Scientists have invented a pocket-sized model of the most common form of amyotrophic lateral sclerosis (ALS). “Chip disease,” created using stem cells, could pave the way for new treatments for progressive conditions, researchers say.
In ALS, brain and spinal cord cells that control spontaneous muscle movements (known as motor neurons) break and die. As a result, the brain can no longer send signals to the muscles, leading to symptoms of muscle weakness and paralysis, as well as difficulty speaking, swallowing and breathing.
In a study published July 3rd in the Journal Cell Stem Cell, scientists have published a new model of sporadic ALS, which accounts for up to 95% of cases of ALS and occurs sporadically without a clear genetic cause or known family history. The platform mimics the early stages of the disease and can be done more accurately than previous lab models.
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To build the model, researchers collected blood cells from young ALS patients under the age of 45 and healthy male donors, and the cells were used to build “healthy” chips for comparison. Blood cells can be reprogrammed into induced pluripotent stem cells (IPSCs) and converted to any type of cells in the body. The stem cells were then converted into spinal motor neurons, allowing movement and degenerating, usually with ALS.
The second set of IPSCs transforms into cells similar to the blood-brain barrier (BBB) and helps prevent harmful bacteria and toxins from entering the brain. Spinal neurons were seeded into one channel within the chip, and BBB cells were placed in another channel.
Two chambers separated by porous membranes were perfused with nutrient-rich liquids to mimic continuous blood flow. The resulting “spinal tip” maintained both sets of sets for about a month, helping neurons mature beyond models where fluid was not permitted.
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The base chip was developed by Biotech Company Emulate and was later customized to be used in the ALS model by researchers at Cedars-Sinai in Los Angeles, California.
Previous models of ALS also used IPSC-derived neurons and structures that mimic those found in the brain, but lacked dynamic flow and it was difficult to capture specific aspects of the disease.
“Our previous models were static, like a dish of cells sitting still, and we couldn’t distinguish between ALS and healthy cells,” said Clive Svendsen, executive director of the board of directors of the Governor’s Institute of Regenerative Medicine at Cedars-Sinai. “We recreated in vitro [lab dish] The breathing and flowing environment like human tissue allowed us to detect early differences in ALS neurons. ”
Other experts agree. “Unlike most lab models that lack vascular features and dynamic flow, this chip improves neuronal health and maturation,” said Dr. Kimberly Idoko, board-certified neurologist and medical director of Everwell Neuro, who was not involved in the study. “It captures early disease signals in ALS that are often difficult to detect,” Idoko told Live Science in an email.
With ALS and a healthy tip in hand, the researchers analyzed the activity of over 10,000 genes in every cell. One of the most prominent findings was abnormal glutamate signaling in neurons within the ALS chip.
Glutamic acid is the main excitatory chemical messenger. This means that neurons will likely be generated and send messages to additional neurons. Its counterpart, GABA, is inhibitory. The team said that the activity of the glutamate receptor gene was increased and the activity of the GABA receptor gene in motor neurons was reduced compared to healthy chips.
“We wanted to find this increase in glutamate activity,” Svenden said. “There were no visible neuronal deaths, but we assume that this overexpandability could lead to degeneration at a later stage.”
This finding is consistent with long-standing theories about ALS, suggesting that the enhanced glutamate signaling contributes to nerve damage. It also supports the mechanism of the ALS drug riluzole, which blocks glutamic acid. The new chips will add to evidence of this mechanism and help to clarify how the patient’s symptoms appear at the earliest stage before they become apparent, Svendsen suggested.
Idoko praised the model, but she realized it lacked Glial cells (an additional nervous system cells involved in ALS) and did not capture the late degeneration seen in ALS. “However, such models could be useful for early drug screening, to study how they pass barriers similar to those in the blood-brain barriers in preparation for animal or human research,” she said.
The team is currently working to maintain cells within the model for up to 100 days. We also want to incorporate other cell types, such as muscle cells, to completely mimic the progression of ALS. As motor neurons die from illness, muscle cells are also wasted.
“Our goal is to build a model where more neurons die, so we can better map disease pathways and test treatments in human-like environments,” Svendsen says. For now, the chip provides a window into early molecular changes in ALS, as well as tools to figure out how to detect and slow down disease before irreversible damage occurs.
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