Motor neuron derivation from human embryonic and induced pluripotent stem cells: experimental approaches and clinical perspectives

Abstract

Motor neurons are cells located in specific areas of the central nervous system, such as brain cortex (upper motor neurons), brain stem, and spinal cord (lower motor neurons), which maintain control over voluntary actions. Motor neurons are affected primarily by a wide spectrum of neurological disorders, generally indicated as motor neuron diseases (MNDs): these disorders share symptoms related to muscular atrophy and paralysis leading to death. No effective treatments are currently available. Stem cell-derived motor neurons represent a promising research tool in disease modeling, drug screening, and development of therapeutic approaches for MNDs and spinal cord injuries. Directed differentiation of human pluripotent stem cells - human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) - toward specific lineages is the first crucial step in order to extensively employ these cells in early human development investigation and potential clinical applications. Induced pluripotent stem cells (iPSCs) can be generated from patients’ own somatic cells (for example, fibroblasts) by reprogramming them with specific factors. They can be considered embryonic stem cell-like cells, which express stem cell markers and have the ability to give rise to all three germ layers, bypassing the ethical concerns. Thus, hiPSCs constitute an appealing alternative source of motor neurons. These motor neurons might be a great research tool, creating a model for investigating the cellular and molecular interactions underlying early human brain development and pathologies during neurodegeneration. Patient-specific iPSCs may also provide the premises for autologous cell replacement therapies without related risks of immune rejection. Here, we review the most recent reported methods by which hESCs or iPSCs can be differentiated toward functional motor neurons with an overview on the potential clinical applications.

Genome-wide RNA-seq of iPSC-derived motor neurons indicates selective cytoskeletal perturbation in Brown–Vialetto disease that is partially rescued by riboflavin

“…Our studies demonstrated that the BVVL-MNs showed a significant reduction in their axonal length, improved by riboflavin treatment. This phenotype is similar to that observed in MN disease such as SMA203031, and this neuropathological feature could be responsible for BVVL neurological motor signs. In fact, several studies have demonstrated a reduction in axonal growth in the MNs derived from SMA-iPSCs relative to control iPSCs2032.…”

ALS-Related Mutant FUS Protein Is Mislocalized to Cytoplasm and Is Recruited into Stress Granules of Fibroblasts from Asymptomatic <b><i>FUS </i></b>P525L Mutation Carriers

“…Yet, they remain at present the best model for the evaluation of some ALS-related mechanistic processes in living ALS patients and in asymptomatic ALS gene mutation carriers. The utilization of fibroblast-derived induced pluripotent stem cells reprogrammed to motor neurons from either ALS patients or asymptomatic mutation carriers [36,40,41] may help in the near future to disclose specific neurodegenerative pathways in asymptomatic mutation carriers. …”

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

“…Additionally, as it has been shown that iPS cells can be generated from human dermal fibroblasts [117,118] and many groups are capitalizing on this chance to produce embryonic-like iPS cells from patients with MN disease such as ALS [119][120][121][122]. Thus, the clinical potential of patientderived iPS lies in the ability for patient-specific disease modeling, high-throughput drug screening, and perhaps eventually gene editing and cell replacement therapy [122,123].…”