Stem cell derived phenotypic human neuromuscular junction model for dose response evaluation of therapeutics.
Stem cell derived phenotypic human neuromuscular junction model for dose response evaluation of therapeutics.
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DOI：
10.1016/j.biomaterials.2018.02.047
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发表时间：
2018-06
期刊：
影响因子：
14
通讯作者：
Hickman JJ
中科院分区：
文献类型：
--
作者：
Santhanam N;Kumanchik L;Guo X;Sommerhage F;Cai Y;Jackson M;Martin C;Saad G;McAleer CW;Wang Y;Lavado A;Long CJ;Hickman JJ
目前还没有由人细胞组成的功能性神经肌肉接头（hNMJ）系统可用于体外药物评价或毒性测试。需要这些系统来评估NMJ的疾病，如肌萎缩性侧索硬化症，脊髓性肌萎缩症或其他神经退行性疾病或损伤状态。当然，没有模型系统，动物或人类，允许运动神经元或肌肉能够产生剂量反应曲线，以评估这些高度专业化的功能单位的药理活性的隔离治疗。开发了一种系统，其中在BioMEMS构建体中的无血清培养基中培养源自干细胞的人肌管和运动神经元。该系统由通过微通道连接的两个腔室组成，以使轴突生长到肌肉腔室，从而允许单独刺激每个组分和生理NMJ功能以及MN刺激的破伤风。运动神经元激活或直接电刺激引起的肌肉收缩，通过图像减影视频记录频率和幅度。生成银环蛇毒素、BOTOX®和箭毒剂量响应曲线以证明表型筛选装置的药理学相关性。这种可量化的功能性hNMJ系统通过包括患者来源的iPSC建立了用于生成患者特异性NMJ模型的平台。
There are currently no functional neuromuscular junction (hNMJ) systems composed of human cells that could be used for drug evaluations or toxicity testing in vitro. These systems are needed to evaluate NMJs for diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy or other neurodegenerative diseases or injury states. There are certainly no model systems, animal or human, that allows for isolated treatment of motoneurons or muscle capable of generating dose response curves to evaluate pharmacological activity of these highly specialized functional units. A system was developed in which human myotubes and motoneurons derived from stem cells were cultured in a serum-free medium in a BioMEMS construct. The system is composed of two chambers linked by microtunnels to enable axonal outgrowth to the muscle chamber that allows separate stimulation of each component and physiological NMJ function and MN stimulated tetanus. The muscle’s contractions, induced by motoneuron activation or direct electrical stimulation, were monitored by image subtraction video recording for both frequency and amplitude. Bungarotoxin, BOTOX® and curare dose response curves were generated to demonstrate pharmacological relevance of the phenotypic screening device. This quantifiable functional hNMJ system establishes a platform for generating patient-specific NMJ models by including patient-derived iPSCs.
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DOI：
10.3390/molecules16010202
发表时间：
2010-12-30
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Li B;Peet NP;Butler MM;Burnett JC;Moir DT;Bowlin TL
通讯作者：
Bowlin TL
影响因子：
7.3
作者：
BLABER, LC
通讯作者：
BLABER, LC
DOI：
10.1111/j.1748-1716.1961.tb02208.x
发表时间：
1961-01-01
期刊：
ACTA PHYSIOLOGICA SCANDINAVICA
影响因子：
--
作者：
LILLEHEIL, G;NAESS, K
通讯作者：
NAESS, K
影响因子：
3.3
作者：
Guo, Xiufang;Johe, Karl;Molnar, Peter;Davis, Hedvika;Hickman, James
通讯作者：
Hickman, James
影响因子：
5.3
作者：
Gould, Thomas W.;Buss, Robert R.;Oppenheim, Ronald W.
通讯作者：
Oppenheim, Ronald W.