STEM-17REPAIR OF RADIATION INJURY TO THE BRAIN USING HUMAN PLURIPOTENT STEM CELL DERIVED OLIGODENDROCYTE PROGENITORS

Abstract

Radiation therapy (RT) to the brain remains a powerful tool in the management of a wide range of cancers of the brain, head and neck regions and brain metastases. It is also used in prophylaxis in treatment regimens for leukemias and small cell cancers. There is an increasing awareness of significant and irreversible long-term side effects associated with RT, including cognitive decline and impairment of motor coordination. Our team and others have shown that depletion of oligodendrocyte progenitors (OPC) and demyelination are major pathological features that are particularly pronounced in younger individuals and severely limit therapeutic options. We have developed protocols for the derivation of oligodendrocyte progenitors from human ES or iPS cells. The cells can be expanded at large scale, and present a gene and protein profiles that are reminiscent of authentic telencephalic oligodendrocyte progenitors. These cells were capable of in vitro myelination in co-cultures with human neurons. We also established a rat model of fractionated brain radiation using a clinically relevant regimen. The rats present behavioral changes several months following radiation. OPCs were grafted in the corpus callosum bilaterally and the animals followed for several months. They were grafted with OPCs expression and protein Here we tested whether human ESC-derived oligodendrocytes can functionally remyelinate the irradiated brain using a rat model. We demonstrate that the cells migrate throughout the major white matter tracts resulting in both structural and functional repair. Behavioral testing showed complete recovery of cognitive function while additional recovery from motor deficits requiredconcomitant transplantation into the cerebellum. The ability to repair radiation-induced damage to the brain could dramatically improve the outlook for cancer survivors and enable more effective use of radiation therapies, especially in children.