Vincristine impairs microtubules and causes neurotoxicity in cerebral organoids
Vincristine impairs microtubules and causes neurotoxicity in cerebral organoids
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长春新碱损害微管并引起脑类器官的神经毒性
DOI：
10.1016/j.neuroscience.2018.12.047
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发表时间：
2019-04
期刊：
影响因子：
3.3
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Liu F;Huang J;Liu Z
纳米技术在药物递送系统中的进步使得几种抗肿瘤药物在中枢神经系统（CNS）中积累，但脑渗透性较差，但也导致对中枢神经毒性的担忧。阿曲斯汀通常作为有效的抗脑肿瘤药物给药。已知它通过干扰微管动力学起作用，但详细阐明其神经毒性机制的模型有限。在这里，我们使用人类诱导的多能干细胞（iPSC）生成脑类器官，以评估神经毒性机制。用不同浓度的长春新碱处理脑类器官48 h，并测量其扩张。我们还测定了脑类器官中的各种细胞标志物、微管相关蛋白和基质金属蛋白酶（MMP）。处理48 h后，我们观察到剂量依赖性神经毒性，包括高浓度下神经元和星形胶质细胞数量减少。阿曲斯汀治疗还损害了微管相关蛋白微管蛋白和纤连蛋白，并下调MMP 10活性。使用STRING数据库的进一步分析发现，MMP 10和纤连蛋白都与MMP 9实验性结合，并且文本挖掘表明MMP 10和纤连蛋白之间存在相互作用。我们的类器官模型系统允许定量研究长春新碱治疗的影响。我们的研究结果表明长春新碱表现出剂量依赖性神经毒性，抑制脑类器官中的纤连蛋白、微管蛋白和MMP 10表达。
The advance of nanotechnology in drug delivery systems has allowed central nervous system (CNS) accumulation of several anti-tumor agents with poor brain penetration but also lead to concerns about central neurotoxicity. Vincristine is commonly administered as an effective anti-brain tumor drug. It is known to act by interfering with microtubule dynamics, but models for detailed elucidation of its mechanism of neurotoxicity are limited. Here we generated cerebral organoids using human-induced pluripotent stem cells (iPSCs) for evaluation of neurotoxic mechanisms. Cerebral organoids were treated with different concentrations of vincristine for 48 h and their expansion was measured. We also assayed various cell markers, microtubule associated proteins, and matrix metalloproteinases (MMP) in cerebral organoids. After treatment for 48 h, we observed dose-dependent neurotoxicity, including reduced neuron and astrocyte numbers at high concentration. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. Further analysis using the STRING database found that, both MMP10 and fibronectin bind with MMP9 experimentally, and text-mining indicated an interaction between MMP10 and fibronectin. Our organoid model system allowed quantitative investigation of the effects of vincristine treatment. Our findings indicated vincristine exhibited dose-dependent neurotoxicity, inhibited fibronectin, tubulin, and MMP10 expression in cerebral organoids.
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影响因子：
3.4
作者：
Huang J;Liu F;Tang H;Wu H;Li L;Wu R;Zhao J;Wu Y;Liu Z;Chen J
通讯作者：
Chen J
影响因子：
11
作者：
Madison, J. M.;Zhou, F.;Nigam, A.;Hussain, A.;Barker, D. D.;Nehme, R.;van der Ven, K.;Hsu, J.;Wolf, P.;Fleishman, M.;O'Dushlaine, C.;Rose, S.;Chambert, K.;Lau, F. H.;Ahfeldt, T.;Rueckert, E. H.;Sheridan, S. D.;Fass, D. M.;Nemesh, J.;Mullen, T. E.;Daheron, L.;McCarroll, S.;Sklar, P.;Perlis, R. H.;Haggarty, S. J.
通讯作者：
Haggarty, S. J.
影响因子：
64.5
作者：
Mariani J;Coppola G;Zhang P;Abyzov A;Provini L;Tomasini L;Amenduni M;Szekely A;Palejev D;Wilson M;Gerstein M;Grigorenko EL;Chawarska K;Pelphrey KA;Howe JR;Vaccarino FM
通讯作者：
Vaccarino FM
影响因子：
3.9
作者：
Murphy, C;Pickles, T;Thiessen, B
通讯作者：
Thiessen, B
影响因子：
3.9
作者：
T. Postma;C. V. van Groeningen;R. Witjes;J. Weerts;J. Kralendonk;J. Heimans
通讯作者：
T. Postma;C. V. van Groeningen;R. Witjes;J. Weerts;J. Kralendonk;J. Heimans