Modeling Motor Neuron Resilience in ALS Using Stem Cells

• Published in: Stem cell reports 2019-06, Vol.12 (6), p.1329-1341
• Main Authors: Allodi, Ilary, Nijssen, Jik, Benitez, Julio Aguila, Schweingruber, Christoph, Fuchs, Andrea, Bonvicini, Gillian, Cao, Ming, Kiehn, Ole, Hedlund, Eva
• Format: Article
• Language: English
• Subjects: ALS; amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Cell Differentiation; Cell Survival; Homeodomain Proteins - metabolism; Humans; LCM sequencing; Medicin och hälsovetenskap; Mice; Motor Neurons - metabolism; Motor Neurons - pathology; Mouse Embryonic Stem Cells - metabolism; Mouse Embryonic Stem Cells - pathology; neuronal vulnerability and resistance; oculomotor neurons; Onuf’s nucleus; Phox2a; Proto-Oncogene Proteins c-akt - metabolism; RNA sequencing; Signal Transduction; spinal motor neurons; stem cells
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2019.04.009

Oculomotor neurons, which regulate eye movement, are resilient to degeneration in the lethal motor neuron disease amyotrophic lateral sclerosis (ALS). It would be highly advantageous if motor neuron resilience could be modeled in vitro. Toward this goal, we generated a high proportion of oculomotor neurons from mouse embryonic stem cells through temporal overexpression of PHOX2A in neuronal progenitors. We demonstrate, using electrophysiology, immunocytochemistry, and RNA sequencing, that in vitro-generated neurons are bona fide oculomotor neurons based on their cellular properties and similarity to their in vivo counterpart in rodent and man. We also show that in vitro-generated oculomotor neurons display a robust activation of survival-promoting Akt signaling and are more resilient to the ALS-like toxicity of kainic acid than spinal motor neurons. Thus, we can generate bona fide oculomotor neurons in vitro that display a resilience similar to that seen in vivo. •Bona fide oculomotor neurons can be derived from stem cells by PHOX2A overexpression•In vitro- and in vivo-generated oculomotor neurons are transcriptionally similar•Stem cell-derived oculomotor neurons display a robust activation of Akt signaling•In vitro-generated oculomotor neurons are relatively resilient to ALS-like toxicity Motor neuron subpopulations show differential vulnerability to degeneration in ALS. Allodi and colleagues report the generation of bona fide oculomotor neurons from stem cells. Similar to their in vivo counterparts, in vitro-derived oculomotor neurons, which showed a high level of protective Akt signaling, were resistant to ALS-like toxicity. Thus, they provide a novel in vitro model for motor neuron resilience in ALS.