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.

抽象的： 周围神经病变是糖尿病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）。雪旺细胞与背根坐骨神经之间的通讯 神经节（DRG）神经元维持周围神经功能的稳态。外泌体、内体衍生的纳米 囊泡携带 RNA 和蛋白质作为其分子货物。外泌体通过以下方式介导细胞间通讯 在源细胞和受体细胞之间转移它们的货物。我们的初步数据表明，治疗类型 雪旺细胞衍生的外泌体 (SC-Exos) 显着改善 II 型糖尿病 db/db 小鼠的神经功能 DPN 功能障碍，与表皮内神经纤维的显着增强有关 坐骨神经的有髓轴突。我们还发现静脉注射的 SC-Exos 被内化 由施万细胞和坐骨神经的神经纤维产生，表明 SC-Exos 作用于施万细胞和坐骨神经 神经。我们的初步数据还表明 SC-Exo 治疗没有显着改变血糖 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 miRNA 和蛋白质网络。基于这些 初步数据，使用高脂肪饮食/链脲佐菌素诱导的 2 型糖尿病的临床相关小鼠模型， 我们建议测试 SC-Exos 与雪旺细胞和坐骨神经相互作用以调节这一假设 miRNA 和蛋白质网络，从而改善 DPN。我们将首先检查 miRNA 货物是否 SC-Exo 的含量有助于 SC-Exos 对 DPN 的治疗效果。然后我们将检查是否有内源性 雪旺细胞和坐骨神经背根神经节 (DRG) 中的 miRNA 增强治疗效果 SC-Exo 的。随后，我们将检查工程 SC-Exos 是否携带升高的选定 miRNA 抑制诱导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 该提案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 一种使用来自健康细胞的外泌体治疗糖尿病周围神经病变的新方法 雪旺细胞。在本提案中，我们还将阐明外泌体的分子机制 治疗有效。这项研究可能会为该研究的转化提供必要的临床前数据。 1 期临床试验的新颖治疗方法。