The goal of this project is to investigate the potential of human embryonic stem (hES) cell derived oligoprogenitors as restorative therapy for radiation-induced damage in the brain at the structural and functional levels. The project is based on a substantial body of preliminary data including high yield derivation of oligoprogenitors from human ES cells (NIH approved lines WA-01 and WA-09), survival and differentiation of hES derived progenitors in rat brains, and a quantitative study of the deleterious and irreversible effects of radiation to the adult rat brain. Radiation damage to the brain is a significant clinical problem in cancer management, affecting patients with primary as well as metastatic brain tumors. The effects of radiation to the brain generally occur late (>6-12 months after exposure) and lead to irreversible deterioration in cognitive function. The pathogenesis of late radiation damage is complex, but the pathological outcome is characterized by demyelination and subsequent cerebral atrophy. The radiation model remains essentially unexplored as a possible target for cell replacement despite significant literature pertaining to histopathological changes and the terrible toll on quality of life of the cancer patient. We demonstrate that irradiation results in exhaustion of the cycling oligodendrocyte progenitor pool, with subsequent inability of the brain to replace mature myelinating cells. We have recently developed protocols for the highly efficient differentiation of hES cells into oligoprogenitors. Here we propose to address their potential for repairing radiation damage to the CNS. We will purify the oligoprogenitor populations and perform pilot studies in irradiated rats in an effort to optimize cell numbers, migration, survival and favorable timing of graft placement post irradiation. Once these parameters are elucidated, we will proceed with long term oligoprogenitor or sham grafts in irradiated rats and perform careful behavioral assessments of learning, memory and cognitive tasks, as well electrical studies on brain slices to study conduction across the corpus callosum. We hope to demonstrate the role of hES derived oligoprogenitors in cytoarchitectural restoration of myelination and tissue and behavioral function post radiation. This proposal will use exclusively NIH approved hES lines: WA-01 and WA-09.
|Major, Tamara; Powers, Ann; Tabar, Viviane (2017) Derivation of telencephalic oligodendrocyte progenitors from human pluripotent stem cells. Curr Protoc Stem Cell Biol 39:1H.10.1-1H.10.23|
|Piao, Jinghua; Major, Tamara; Auyeung, Gordon et al. (2015) Human embryonic stem cell-derived oligodendrocyte progenitors remyelinate the brain and rescue behavioral deficits following radiation. Cell Stem Cell 16:198-210|
|Tabar, Viviane; Studer, Lorenz (2014) Pluripotent stem cells in regenerative medicine: challenges and recent progress. Nat Rev Genet 15:82-92|