Human neural precursor cell-mediated therapy in a viral model of demyelination

脱髓鞘病毒模型中的人神经前体细胞介导的治疗

• 批准号: 10076583
• 负责人: Thomas E Lane
• 金额: $ 25.01万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10076583
• 关键词: Human; neural; precursor; cell; mediated; Human; neural; precursor; cell; mediated

 DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by multifocal regions of inflammation and myelin destruction. Typically, MS runs a protracted clinical course lasting over several decades with episodes of exacerbation followed by variable periods of remission. Available evidence indicates that the cause of MS is multifactorial and includes the genetic background of the individual as well as environmental influences e.g., viral infection. The development of animal models in which the clinical and histologic pathology is similar to that observed in the majority of MS patients is imperative in order to attempt to better understand the underlying pathological mechanisms contributing to MS. Viral models of demyelination are important tools for studying the pathogenesis of disease. Persistent infection of mice with the neurotropic JHM strain of mouse hepatitis virus (MHV) is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and histologically with the human demyelinating disease multiple sclerosis (MS). Combined with the fact that an environmental agent such as a virus is considered to be a contributing cause of MS, the MHV system offers an excellent model in which to study both the underlying immunopathological mechanisms that may drive demyelination in MS patients as well as novel therapeutic methods for promoting remyelination. Stem cells offer an exciting new avenue for treatment of many autoimmune diseases including MS. We now have determined that intraspinal transplantation of human pluripotent-derived neural precursor cells (hNPCs) into MHV-infected mice with established demyelination results in sustained clinical improvement that is associated with reduced neuroinflammation and remyelination. Our findings indicate that transplanted hNPCs are rejected indicating that these cells are capable of modulating the microenvironment that allow for prolonged clinical recovery. Preliminary results indicate that hNPC-mediated recovery is associated with the emergence of regulatory T cells that presumably dampen neuroinflammation as well as activation/maturation of endogenous oligodendrocyte progenitor cells that likely contribute to remyelination. This application will interrogate the underlying mechanisms by which hNPCs contribute to repair and recovery of motor skills.

 描述（由适用提供）：多发性硬化症（MS）是中枢神经系统（CNS）的慢性疾病，其特征是炎症和髓磷脂破坏的多灶区域。通常，MS运行了持续数十年的长期临床过程，并发作加重，随后发生了可变的缓解周期。现有证据表明，MS的原因是多因素的，包括个体的遗传背景以及环境影响，例如病毒感染。为了更好地理解有助于MS的基本病理机制，必须进行临床和组织学病理学与大多数MS患者相似的动物模型的发展。脱髓鞘的病毒模型是研究疾病发病机理的重要工具。用小鼠肝炎病毒（MHV）的神经型JHM菌株对小鼠的持续感染的特征是持续的脱髓鞘是由炎性T细胞和巨噬细胞介导的，在临床和组织学上与人类脱氧蛋白疾病疾病多发性硬化症（MS）在临床学和组织学上相似。结合以下事实：MHV系统提供了一种促成MS的促成原因，它提供了一种出色的模型，在该模型中，可以研究MS患者可能会驱动脱髓鞘的潜在免疫病理学机制，以及用于促进再递送的新型治疗方法。干细胞为治疗包括MS在内的许多自身免疫性疾病提供了令人兴奋的新途径。现在，我们已经确定，人类多能衍生的神经元前体细胞（HNPC）对具有确定脱髓鞘的MHV感染小鼠进行了脊柱内移植，从而导致持续的临床改善，这与降低的神经炎症和重新启示有关。我们的发现表明，移植的HNPC被拒绝，表明这些细胞能够调节可延长临床恢复的微环境。初步结果表明，HNPC介导的恢复与调节性T细胞的出现有关，可能会抑制神经炎症，以及内源性少突胶质细胞祖细胞的激活/成熟，这可能有助于再髓样。该应用将询问HNPC有助于修复运动技能的基本机制。