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Cell. 2019 Jan 10;176(1-2):43-55.e13. doi: 10.1016/j.cell.2018.10.049. Epub 2018 Dec 6.

Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment.

Author information

1
Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA 94305, USA.
2
Department of Neurobiology, Stanford University, Palo Alto, CA 94305, USA.
3
Department of Neurobiology, Stanford University, Palo Alto, CA 94305, USA; Department of Neuroscience and Physiology, NYU Neuroscience Institute, New York University School of Medicine, New York, NY 10016, USA.
4
Department of Pathology, Stanford University, Palo Alto, CA 94305, USA.
5
Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA 94305, USA; Department of Pathology, Stanford University, Palo Alto, CA 94305, USA; Department of Pediatrics, Stanford University, Palo Alto, CA 94305, USA; Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94305, USA. Electronic address: mmonje@stanford.edu.

Abstract

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. VIDEO ABSTRACT.

KEYWORDS:

OPC; astrocyte; chemobrain; chemotherapy; chemotherapy-related cognitive impairment; microglia; myelin; oligodendrocyte

PMID:
30528430
PMCID:
PMC6329664
[Available on 2020-01-10]
DOI:
10.1016/j.cell.2018.10.049

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