用的特定细胞内途径，2)ASC分化成周细胞形成稳定血管网络的机制，3)ASC融入宿主血管系统和修复视网膜损伤和改善视网膜功能的时间过程，以及4)ASC治疗的有效性和安全性。该项目的长期目标是从脂肪组织中建立一种易于获得的新型成体干细胞来源，可用于限制糖尿病视网膜损伤。因此，本研究将探讨糖尿病血管并发症中ASC自体治疗的有益方面。预计我们的结果将为基于asc的治疗方法的I期人体临床试验铺平道路。

DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is the most common vascular complication in patients with long-standing diabetes, and is the leading cause of blindness in working-age adults. The estimated prevalence in the USA is 3.4% (nearly 4.1 million individuals) and about 40% of individuals with diabetes develop vision threating retinopathy. Future projections suggest that DR will become a larger public health problem, with an increase in the aging population as well as an increased prevalence of diabetes. In the early stages of DR, pericyte loss, basement membrane thickening, and endothelial dysfunction results in loss of blood-retinal barrier integrity leading to severe macular edema. In the subsequent stages, progressive capillary and neurodegeneration results in significant loss of vision. In recent years, the concept of repairing terminally differentiated organs with a cell base therapy has evolved. Cells derived from the stromal fraction of human adipose tissue (ASC, adipose stem/stromal cells) could potentially be used as a therapeutic strategy in DR. In this study we hypothesized that adipose tissue may provide a novel autologous source of putative stem cells with significant potential for tissue repair and rescue from diabetic injury. Preliminar data generated in a rat model of streptozotocin (STZ)-induced diabetes and a ischemia-reperfusion (I/R) injury model, ASC treatment significantly improved the vascular pathology and enhanced visual function. Based on these preliminary data, the major goal of this project is to investigate the hypothesis that treatment with ASC will rescue the vascular and neuronal damage induced in diabetes by decreasing ischemia/inflammation-induced cell death and stabilizing the vasculature by forming perivascular pericytes. We propose to investigate our hypothesis through the following specific aims: Specific aim 1: To evaluate the potential mechanisms by which ASC resist hyperglycemic stress to protect retinal cells and contribute to enhanced vascular integrity as pericytes in vitro. Specific aim 2: To determine the therapeutic efficacy of ASC transplanted into the vitreous humor of an STZ-induced diabetic and I/R injury rat models. Overall, we anticipate the findings through the specific aims will characterize 1) the specific intracellular pathways through which ASC produce beneficial effects on retinal neuronal and endothelial cells, 2) mechanisms by which ASC differentiate into pericytes to form stable vascular networks, 3) time course of ASC integration into host vasculature and repair of retinal damage and improvements in retinal function, and 4) efficacy and safety of ASC therapeutics. The long-term goal of this project is to establish a readily available novel adult stem cell sourc from fat tissue that can be employed to limit the diabetic retinal damage. Thus, this proposal wil address beneficial aspects of autologous therapy of ASC in diabetic vascular complications. It is expected that our results will pave the way for Phase I human clinical trials of ASC-based therapeutics.