Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment
Methotrexate Chemotherapy Induces Persistent Tri-glial Dysregulation that Underlies Chemotherapy-Related Cognitive Impairment
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DOI：
10.1016/j.cell.2018.10.049
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发表时间：
2019-01-10
期刊：
影响因子：
64.5
通讯作者：
Monje, Michelle
中科院分区：
文献类型：
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作者：
Gibson, Erin M.;Nagaraja, Surya;Monje, Michelle
化疗导致一种常见但知之甚少的长期神经功能缺损综合征。神经前体细胞功能障碍和白色物质功能障碍被认为有助于这种衰弱综合征。在这里，我们证明了接受化疗的人中少突胶质细胞谱系细胞的持续耗竭。通过建立甲氨蝶呤化疗诱导的神经功能障碍的小鼠模型，我们发现白色OPCs也出现类似的耗竭，OPC分化增加但不完全，髓鞘形成持续缺陷。当移植到先前暴露于甲氨蝶呤的大脑的微环境中时，来自化疗幼稚小鼠的OPC类似地表现出增加的分化，表明潜在的微环境扰动。甲氨蝶呤导致小胶质细胞的持续活化和随后的星形胶质细胞活化，其依赖于炎性小胶质细胞。甲氨蝶呤化疗后小胶质细胞耗竭使少突胶质细胞谱系动力学、髓鞘微结构和认知行为正常化。这些研究结果表明，甲氨蝶呤化疗暴露与持续性三胶质细胞失调有关，并确定炎性小胶质细胞作为消除化疗相关认知障碍的治疗靶点。
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.