Abstract
The neuromuscular junction (NMJ) is a specialized cholinergic synaptic interface between a motor neuron and a skeletal muscle fiber that translates presynaptic electrical impulses into motor function. NMJ formation and maintenance require tightly regulated signaling and cellular communication among motor neurons, myogenic cells, and Schwann cells. Neuromuscular diseases (NMDs) can result in loss of NMJ function and motor input leading to paralysis or even death. Although small animal models have been instrumental in advancing our understanding of the NMJ structure and function, the complexities of studying this multi-tissue system in vivo and poor clinical outcomes of candidate therapies developed in small animal models has driven the need for in vitro models of functional human NMJ to complement animal studies. In this review, we discuss prevailing models of NMDs and highlight the current progress and ongoing challenges in developing human iPSC-derived (hiPSC) 3D cell culture models of functional NMJs. We first review in vivo development of motor neurons, skeletal muscle, Schwann cells, and the NMJ alongside current methods for directing the differentiation of relevant cell types from hiPSCs. We further compare the efficacy of modeling NMDs in animals and human cell culture systems in the context of five NMDs: amyotrophic lateral sclerosis, myasthenia gravis, Duchenne muscular dystrophy, myotonic dystrophy, and Pompe disease. Finally, we discuss further work necessary for hiPSC-derived NMJ models to function as effective personalized NMD platforms.
Highlights
Neuromuscular diseases (NMDs) are a broadly defined group of disorders that lead to progressive impairment of motor function
Neural crest stem cells have been derived from human iPSC-derived (hiPSC) via fluorescenceactivated cell sorting (FACS) selection of p75+ cells derived from embryoid bodies (EBs) cultured in stromal-cell-conditioned media, FGF2, and B-27 supplement (Liu et al, 2012)
We have compared the utility of these models for studying the neuromuscular junction (NMJ) structure and function and discussed the current state of disease modeling in the context of five specific NMDs
Summary
Neuromuscular diseases (NMDs) are a broadly defined group of disorders that lead to progressive impairment of motor function. The NMDs primarily involve dysfunction of motor neurons (MNs), skeletal muscle (SkM), or their synaptic connection, the neuromuscular junction (NMJ). Different NMDs have distinct tissue origins such as MNs [e.g., amyotrophic lateral sclerosis (ALS) either from direct loss or retrograde degeneration of MNs], muscle [e.g., Duchenne muscular dystrophy (DMD) or myotonic dystrophy (DM)], NMJs [e.g., myasthenia gravis (MG) or congenital myasthenic syndromes (CMS)], or a combination thereof (e.g., Pompe disease). Regardless of the origin, the structural and/or functional deficit in a targeted tissue will resonate throughout the entire motor unit, leading to multiple shared symptoms among different NMDs. NMDs are estimated to affect 160 per 100,000 people worldwide (Deenen et al, 2015); despite this high prevalence, outcomes are often fatal as few curative treatments are available NMDs are estimated to affect 160 per 100,000 people worldwide (Deenen et al, 2015); despite this high prevalence, outcomes are often fatal as few curative treatments are available.
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