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Modeling ALS with motor neurons derived from human induced pluripotent stem cells

Abstract

Directing the differentiation of induced pluripotent stem cells into motor neurons has allowed investigators to develop new models of amyotrophic lateral sclerosis (ALS). However, techniques vary between laboratories and the cells do not appear to mature into fully functional adult motor neurons. Here we discuss common developmental principles of both lower and upper motor neuron development that have led to specific derivation techniques. We then suggest how these motor neurons may be matured further either through direct expression or administration of specific factors or coculture approaches with other tissues. Ultimately, through a greater understanding of motor neuron biology, it will be possible to establish more reliable models of ALS. These in turn will have a greater chance of validating new drugs that may be effective for the disease.

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Figure 1: Emulating MN developmental signaling in vitro.
Figure 2: Comparison of published LMN differentiation protocols.
Figure 3: Induced action potentials evolve over time.
Figure 4: (a) Coculture of the neuromuscular circuit.
Figure 5: Classification of diverse neocortical projection neurons.
Figure 6: Cell-extrinsic and cell-intrinsic factors regulate the development of corticofugal projection neurons in sequential, 'nested' stages of differentiation.

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Acknowledgements

We would like to thank S. Svendsen for assistance in editing this manuscript. All authors were funded by various grants from the ALS Association. The corticospinal motor neuron, UMN and cortical projection neuron work of J.D.M. and C.S. was supported by US National Institutes of Health grants R01NS075672, R01NS045523, R01NS049553 and R37NS041590, and by grants from the ALS Association and Spastic Paraplegia Foundation. Work of H.W. and E.L. was also funded in part by Project ALS and Track ALS. Work of J.K. was funded in part by Project ALS. Contributions from S.C.Z. were funded by ALS Association grant 15-IIP-194.

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Correspondence to Clive N Svendsen.

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Sances, S., Bruijn, L., Chandran, S. et al. Modeling ALS with motor neurons derived from human induced pluripotent stem cells. Nat Neurosci 19, 542–553 (2016). https://doi.org/10.1038/nn.4273

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