Wheeler Heather E, Wing Claudia, Delaney Shannon M, Komatsu Masaaki, Dolan M Eileen
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, United States of America.
PLoS One. 2015 Feb 17;10(2):e0118020. doi: 10.1371/journal.pone.0118020. eCollection 2015.
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.
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反应，目前尚无有效的预防或治疗药物。因此，我们试图评估诱导多能干细胞（iPSC）来源的人神经元样细胞在研究CIPN中的作用。我们利用高内涵成像测量神经突生长表型，以比较iPSC来源的神经元细胞在不同药物作用下以及不同个体之间对几类化疗药物的反应变化。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，我们发现不同药物在5种形态学表型上存在显著差异，包括总生长量、平均/中位数/最大突起长度和平均生长强度（P<0.05）。不同药物造成的损伤差异反映了它们作用机制和临床CIPN表现的差异。我们通过证明TUBB2A表达降低导致神经元对紫杉醇的敏感性显著增加（总神经突生长减少0.23±0.06，P=0.011），展示了该模型在基因扰动研究中的潜力。在用一种神经毒性药物处理后，来自四个不同个体的神经元之间，几种神经突生长和凋亡表型的差异显著大于神经元内部的差异（P<0.05），这表明iPSC来源的神经元有潜力作为CIPN的基因多样化模型。这种人类神经元模型将有助于对临床研究中发现的特定基因和基因变异进行机制研究，也有助于筛选预防或治疗CIPN的新药。
