Reprogrammed cell therapy for white matter restoration in aged brain ischemia

重编程细胞疗法用于老年脑缺血白质恢复

• 批准号: 10421267
• 负责人: GUODONG CAO
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10421267
• 关键词: Astrocytes; Axon; Biology; Brain; Brain Ischemia; CSPG4 gene; Cell Therapy; Cells; Central Nervous System Diseases; Chronic; Cicatrix; Coculture Techniques; Demyelinations; Electron Microscopy; Electrophysiology (science); Ensure; Failure; Functional disorder; Gender; Goals; Human; Hypoxia; Image; Immune response; Impaired cognition; In Situ; In Vitro; Infarction; Infusion procedures; Ischemia; Ischemic Stroke; Knowledge; Lentivirus Vector; Lesion; Light; Measures; Medical; Methods; Middle Cerebral Artery Occlusion; Mission; Modeling; Multiple Sclerosis; Mus; Myelin; Names; Natural regeneration; Nerve Tissue; Nervous System Physiology; Neurologic; Neurons; Oligodendroglia; Patient Care; Proliferating; Proteins; Recombinants; Recovery; Recovery of Function; Role; Stroke; Structure; System; Testing; Therapeutic; United States; Work; aged; aging brain; axon injury; base; behavior measurement; behavior test; brain repair; cell replacement therapy; clinically relevant; histological image; improved; in vivo; military veteran; myelination; neurological recovery; neuronal survival; neurotransmission; novel; novel strategies; novel therapeutic intervention; oligodendrocyte progenitor; overexpression; physically handicapped; post stroke; relating to nervous system; remyelination; repaired; restoration; stem cell replacement; stem cells; stroke patient; subcortical ischemic vascular disease; tissue repair; transcription factor; translational potential; white matter

Abstract Ischemia causes a massive loss of both oligodendrocytes and its progenitor cells (OPCs), the only cells responsible for myelination in the CNS, leading to axonal damage and demyelination, failure of nerve signal conduction, sensorimotor dysfunction, and cognitive impairments. Thus, OPC replacement therapy is a critical prerequisite for WM restoration and brain repair, especially for aged subjects who have more severe WMI and poor oligodendrocyte proliferative capacity compared to young subjects. We have successfully reprogrammed reactive astrocytes surrounding the infarct core into OPCs by forced overexpression of three transcription factors in the ischemic brain. Reprogrammed OPCs can proliferate/differentiate into mature oligodendrocytes, remyelinate axons, and improve neurological function after brain ischemia. We further discovered that iOPCs increase neuronal survival and axonal outgrowth. The central hypothesis to be tested is that in vivo reprogrammed oligodendrocytes improve neurological function by enhancing white matter remodeling, including axonal remyelination and axonal outgrowth. The following three Aims are proposed: 1) Characterize the maturity of iOPCs and their role in improving neurological function after brain ischemia in aged mice in both genders. 2) Investigate whether iOPCs restore WM by enhancing axonal remyelination and stimulating axonal outgrowth after brain ischemia. 3) Aim 3: Test whether local brain infusions of recombinant SOA can reprogram reactive astrocytes into oligodendrocytes, restore WM, and improve neurological function after brain ischemia. Our long-term goal is to develop novel and unique strategies for long term recovery of white matter and neurological function.

抽象的 缺血会导致少突胶质细胞及其祖细胞 (OPC) 大量损失， 中枢神经系统中唯一负责髓鞘形成的细胞，导致轴突损伤和脱髓鞘， 神经信号传导障碍、感觉运动功能障碍和认知障碍。因此， OPC 替代疗法是 WM 恢复和脑修复的关键先决条件， 尤其是对于 WMI 较严重且少突胶质细胞较差的老年受试者 与年轻受试者相比的增殖能力。我们已成功重新编程 通过强制过度表达三种蛋白，将梗死核心周围的反应性星形胶质细胞转化为 OPC 缺血脑中的转录因子。重新编程的 OPC 可以增殖/分化 转化为成熟的少突胶质细胞，使轴突髓鞘再生，改善脑后神经功能 缺血。我们进一步发现 iOPC 可以增加神经元存活和轴突生长。 要测试的中心假设是体内重编程的少突胶质细胞 通过增强白质重塑（包括轴突）来改善神经功能 髓鞘再生和轴突生长。提出以下三个目标：1) 描述 iOPC 的成熟度及其在改善神经功能中的作用 老年小鼠的脑缺血（无论性别）。 2) 研究iOPC是否恢复WM 通过增强轴突髓鞘再生并刺激脑后轴突生长 缺血。 3) 目标3：测试重组SOA局部脑输注是否可以重新编程 反应性星形胶质细胞转化为少突胶质细胞，恢复 WM，改善神经功能 脑缺血。我们的长期目标是制定新颖且独特的长期战略 白质和神经功能的恢复。