Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons.
Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons.
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DOI：
10.1126/sciadv.aat5847
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发表时间：
2018-10
期刊：
影响因子：
13.6
通讯作者：
Kamm RD
中科院分区：
文献类型：
--
作者：
Osaki T;Uzel SGM;Kamm RD
神经肌肉接头的三维生理模型有助于药物筛选和ALS发病机制的研究。肌萎缩性侧索硬化症（ALS）是一种进行性神经退行性疾病，涉及运动神经元（MN）丢失和肌肉萎缩，尽管进行了大量研究，但仍然没有有效的治疗方法。为了提供用于测试候选药物和研究ALS的发病机制的平台，我们开发了ALS芯片技术（即，ALS运动单位），使用三维骨骼肌束沿着来自散发性ALS患者的诱导多能干细胞（iPSC）衍生的和光敏通道视紫红质-2诱导的MN球状体。每个组织在微流体装置的不同隔室中培养。轴突生长在肌纤维束上形成神经肌肉接头。光被用来激活肌肉收缩，这是基于支柱偏转来测量的。与非ALS运动单元相比，ALS运动单元产生较少的肌肉收缩，存在MN降解，并且肌肉中的细胞凋亡增加。此外，肌肉收缩通过单独处理和与雷帕霉素（雷帕霉素抑制剂的机制靶点）和博舒替尼（Src/c-Abl抑制剂）的共处理而恢复。这种恢复与MN中自噬的上调和TAR DNA结合蛋白-43的降解有关。此外，通过内皮细胞屏障给药可降低内皮细胞中P-糖蛋白（转运博舒替尼的外排泵）的表达，表明雷帕霉素和博舒替尼联合治疗ALS具有相当大的潜力。这种ALS-on-a-chip和光遗传学技术可以帮助阐明ALS的发病机制并筛选候选药物。
3D physiological models of neuromuscular junctions could facilitate drug screening and research on pathogenesis of ALS. Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease involving loss of motor neurons (MNs) and muscle atrophy, still has no effective treatment, despite much research effort. To provide a platform for testing drug candidates and investigating the pathogenesis of ALS, we developed an ALS-on-a-chip technology (i.e., an ALS motor unit) using three-dimensional skeletal muscle bundles along with induced pluripotent stem cell (iPSC)–derived and light-sensitive channelrhodopsin-2–induced MN spheroids from a patient with sporadic ALS. Each tissue was cultured in a different compartment of a microfluidic device. Axon outgrowth formed neuromuscular junctions on the muscle fiber bundles. Light was used to activate muscle contraction, which was measured on the basis of pillar deflections. Compared to a non-ALS motor unit, the ALS motor unit generated fewer muscle contractions, there was MN degradation, and apoptosis increased in the muscle. Furthermore, the muscle contractions were recovered by single treatments and cotreatment with rapamycin (a mechanistic target of rapamycin inhibitor) and bosutinib (an Src/c-Abl inhibitor). This recovery was associated with up-regulation of autophagy and degradation of TAR DNA binding protein–43 in the MNs. Moreover, administering the drugs via an endothelial cell barrier decreased the expression of P-glycoprotein (an efflux pump that transports bosutinib) in the endothelial cells, indicating that rapamycin and bosutinib cotreatment has considerable potential for ALS treatment. This ALS-on-a-chip and optogenetics technology could help to elucidate the pathogenesis of ALS and to screen for drug candidates.
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影响因子：
23.9
作者：
Abernathy DG;Kim WK;McCoy MJ;Lake AM;Ouwenga R;Lee SW;Xing X;Li D;Lee HJ;Heuckeroth RO;Dougherty JD;Wang T;Yoo AS
通讯作者：
Yoo AS
DOI：
10.1016/0360-3016(95)02065-9
发表时间：
1996-01-15
影响因子：
7
作者：
Groebe, K;MuellerKlieser, W
通讯作者：
MuellerKlieser, W
影响因子：
12.3
作者：
Fisher S;Barry A;Abreu J;Minie B;Nolan J;Delorey TM;Young G;Fennell TJ;Allen A;Ambrogio L;Berlin AM;Blumenstiel B;Cibulskis K;Friedrich D;Johnson R;Juhn F;Reilly B;Shammas R;Stalker J;Sykes SM;Thompson J;Walsh J;Zimmer A;Zwirko Z;Gabriel S;Nicol R;Nusbaum C
通讯作者：
Nusbaum C
影响因子：
5.3
作者：
Madji Hounoum B;Vourc'h P;Felix R;Corcia P;Patin F;Guéguinou M;Potier-Cartereau M;Vandier C;Raoul C;Andres CR;Mavel S;Blasco H
通讯作者：
Blasco H
影响因子：
4.8
作者：
Caccamo, Antonella;Majumder, Smita;Oddo, Salvatore
通讯作者：
Oddo, Salvatore