Fractionation enhances acute oligodendrocyte progenitor cell radiation sensitivity and leads to long term depletion

• Published in: Glia Vol. 66; no. 4; pp. 846 - 861
• Main Authors: Begolly, Sage, Olschowka, John A., Love, Tanzy, Williams, Jacqueline P., O'Banion, M. Kerry
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.04.2018
• Subjects: Animals; Antineoplastic Agents, Hormonal - pharmacology; apoptosis; Apoptosis - drug effects; Apoptosis - radiation effects; Attention Deficit Hyperactivity Disorder; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Brain; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain - radiation effects; Bromodeoxyuridine; Cell Proliferation - drug effects; Cell Proliferation - radiation effects; Cells (biology); Central nervous system; Cesium Radioisotopes; Cognition; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Exposure; Female; Fractionation; Glial stem cells; Glutathione S-Transferase pi - genetics; Glutathione S-Transferase pi - metabolism; I.R. radiation; Immunohistochemistry; Ionizing radiation; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Male; Metastases; Mice, Transgenic; myelin; Oligodendrocyte Precursor Cells - drug effects; Oligodendrocyte Precursor Cells - metabolism; Oligodendrocyte Precursor Cells - pathology; Oligodendrocyte Precursor Cells - radiation effects; Progenitor cells; proliferation; Radiation effects; Radiation therapy; Radiation Tolerance - drug effects; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Recovery of Function; Remission; Schedules; Sensitivity; Sex Characteristics; Side effects; Substantia alba; Tamoxifen - pharmacology; white matter; myelin; white matter; apoptosis; proliferation; ionizing radiation
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23288

Ionizing radiation (IR) is commonly used to treat central nervous system (CNS) cancers and metastases. While IR promotes remission, frequent side effects including impaired cognition and white matter loss occur following treatment. Fractionation is used to minimize these CNS late side effects, as it reduces IR effects in differentiated normal tissue, but not rapidly proliferating normal or tumor tissue. However, side effects occur even with the use of fractionated paradigms. Oligodendrocyte progenitor cells (OPCs) are a proliferative population within the CNS affected by radiation. We hypothesized that fractionated radiation would lead to OPC loss, which could contribute to the delayed white matter loss seen after radiation exposure. We found that fractionated IR induced a greater early loss of OPCs than an equivalent single dose exposure. Furthermore, OPC recovery was impaired following fractionated IR. Finally, reduced OPC differentiation and mature oligodendrocyte numbers occurred in single dose and fractionated IR paradigms. This work demonstrates that fractionation does not spare normal brain tissue and, importantly, highlights the sensitivity of OPCs to fractionated IR, suggesting that fractionated schedules may promote white matter dysfunction, a point that should be considered in radiotherapy. Main Points Maternal allergic asthma induces changes in DNA methylation and transcription in juvenile offspring microglia. Differentially methylated regions are enriched for functions and transcription factor binding motifs involved in inflammation and microglial development. Differentially expressed genes and differentially methylated regions are enriched for genes dysregulated in Autism Spectrum Disorders.