Limitations and Challenges in Modeling Diseases Involving Spinal Motor Neuron Degeneration in Vitro

Pathogenic conditions involving degeneration of spinal motor neurons (MNs), such as amyotrophic lateral sclerosis, sarcopenia, and spinal cord injury, mostly occur in individuals whose spinal MNs are fully mature. There is currently no effective treatment to prevent death or promote axonal regeneration of the spinal MNs affected in these patients. To increase our understanding and find a cure for such conditions, easily controllable and monitorable cell culture models allow for a better dissection of certain molecular and cellular events that cannot be teased apart in whole organism models. To date, various types of spinal MN cultures have been described. Yet these models are all based on the use of immature neurons or neurons uncharacterized for their degree of maturity after being isolated and cultured. Additionally, studying only MNs cannot give a comprehensive and complete view of the neurodegenerative processes usually involving other cell types. To date, there is no confirmed in vitro model faithfully emulating disease or injury of the mature spinal MNs. In this review, we summarize the different limitations of currently available culture models, and discuss the challenges that have to be overcome for developing more reliable and translational platforms for the in vitro study of spinal MN degeneration

iPSC-Derived Neural Stem Cells Act via Kinase Inhibition to Exert Neuroprotective Effects in Spinal Muscular Atrophy with Respiratory Distress Type 1

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a motor neuron disease caused by mutations in the IGHMBP2 gene, without a cure. Here, we demonstrate that neural stem cells (NSCs) from human-induced pluripotent stem cells (iPSCs) have therapeutic potential in the context of SMARD1. We show that upon transplantation NSCs can appropriately engraft and differentiate in the spinal cord of SMARD1 animals, ameliorating their phenotype, by protecting their endogenous motor neurons. To evaluate the effect of NSCs in the context of human disease, we generated human SMARD1-iPSCs motor neurons that had a significantly reduced survival and axon length. Notably, the coculture with NSCs ameliorate these disease features, an effect attributable to the production of neurotrophic factors and their dual inhibition of GSK-3 and HGK kinases. Our data support the role of iPSC as SMARD1 disease model and their translational potential for therapies in motor neuron disorders