Reprogrammed cell therapy for white matter restoration in aged brain ischemia

摘要 缺血会导致少突胶质细胞及其祖细胞(OPC)的大量丧失， 只有负责中枢神经系统髓鞘形成，导致轴突损伤和脱髓鞘的细胞， 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前提， 尤其是对于WMI较严重、少突胶质细胞较差的老年人 与年轻受试者相比具有增殖能力。我们已经成功地重新编程 梗死灶周围星形胶质细胞被迫过表达成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，使轴突重新髓鞘，并改善脑后神经功能 缺血症。我们进一步发现iOPC增加了神经元的存活和轴突的生长。 需要检验的中心假设是，体内重新编程的少突胶质细胞 通过增强包括轴突在内的白质重塑来改善神经功能 髓鞘再生和轴突生长。提出了以下三个目标：1) 表征iOPC的成熟度及其在改善术后神经功能中的作用 老龄小鼠脑缺血模型的建立。2)调查iOPC是否恢复WM 促进脑后轴突再髓鞘形成和刺激轴突生长 缺血症。3)目标3：测试局部注射重组SOA能否重新编程 反应后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。我们的长期目标是发展新的和独特的长期战略 脑白质和神经功能的恢复。

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.