Modeling neuromuscular junctions in vitro : A review of the current progress employing human induced pluripotent stem cells

Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disorder of undetermined etiology with no effective treatments. Motor weakness and bulbar dysfunction lead to premature death, usually resulting from respiratory failure. While much of the research has focused on the role of neuronal dysfunction in ALS etiology, evidence from human patients and animal models indicates that the neuromuscular junction (NMJ) shows significant functional and structural abnormalities prior to the onset of motor neuron degeneration and behavioral symptoms. The development of novel experimental approaches will allow the study and manipulation of human NMJs and significantly contribute to our understanding of ALS pathogenesis, leading to advances in pharmacological treatments for the disease. A novel approach that has been employed in recent years is the use of human induced pluripotent stem cells (iPSCs) to generate cell types contributing to synaptic connectivity at the NMJ. The generation and differentiation of cells derived from ALS patient iPSCs is a promising method for investigating disease mechanisms and drug screening at NMJs in vitro . In this review, we cover the theories underlying the mechanisms of ALS pathogenesis at the NMJ, an overview of the recent developments in the generation of functional human neuromuscular connectivity in vitro , and the advances in human iPSC programming and differentiation technology.