Department of Rehabilitation Medicine, University of Washington, Seattle, Washington, USA.
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA.
Muscle Nerve. 2021 Oct;64(4):388-403. doi: 10.1002/mus.27360. Epub 2021 Jul 30.
Recent development of novel therapies has improved mobility and quality of life for people suffering from inheritable neuromuscular disorders. Despite this progress, the majority of neuromuscular disorders are still incurable, in part due to a lack of predictive models of neuromuscular junction (NMJ) breakdown. Improvement of predictive models of a human NMJ would be transformative in terms of expanding our understanding of the mechanisms that underpin development, maintenance, and disease, and as a testbed with which to evaluate novel therapeutics. Induced pluripotent stem cells (iPSCs) are emerging as a clinically relevant and non-invasive cell source to create human NMJs to study synaptic development and maturation, as well as disease modeling and drug discovery. This review will highlight the recent advances and remaining challenges to generating an NMJ capable of eliciting contraction of stem cell-derived skeletal muscle in vitro. We explore the advantages and shortcomings of traditional NMJ culturing platforms, as well as the pioneering technologies and novel, biomimetic culturing systems currently in use to guide development and maturation of the neuromuscular synapse and extracellular microenvironment. Then, we will explore how this NMJ-in-a-dish can be used to study normal assembly and function of the efferent portion of the neuromuscular arc, and how neuromuscular disease-causing mutations disrupt structure, signaling, and function.
新型疗法的最新进展改善了遗传性神经肌肉疾病患者的活动能力和生活质量。尽管取得了这一进展，但大多数神经肌肉疾病仍然无法治愈，部分原因是缺乏对神经肌肉接头 (NMJ) 破裂的预测模型。在扩展我们对神经肌肉发育、维持和疾病的基本机制的理解方面，以及作为评估新型治疗方法的试验台方面，改善 NMJ 的预测模型将具有变革性。诱导多能干细胞 (iPSC) 作为一种具有临床相关性和非侵入性的细胞来源，正在成为创建能够体外引发干细胞衍生骨骼肌收缩的人类 NMJ 的方法，用于研究突触发育和成熟，以及疾病建模和药物发现。这篇综述将重点介绍生成能够引发体外干细胞衍生骨骼肌收缩的 NMJ 的最新进展和仍然存在的挑战。我们探讨了传统 NMJ 培养平台的优缺点，以及目前用于指导神经肌肉突触和细胞外微环境发育和成熟的开创性技术和新型仿生培养系统。然后，我们将探讨这种“类器官中的 NMJ”如何用于研究神经肌肉弧传出部分的正常组装和功能，以及神经肌肉疾病引起的突变如何破坏结构、信号传递和功能。
