Modeling chemotherapeutic neurotoxicity with human induced pluripotent stem cell-derived neuronal cells.
Modeling chemotherapeutic neurotoxicity with human induced pluripotent stem cell-derived neuronal cells.
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DOI：
10.1371/journal.pone.0118020
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Dolan ME
中科院分区：
文献类型：
--
作者：
Wheeler HE;Wing C;Delaney SM;Komatsu M;Dolan ME
化疗引起的周围神经病变（CIPN）是化疗最常见的非血液学毒性，目前尚无有效的药物预防或治疗。因此，我们试图评估来自诱导多能干细胞（iPSC）的人神经元样细胞作为研究CIPN的手段的效用。我们使用神经突生长表型的高含量成像测量来比较药物之间和个体之间iPSC衍生的神经元细胞响应于几类化疗药物而发生的变化。在用神经毒性药物紫杉醇、长春新碱或顺铂处理这些神经元细胞后，我们确定了药物之间的五种形态学表型的显著差异，包括总生长、平均/中位/最大突起长度和平均生长强度（P < 0.05）。药物之间损害的差异反映了其作用机制和临床CIPN表现的差异。我们通过证明TUBB 2A表达的降低导致神经元对紫杉醇的敏感性显著增加（总轴突生长减少0.23 ± 0.06，P = 0.011）来显示该模型用于基因扰动研究的潜力。在用一种神经毒性药物治疗后，几种神经突生长和凋亡表型的变化在源自四个不同个体的神经元之间显著大于在源自四个不同个体的神经元内（P < 0.05），证明iPSC衍生的神经元作为CIPN的遗传多样性模型的潜力。人类神经元模型将允许对临床研究中发现的特定基因和遗传变异进行机制研究，并筛选预防或治疗CIPN的新药。
There are no effective agents to prevent or treat chemotherapy-induced peripheral neuropathy (CIPN), the most common non-hematologic toxicity of chemotherapy. Therefore, we sought to evaluate the utility of human neuron-like cells derived from induced pluripotent stem cells (iPSCs) as a means to study CIPN. We used high content imaging measurements of neurite outgrowth phenotypes to compare the changes that occur to iPSC-derived neuronal cells among drugs and among individuals in response to several classes of chemotherapeutics. Upon treatment of these neuronal cells with the neurotoxic drug paclitaxel, vincristine or cisplatin, we identified significant differences in five morphological phenotypes among drugs, including total outgrowth, mean/median/maximum process length, and mean outgrowth intensity (P < 0.05). The differences in damage among drugs reflect differences in their mechanisms of action and clinical CIPN manifestations. We show the potential of the model for gene perturbation studies by demonstrating decreased expression of TUBB2A results in significantly increased sensitivity of neurons to paclitaxel (0.23 ± 0.06 decrease in total neurite outgrowth, P = 0.011). The variance in several neurite outgrowth and apoptotic phenotypes upon treatment with one of the neurotoxic drugs is significantly greater between than within neurons derived from four different individuals (P < 0.05), demonstrating the potential of iPSC-derived neurons as a genetically diverse model for CIPN. The human neuron model will allow both for mechanistic studies of specific genes and genetic variants discovered in clinical studies and for screening of new drugs to prevent or treat CIPN.
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影响因子：
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