期刊
CELL
卷 176, 期 1-2, 页码 43-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.10.049
关键词
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资金
- California Institute for Regenerative Medicine [CIRM RB4-06093, RN3-06510]
- Unravel Pediatric Cancer
- McKenna Claire Foundation
- Virginia and D.K. Ludwig Fund for Cancer Research
- National Institutes of Neurological Disorders and Stroke [R01NS092597]
- Stanford Neuroscience Institute
- Stanford Maternal and Child Health Research Institute
- Stanford CTSA [UL1 RR025744]
- BioX Institute
- McCormick Fellowship
- Stanford MedScholars Program
- Christopher and Dana Reeve Foundation
- Novartis Institute for Biomedical Research
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- JPB Foundation
- Cure Alzheimer's Fund
- Glenn Foundation
- Esther B. O'Keeffe Charitable Foundation
- Australian National Health and Medical Research Council [GNT1052961]
- Glenn Foundation Glenn Award
- Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases
- Stanford Medical Scientist Training Program
Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent on inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-related cognitive impairment.
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