Using induced pluripotent stem cells (iPSC) to model human neuromuscular connectivity: promise or reality?

Abstract

Motor neuron diseases (MND) such as amyotrophic lateral sclerosis and spinal muscular atrophy are devastating, progressive and ultimately fatal diseases for which there are no effective treatments. Recent evidence from systematic studies of animal models and human patients suggests that the neuromuscular junction (NMJ) is an important early target in MND, demonstrating functional and structural abnormalities in advance of pathological changes occurring in the motor neuron cell body. The ability to study pathological changes occurring at the NMJ in humans is therefore likely to be important for furthering our understanding of disease pathogenesis, and also for designing and testing new therapeutics. However, there are many practical and technical reasons why it is not possible to visualise or record from NMJs in pre-and early-symptomatic MND patients in vivo. Other approaches are therefore required. The development of stem cell technologies has opened up the possibility of creating human NMJs in vitro, using pluripotent cells generated from healthy individuals and patients with MND. This review covers historical attempts to develop mature and functional NMJs in vitro, using cocultures of muscle and nerve from animals, and discusses how recent developments in the generation and specification of human induced pluripotent stem cells provides an opportunity to build on these previous successes to recapitulate human neuromuscular connectivity in vitro.

Mechanisms, models and biomarkers in amyotrophic lateral sclerosis

“…If used to screen for potentially relevant ALS drug targets, standardization of cell lines across laboratories will be important for validation of drug effects. Future aims include the development of more complex integrated structures, for example the neuromuscular junction using muscle and neuronal cell cocultures (61). …”

Developmental and Functional Nature of Human iPSC Derived Motoneurons

“…These systems might help in understanding cell type specific behavior e.g. development, proliferation, differentiation or even degeneration [40,185,198]. Cells differentiated from disease specific hiPSCs eventually feature a predicted phenotype.…”

“…Consequently, co-culturing hiPSCs derived motoneurons together with hiPSCs derived oligodendrocytes [58,139,198] from the same donor, provides the ability to investigate not only basic interactions between glial cell and motoneurons in a human system but also the influence of mutated respectively unaffected glial cells on patient derived motoneurons.…”

Controversies and priorities in amyotrophic lateral sclerosis

“…It marks a significant divergence from the traditional view of stem cells as a potential therapy for ALS 120. One of the major challenges will be to overcome the great heterogeneity across cell colonies, and to model the in-vivo network environment of such cells, which might be as important as any individual cellular dysfunction observed in isolation 121.…”