Adipose Stem Cells for Diabetic Retinopathy

描述（由申请人提供）：患病率估计表明，2360万美国居民患有糖尿病，预计这一数字将在未来三十年翻一番。糖尿病视网膜病变是导致失明的主要原因，在诊断后的20年内，100%的1型糖尿病患者和60%的2型糖尿病患者会发生糖尿病视网膜病变，每年有超过12000名患者因该疾病引起的眼部并发症而失明。糖尿病视网膜病变的根本原因是慢性高血糖对视网膜微血管的损害，导致血管通透性增加和血管闭塞。最近的证据表明，所有这些事件都是由视网膜微血管上的周细胞最初丢失引起的，这使得内皮细胞容易受到糖尿病的影响，从而导致微动脉瘤、静脉改变、视网膜毛细血管丢失和视网膜缺血。我们建议通过开发和评估一种新的成体干细胞疗法来针对周细胞的异常损失，我们假设，这种疗法将补充天然周细胞数量并维持微血管稳态，从而防止最终导致黄斑水肿的下游效应。我们最近的研究表明，成年人脂肪来源的干细胞（hASCs）亚群在体内注射后会自发分化为周细胞，并在此过程中稳定微血管内皮。我们将在三种相关的小鼠模型中验证培养的ASCs包含一个周细胞亚群（或周细胞前体）的假设，这些细胞表现出细胞内信号机制、收缩特性和功能能力，以减少微血管泄漏、减少毛细血管脱落、防止病理性血管生成诱导和/或EC过度增殖：氧诱导视网膜病变（OIR）、链脲霉素诱导糖尿病（STZ）和Akimba，其病理结果与人类dr的早期非增殖性和晚期增殖性方面有关。我们的策略是补充内源性周细胞群，以增强内皮稳定性和防止血管损失。因此，我们设计了三个目标来评估视网膜中hASCs的周细胞容量。目的1：鉴定能够在体外成为功能性周细胞的hASC亚群；目的2：确定hASCs稳定视网膜血管对抗急性（OIR）和慢性（STZ & Akimba）血管损伤的能力；目的3：确定hASCs在急性（OIR）和慢性（STZ & Akimba）血管损伤后增强视网膜血管重建和稳定异常新生血管的能力。

DESCRIPTION (provided by applicant): Prevalence estimates suggest that 23.6 million US residents have diabetes, and this number is predicted to double over the next thirty years. Diabetic retinopathy is the leading cause of blindness, and occurs in 100% of Type 1 and 60% of Type 2 diabetic patients within 20 years of diagnosis, and more than 12,000 patients become blind each year due to ocular complications from this disease. The underlying cause of diabetic retinopathy is damage to the retinal microvasculature from chronic hyperglycemia leading to increased vascular permeability and vascular occlusion. Recent evidence has shown that all of these events follow from the initial loss of pericytes on microvessels in the retina, which makes endothelial cells susceptible to diabetic conditions that result in the microaneurysms, venous changes, retinal capillary loss, and retinal ischemia. We propose to target the aberrant loss of pericytes by developing and evaluating a novel adult stem cell therapy that, we hypothesize, will supplement the native pericyte population and maintain microvessel homeostasis, thereby preventing the downstream effects that ultimately lead to macular edema. We have recently shown that a sub-population of adult human adipose-derived stem cells (hASCs) spontaneously differentiates into pericytes when injected in vivo, and in so doing, stabilizes the microvascular endothelium. We will test the hypothesis that cultured ASCs contain a sub-population of pericytes (or, pericyte precursors) that exhibits the intracellular signaling machinery, contractil properties, and functional abilities to diminish microvascular leakage, reduce capillary dropout, and prevent pathologic angiogenic induction and/or EC hyper-proliferation in three relevant murine models: oxygen-induced retinopathy (OIR), streptozocin induced diabetes (STZ), and Akimba whose pathological outcomes are related to early non-proliferative and late proliferative aspects of human DR. Our strategy is to supplement the endogenous pericyte population in order to enhance endothelial stability and prevent vessel loss. Therefore, we have designed three aims to evaluate the putative pericyte capacity of hASCs in the retina. Aim 1: Identify the hASC subpopulation(s) capable of becoming functional pericytes in vitro; Aim 2: Determine the capacity of hASCs to stabilize retinal vessels against acute (OIR) and chronic (STZ & Akimba) vascular insults; Aim 3: Determine the capacity of hASCs to enhance retinal revascularization and stabilize aberrant neovascularization following acute (OIR) and chronic (STZ & Akimba) vascular insults.