Schwann cell derived exosomes improve diabetic peripheral neuropathy in type II diabetic mice

摘要： 周围神经病变是糖尿病的主要常见并发症之一。迫切需要 开发有效的治疗方法，专门用于改善由以下原因引起的神经功能 糖尿病周围神经病变(DPN)。后根雪旺细胞与坐骨神经的联系 神经节(DRG)神经元维持周围神经功能的动态平衡。外切体，内切体衍生的纳米 囊泡携带RNA和蛋白质作为其分子货物。胞外体通过以下途径介导细胞间的通讯 在源细胞和接收细胞之间转移它们的货物。我们的初步数据显示，治疗的类型 雪旺细胞衍生外切体(SC-Exos)对糖尿病db/db小鼠神经功能的显著改善 DPN功能障碍，这与表皮内神经纤维显著增加和 坐骨神经的有髓轴突。我们还发现，静脉给药的SC-Exos内化 Sc-Exos通过雪旺细胞和坐骨神经神经纤维作用于雪旺细胞和坐骨神经 太紧张了。我们的初步数据还显示，SC-Exo治疗并没有显著改变血糖 和糖化血红蛋白(HbA1c)水平和肝功能；然而，重要的是，SC-Exos逆转了 坐骨神经组织中介导DPN发展的miRNAs和蛋白质网络。基于这些 初步数据，使用临床相关的高脂饮食/链脲佐菌素诱导的2型糖尿病小鼠模型， 我们建议测试SC-Exos与雪旺细胞和坐骨神经相互作用的假设，以调节这一点 MiRNAs和蛋白质的网络，从而改善DPN。我们将首先检查miRNA货物是否 SC-Exo参与了SC-Exos对DPN的治疗作用。然后我们将检查内生性 雪旺细胞和背根节坐骨神经中的miRNAs增强疗效 SC-Exo。随后，我们将研究携带提升的选定miRNAs的工程SC-Exo是否会 抑制导致轴突损伤和脱髓鞘的基因进一步减少DPN的神经功能障碍。 相关声明：糖尿病周围神经病变是影响数百万美国人的一种主要残疾。在……里面 这项建议，利用临床相关的糖尿病周围神经病变的动物模型，我们试图开发 利用健康人来源的外切体治疗糖尿病周围神经病变的新方法 雪旺细胞。在这项提案中，我们还将阐明外切体被 治疗效果很好。这项研究可能会为翻译这项研究提供必要的临床前数据。 一期临床试验的新治疗方法。

Abstract: Peripheral neuropathy is one of the major common complications of diabetes. There is a compelling need to develop effective therapeutic approaches specifically designed to improve neurological function caused by diabetic peripheral neuropathy (DPN). Communications between Schwann cells and sciatic nerves of dorsal root ganglia (DRG) neurons maintain homeostasis of peripheral nerve function. Exosomes, endosome-derived nano vesicles carry RNAs and proteins as their molecular cargo. Exosomes mediate intercellular communication by transferring their cargo between source and recipient cells. Our preliminary data showed that treatment of type II diabetes db/db mice with Schwann cell derived exosomes (SC-Exos) remarkably ameliorated neurological dysfunction of DPN, which was associated with significant augmentation of intraepidermal nerve fibers and myelinated axons of the sciatic nerve. We also found that intravenously administered SC-Exos were internalized by Schwann cells and nerve fibers of the sciatic nerve, suggesting that SC-Exos act on Schwann cells and sciatic nerves. Our preliminary data also showed that the SC-Exo treatment did not significantly change blood glucose and glycosylated hemoglobin (HbA1c) levels and liver function; however, importantly, SC-Exos reversed a network of miRNAs and proteins in the sciatic nerve tissues that mediate development of DPN. Based on these preliminary data, using a clinically relevant mouse model of high fat diet/streptozotocin-induced Type 2 diabetes, we propose to test the hypothesis that SC-Exos interact with Schwann cells and sciatic nerves to modulate this network of miRNAs and proteins and thereby ameliorate DPN. We will first examine whether the miRNA cargo of SC-Exo contribute to the therapeutic effect of SC-Exos on DPN. We will then examine whether endogenous miRNAs in Schwann cells and in the sciatic nerve of dorsal root ganglion (DRG) enhance the therapeutic effect of SC-Exo. Subsequently, we will examine whether engineered SC-Exos carrying elevated selected miRNAs to suppress genes that induce axonal injury and demyelination further reduce neurological dysfunction of DPN. Relevance Statement: Diabetic peripheral neuropathy is a major disability affecting millions of Americans. In this proposal, employing clinically relevant animal models of diabetic peripheral neuropathy, we seek to develop a novel therapeutic approach to treat diabetic peripheral neuropathy using exosomes derived from healthy Schwann cells. In this proposal, we will also elucidate the molecular mechanisms by which exosomes are therapeutically effective. This research will potentially provide the essential pre-clinical data for translation of this novel therapeutic approach to a phase 1 clinical trial.