Response of Oligodendrocyte Progenitor Cells to Single Dose and Fractionated Irradiation: Potential Implications for Central Nervous System Radiation Late Effects

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Environmental Medicine, 2015.Ionizing radiation (IR) is commonly used in the treatment of central nervous system (CNS) cancers and metastases, for cancer prophylaxis, and during bone marrow transplantation. Frequent side effects resulting from normal brain tissue irradiation include impaired cognition, memory, and attention, as well as necrosis and demyelination; these effects can occur months to years following exposure. Over the decades, radiation oncologists have tried to reduce such effects by delivering the required doses of IR broken down into smaller doses given over the course of several weeks, a process referred to as fractionation. Fractionation selectively spares late responding tissues consisting of post-mitotic, differentiated cells. Proliferating normal and tumor tissue are not spared by fractionation due to the predominant response of acute cell death to radiation exposure in proliferating cells; synchronization of the cell cycle and recruitment of quiescent cells may even enhance cell loss by fractionated radiation in proliferative tissue. The brain is considered to be relatively radiation-resistant due to the differentiation of its constituent cell populations. Therefore, fractionation is used in order to minimize late side effects in the CNS. However, the brain contains stem and progenitor populations that may not benefit from a fractionation protocol, like oligodendrocyte progenitor cells (OPCs). Therefore, we hypothesized that a fractionated regimen may induce a similar acute cell loss to an equivalent single dose. Furthermore, despite the potential for recovery, this acute cell loss would result in impaired maturation and reduced myelin integrity and function. To address these hypotheses, Pdgfrα-CreERT2:Rosa26R-YFP mice, which express inducible yellow fluorescent protein (YFP) under the OPC specific platelet derived growth factor receptor-α (PDGFRα) promoter, were exposed to single dose and vii fractionated IR paradigms and examined at time points ranging from 8 hours to 18 months post-irradiation. We found that fractionation induced an acute loss of OPCs due in part to cell cycle synchrony and entry of quiescent cells into the cycle, which are usually associated with early reacting tissue and not thought to occur in the late responding CNS. Furthermore, recovery of OPCs was impaired following fractionated IR compared to single dose exposure, with the time course of recovery being sexdependent. Finally, reduced OPC maturation and myelination, as well as changes in myelin functionality as assessed by corpus callosum conduction, occurred in both single dose and fractionated IR paradigms. Overall, this work demonstrates that fractionation does not spare all normal brain tissue and, importantly, by depleting a vital progenitor cell pool, fractionated schedules may promote greater white matter dysfunction than single dose exposures, a point that should be considered when designing fractionation regimens in radiotherapy. This suggests that the weight of the therapeutic ratio, or ratio of tumor control to normal tissue damage, in fractionated radiation, falls on eliminating tumor cells, and that efforts should be made to limit radiation exposure to normal brain tissue through stereotactic methods in order to reduce side effects