Investigating How Stem Cells Become Motor Neurons
Material below is adapted from the SfN Short Course Stem Cells As a Tool for Studying the Developmental Regulation of Gene Expression, by Hynek Wichterle, PhD, et al. Short Courses are daylong scientific trainings on emerging neuroscience topics and research techniques held the day before SfN’s annual meeting.
Muscle movements, such as breathing, walking, speaking, and fine motor skills, are controlled by the activity of motor neurons. These cells originate in the spinal cord and carry signals from the brain to the muscles.
The loss of motor neuron function is at the root of several neurological disorders with symptoms ranging from muscular weakness and atrophy to paralysis. No effective treatments are available for such motor neuron diseases or spinal cord injuries.
The development of treatments has been hindered by the inability to produce sufficient numbers of motor neurons in the lab to accurately model disease and injury and perform mechanistic studies or drug screens. However, recent advances in stem cell and reprogramming technology may change this by allowing the efficient production of motor neurons in the lab.
Stem cells are defined by the ability to proliferate indefinitely while maintaining the potential to differentiate into any kind of specialized cell. Stem cell-derived motor neurons are a promising research tool for modeling disease and injury and developing therapeutic approaches.
In order to create motor neurons from stem cells in the lab, scientists must direct the differentiation of stem cells into specific kinds of motor neurons. During normal embryonic development, the fate of stem cells is controlled by transcription factors, proteins that act in the cell nucleus to regulate gene function. Transcription factors tell the genes in a cell to turn on and off and cause specific genetic expression that leads to cell differentiation.
Studies indicate stem cells in culture dishes in the lab respond to the same transcription factors guiding differentiation into neurons during embryological development. The forced expression of transcription factor combinations known as programming modules has been used to produce specific types of neurons in the lab.
But the detailed mechanisms by which transcription factors regulate gene expression and specify cell identity remain largely enigmatic. A better understanding of these mechanisms would both shed light on the process of cell differentiation during normal embryonic development and help the design of programming modules to produce specific cell types in the lab.
Early methods for motor neuron differentiation from stem cells were relatively inefficient and required several weeks for the cells to mature. Now, scientists have developed a stem cell-differentiation system that allows for the investigation of transcriptional regulatory networks controlling the identity of spinal motor neurons.
The process recapitulates normal embryonic development providing the opportunity to study neural development in a controlled environment outside of the embryo. The expression of a specific programming module (known as NIL factors) rapidly and efficiently turns neural progenitor cells derived from human stem cells into mature spinal motor neurons. These so-called induced motor neurons possess characteristics of normally developed motor neurons, including distinctive electrophysiological responses and the ability to engraft into the developing spinal cord. Induced motor neurons express specific molecular markers and have functional properties indicative of mature motor neurons.
Motor neuron diseases like amyotrophic lateral sclerosis and spinal muscular atrophy, which are caused by the loss or degeneration of motor neurons, are complex and have no cure. Current treatments are limited and involve helping patients with some symptoms. This method can be used to produce specific types of motor neurons from stem cells to study how these cells work and what happens when they deteriorate.