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Familial amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disorder that is due tomutations in one of several target genes, including SOD1. So far, clinical records, rodent studies, and in vitro models have yielded arguments for either a primary motor neuron disease, or a pleiotropic pathogenesis of ALS. While mouse models lack the human origin, in vitromodels using human induced pluripotent stem cells (hiPSC) have been recently developed for addressing ALS pathogenesis. In spite of improvements regarding the generation ofmuscle cells fromhiPSC, the degree of maturation ofmuscle cells resulting fromthese protocols has remained limited. To fill these shortcomings, we here present a new protocol for an enhanced myotube differentiation fromhiPSC with the option of furthermaturation upon coculture with hiPSC-derived motor neurons. The described model is the first to yield a combination of key myogenic maturation features that are consistent sarcomeric organization in association with complex nAChR clusters in myotubes derived from control hiPSC. In this model, myotubes derived from hiPSC carrying the SOD1 D90A mutation had reduced expression of myogenic markers, lack of sarcomeres, morphologically different nAChR clusters, and an altered nAChR-dependent Ca2+ response compared to control myotubes. Notably, trophic support provided by control hiPSC-derived motor neurons reduced nAChR cluster differences between control and SOD1 D90A myotubes. In summary, a novel hiPSC-derived neuromuscular model yields evidence for both muscle-intrinsic and nerve-dependent aspects of neuromuscular dysfunction in SOD1-based ALS. [ABSTRACT FROM AUTHOR]

Neuromuscular cell culture models are used to investigate synapse formation and function, as well as mechanisms of de-and regeneration in neuromuscular diseases. Recent developments including 3D culture technique and hiPSC technology have propelled their ability to complement insights from in vivo models. However, most cultures have not considered Schwann cells, the glial part of NMJs. In the following, a brief overview of different types of neuromuscular cocultures is provided alongside examples for studies that included Schwann cells. From these, findings concerning the effects of Schwann cells on those cultures are summarized and future lines of research are proposed. [ABSTRACT FROM AUTHOR]

Cell biology and molecular imaging technologies have made enormous progress in basic research. However, the transfer of this knowledge to the pharmaceutical drug discovery process, or even therapeutic improvements for disorders such as neuronal diseases, is still in its infancy. This transfer needs scientists who can integrate basic research with imaging technologies and clinical applications. The graduate training programme described can provide this knowledge based on a translational approach. It integrates the expertise in basic and clinical research within the University of Heidelberg and the applied research established within the Department of Biotechnology of the University of Applied Sciences Mannheim. (Contains 1 figure.)