ALS-on-a-chip: New ways to study Lou Gehrig’s Disease

Written By: Ritu Raman

Original Article: Osaki et al. Science Advances 2018
The Gist of It:
Treating a disease requires understanding it: What goes wrong? When does it go wrong? Does it get worse with time? With amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrig’s disease, the cause of gradually and progressive death of the motor neurons (brain cells) that control skeletal muscle is generally unknown and, thus far, unsolved. A new way that scientists are trying to understand the onset and progression of diseases is through “organ-on-a-chip” technology. This is exactly what it sounds like – small volumes of engineered living tissues are grown inside a polymer device called a microfluidic chip. To study a disease like ALS requires an ALS-on-a-chip device that contains two types of tissues: motor neurons and skeletal muscle. In this paper, Osaki et al. develop an ALS-on-a-chip device using cells from a patient with sporadic ALS. They cultured neurons in one compartment of the device and muscle in another, and allowed them to form connections called “neuromuscular junctions” similar to how these tissues are connected in our bodies. In our bodies, when neurons are stimulated, the signal travels down through the neuromuscular junction to make the muscle contract. This group of scientists showed that, compared to healthy neurons, ALS neurons degrade and generate fewer contractions in the muscle. They were then able to test a few different drugs on their chip and showed that treatment with the drugs rapamycin and bosutinib in parallel could potentially help treat ALS. The platform Osaki et al. have developed allows us to study a debilitating and deadly disease and help test potential treatments in the lab before testing them in humans. This makes it more likely that a clinical trial conducted with these treatments will be effective. ALS-on-a-chip is one of many organ-on-a-chip systems being developed by engineers and scientists, and this technology could help us understand and treat many diseases that affect our lives and communities.
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Organ-on-a-chip: Looking at the neuro-muscular junction

The Nitty Gritty
Osaki et al. manufactured microfluidic devices using poly (dimethylsiloxane) (PDMS). Within each device were distinct spatial regions for neurons and muscle, with a region in between for the formation of neuromuscular junctions. Both cell types were derived from human induced pluripotent stem cells (iPSCs). The ALS cells were harvested from a patient with sporadic ALS, and all neurons were genetically engineered to incorporate the light-sensitive ion channel, channelrhodopsin-2, ensuring that the neurons could be externally stimulated using blue light. Neurons and muscle cells were seeded separately and cultured until neurites extended to form neuromuscular junctions with muscle fiber bundles. Light stimulation of neurons was used to drive muscle contraction, and the force of muscle contraction was measured by tracking the deflection of flexible micro-pillars to which the muscle was attached inside the device. Immunostaining and fluorescent imaging of the tissue was used to confirm the spatial patterning and integration of the two cell types. The team then tested the effect of rapamycin and bosutinib on the morphology, viability, and functionality of the ALS-on-a-chip unit, demonstrating that this platform could be used to both understand disease progression and conduct high-throughput screening of therapeutic drugs with potential to treat ALS.
Original Research Article: Osaki, T., Uzel, S.G. and Kamm, R.D., 2018. Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neuronsScience advances4(10), p.eaat5847.

 

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