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.
Highlights
Motor neurons (MNs) are differentiated cells that control voluntary actions and are affected primarily by a wide spectrum of neurological disorders, generally indicated as motor neuron diseases (MNDs)
Motor neuron generation from human pluripotent stem cells Different methods for MN differentiation have been performed (Table 1); here, we summarize a selection of the recently published and most significant protocols for obtaining a highly pure population of MNs differentiated from human pluripotent stem cells
Wada and colleagues [46] differentiated Human embryonic stem cell (hESC) toward MNs through neural rosette formation: neural precursors derived from hESCs were treated with 1 μM retinoic acid (RA) and 500 ng/mL Sonic hedgehog (Shh), resulting in large numbers of Tubulin β III+, Hb9+, Islet1+, and choline acetyltransferase-positive (ChAT+) neurons
Summary
Motor neurons (MNs) are differentiated cells that control voluntary actions and are affected primarily by a wide spectrum of neurological disorders, generally indicated as motor neuron diseases (MNDs). Obtaining fully differentiated cells is crucial to model in simplified in vitro platforms the complex processes underlying physiological development and disease pathogenetic mechanisms, with the ultimate aim to find a cure for orphan disorders This could be important for those pathologies, such as MNDs, for which obtaining affected relevant cells from human patients can be challenging. In 2002, Wichterle and colleagues [27] were the first ones to exploit RA and Shh to differentiate mouse ESCs through EB formation; Table 1 Experimental protocols for motor neuron induction from human embryonic and induced pluripotent stem cells
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