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

雪旺细胞衍生的外泌体改善 II 型糖尿病小鼠的糖尿病周围神经病变

• 批准号: 10121320
• 负责人: Lei Wang
• 金额: $ 41.12万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10121320
• 关键词: Ablation; Affect; American; Animal Model; Axon; Blood Glucose; Cells; Clinical Data; Communication; Complications of Diabetes Mellitus; Data; Demyelinations; Development; Diabetes Mellitus; Diabetic mouse; Electrons; Endosomes; Engineering; Family member; Funding; Gene Family; Genes; Glycosylated Hemoglobin; Glycosylated hemoglobin A; High Fat Diet; Homeostasis; Homologous Gene; Intravenous; Investigation; Mediating; MicroRNAs; Microscopic; Molecular; Mus; Nerve Fibers; Nerve Tissue; Nervous System Physiology; Neurologic Dysfunctions; Neurological outcome; Neurons; Neurophysiology - biologic function; Non-Insulin-Dependent Diabetes Mellitus; PTEN gene; Peripheral Nerves; Peripheral Nervous System Diseases; Phase I Clinical Trials; Physiological; Play; Proteins; Proteolipids; RNA; Research; Role; Schwann Cells; Semaphorins; Somatostatin; Source; Spinal Ganglia; Streptozocin; Testing; Therapeutic Effect; Translations; Treatment Efficacy; Type 2 diabetic; Wild Type Mouse; axon injury; base; clinically relevant; db/db mouse; design; diabetic; disability; effective therapy; exosome; improved; intercellular communication; intravenous administration; knock-down; liver function; mouse model; nanovesicle; novel; novel therapeutic intervention; pre-clinical; sciatic nerve; transmission process

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.

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）。背根雪旺细胞与坐骨神经的交通联系 神经节（DRG）神经元维持外周神经功能的稳态。外泌体，内体衍生的纳米 囊泡携带RNA和蛋白质作为它们的分子货物。外泌体介导细胞间通讯， 在源细胞和受体细胞之间转移它们的货物。我们的初步数据显示， 具有雪旺细胞衍生的外泌体（SC-Exos）的II型糖尿病db/db小鼠显著改善神经功能 DPN功能障碍，这与表皮内神经纤维的显著增加有关， 坐骨神经的有髓轴突。我们还发现，静脉注射SC-外骨骼肌可以内化， 通过雪旺细胞和坐骨神经的神经纤维，表明SC-Exos作用于雪旺细胞和坐骨神经， 神经我们的初步数据还显示，SC-Exo治疗没有显著改变血糖 和糖化血红蛋白（HbA 1c）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miRNA和蛋白质网络。基于这些 初步数据，使用高脂饮食/链脲霉素诱导的2型糖尿病的临床相关小鼠模型， 我们建议验证SC-Exos与雪旺细胞和坐骨神经相互作用以调节这种作用的假设。 通过miRNA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对糖尿病周围神经病变的治疗作用可能与SC-Exo对糖尿病周围神经病变的治疗作用有关。然后我们将研究是否内源性 雪旺细胞和坐骨神经背根节（DRG）中的miRNA增强治疗效果 关于SC-Exo随后，我们将研究是否工程化的SC-Exos携带升高的选定的miRNA， 抑制诱导轴突损伤和脱髓鞘基因进一步减少DPN的神经功能障碍。 相关性声明：糖尿病周围神经病变是影响数百万美国人的主要残疾。在 该建议采用临床相关的糖尿病周围神经病变动物模型，我们寻求开发 使用源自健康人的外泌体治疗糖尿病周围神经病变的新治疗方法 雪旺氏细胞。在这个提议中，我们还将阐明外泌体被 治疗有效。这项研究可能会提供必要的临床前数据， 一种新的治疗方法进入1期临床试验。