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: 10609426
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609426
• 关键词: Aging; Astrocytes; Axon; Biology; Brain; Brain Hypoxia-Ischemia; 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; Generations; Goals; Histologic; Human; Image; Immune response; Impaired cognition; In Situ; In Vitro; Infarction; Infusion procedures; Ischemia; Ischemic Stroke; Knowledge; Lentivirus Vector; Lesion; Measures; Medical; Methods; Middle Cerebral Artery Occlusion; Mission; Modeling; Multiple Sclerosis; Mus; Myelin; Names; Natural regeneration; Nerve Tissue; Nervous System Physiology; Neurologic Dysfunctions; Neurons; Oligodendroglia; Patient Care; Proliferating; Proteins; Recombinants; Recovery of Function; Role; Stroke; Structure; System; Testing; Therapeutic; United States; Work; aged; aging brain; axon injury; behavior measurement; behavior test; brain repair; cell replacement therapy; clinically relevant; improved; in vivo; long term recovery; military veteran; myelination; neural; neurological recovery; neuronal survival; neurotransmission; novel; novel strategies; novel therapeutic intervention; oligodendrocyte progenitor; overexpression; physically handicapped; post stroke; programs; 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.

摘要

项目成果

Microglia-mediated neuroinflammation and neuroplasticity after stroke.

• DOI: 10.3389/fncel.2022.980722
• 发表时间: 2022
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3

Complement Complex C5b-9 Levels Are Associated with the Clinical Outcomes of Acute Ischemic Stroke and Carotid Plaque Stability.

补体复杂的C5B-9水平与急性缺血性中风和颈动脉斑块稳定性的临床结果有关。

• DOI: 10.1007/s12975-018-0658-3
• 发表时间: 2019-06
• 期刊: Translational stroke research
• 影响因子: 6.9
• 作者: Si W;He P;Wang Y;Fu Y;Li X;Lin X;Chen F;Cao G;Zhang H
• 通讯作者: Zhang H

Elevated Lipoprotein-Associated Phospholipase A2 Is Associated With Intracranial Atherosclerosis.

• DOI: 10.3389/fneur.2022.858302
• 发表时间: 2022
• 期刊: FRONTIERS IN NEUROLOGY
• 影响因子: 3.4
• 作者: Wang, Yuan;Liu, Gang;Song, Haiqing;Cao, Catherine;Ji, Xunming;Cao, Guodong
• 通讯作者: Cao, Guodong

Attenuating vascular stenosis-induced astrogliosis preserves white matter integrity and cognitive function.

• DOI: 10.1186/s12974-021-02234-8
• 发表时间: 2021-08-28
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3
• 作者: Liu Q;Bhuiyan MIH;Liu R;Song S;Begum G;Young CB;Foley LM;Chen F;Hitchens TK;Cao G;Chattopadhyay A;He L;Sun D
• 通讯作者: Sun D

Stem cell therapies in age-related neurodegenerative diseases and stroke.

干细胞疗法治疗与年龄相关的神经退行性疾病和中风

• DOI: 10.1016/j.arr.2016.11.002
• 发表时间: 2017-03
• 期刊: Ageing research reviews
• 影响因子: 13.1
• 作者: Wang Y;Ji X;Leak RK;Chen F;Cao G
• 通讯作者: Cao G