Reprogrammed cell therapy for white matter restoration in aged brain ischemia

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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.