13 December 2017
Making neuromuscular junctions in culture with human stem cells - a more clinically relevant model of Amyotrophic Lateral Sclerosis
Claire Hetherington, University of Aberdeen
Amyotrophic Lateral Sclerosis is a neurodegenerative disease that causes selective death of motor neurons – the cells that control muscle movement. There are two types of motor neurons, both of which are affected in ALS. Upper motor neurons reside in the brain. Lower motor neurons reside in the spinal cord, but form long projections (called axons) that connect to muscle cells, and the area where they meet is called a neuromuscular junction. One of the initial features of ALS is known as the “dying-back” phenomenon, where the neuromuscular junction starts to degrade, before the motor neurons in the brain and spinal cord begin to die. If early intervention could prevent this degeneration of the neuromuscular junction, it could preserve muscle function as well as prevent the death of motor neurons.
ALS is invariably fatal, with the majority of those diagnosed dying within 3-5 years of diagnosis, and most patients develop it between the ages of 40 and 70. There are many different types; some types are genetic and inherited, but others are sporadic with no known direct genetic cause. Despite many years of intensive research there is no cure and extremely limited treatments. Recent advances in stem-cell technology provide a new avenue of research into treatments for ALS. Induced pluripotent stem cells (iPSCs) are produced by taking skin cells from a donor and reverting them to a stem-cell state, which allows them to divide indefinitely as well as be directed to become specialized cells such as motor neurons. These motor neurons can then be used to study their function, as well as testing for possible new medications. iPSCs taken from ALS patients have been shown to develop motor neuron disease characteristics in the lab, and can be compared to those from healthy adults.
My PhD project aims to develop a neuromuscular junction using human stem cells and microfluidic devices, as a type of ‘organ-on-a-chip’. Microfluidic devices are small devices that contain microscopic channels through which very small volumes of liquid can flow, and inside which cells can be grown. In the human body, motor neurons and muscles are separated by a long distance, connected only by neuronal axons – using a specially-designed microfluidic device, this can be simulated by growing the neurons and muscle cells in separated compartments connected only by tiny channels through which the axons can grow to meet the muscle. Using microfluidic devices has other advantages; due to their small scale they reduce the cost of culture and allow precise control of the culture environment.
Neuromuscular junctions ‘on-a-chip’ are exemplary of a technology ‘where science meets business’. In addition to their use in physiology research and understanding of the causes of diseases like ALS, they could be a potent tool within commercial pharmaceutical development, for example by allowing automation of culture and high-throughput drug screening. Their use in toxicology studies could streamline drug development pipelines and reduce usage of animals in research. This is of particular importance for ALS, where there is a strong need for new and effective treatments, and where drug development has generally failed at the clinical trial stage. By making our research models more clinically relevant, the quality and efficiency of basic research and commercial drug development can be drastically improved.