Transplanting motor neurons strengthens muscles in mouse model
Healthy nerve cells connected with muscle cells, controlling movement
Scientists have devised a technique for transplanting healthy motor neurons — the nerve cells that are lost in amyotrophic lateral sclerosis (ALS) — in a mouse model with “highly aggressive” disease.
Transplanted motor neurons, given stimulation, were able to form healthy connections with muscle cells to control the animals’ muscle movement, and they also helped to lessen muscle atrophy or wasting.
“Our study demonstrates that replacement motor neurons can robustly and reliably reinnervate target muscles in an advanced model of ALS,” Linda Greensmith, PhD, a study co-author and professor in the department of neuromuscular diseases at University College London (UCL), said in a UCL press release.
The study, “An optogenetic cell therapy to restore control of target muscles in an aggressive mouse model of Amyotrophic Lateral Sclerosis,” was published in eLife.
Transplanted motor neurons placed close to target muscles, then stimulated
Motor neurons are the specialized nerve cells that control muscle movement. ALS, caused by the progressive dysfunction and death of these cells, results in a loss of control over muscle movement.
“The cellular and molecular changes that underlie neuron degeneration in ALS are extremely complex, and can vary greatly between individual patients. Due to this, there are currently no therapies that can prevent the progression of symptoms in ALS patients,” said Barney Bryson, the study’s co-senior author and a senior fellow at UCL’s neurology institute.
Researchers explored a technique aiming to transplant healthy motor neurons to restore muscle movement in ALS. In this technique, the transplanted neurons are placed very close to target muscles, which helps them to form connections with the muscles. But this placement also means that the motor neurons aren’t hooked into the brain or spinal cord, so they aren’t getting any of the signals that normally tell motor neurons when to activate.
Instead, the transplanted motor neurons are activated using a technique called optogenetics, where the cells are engineered to fire when a specific type of light is shone on them. The research team also has been developing implantable devices that use light to control motor neurons in this way.
The scientists previously conducted proof-of-principle experiments in a mouse model of nerve injury, where existing motor neurons were severed and then replaced with transplanted ones. Here, they aimed to translate the approach into a mouse model of severe ALS caused by a mutation in the SOD1 gene.
For these ALS model experiments, the scientists used healthy motor neurons generated from mouse stem cells in a lab. They suggested that similar procedures might be used to provide healthy cells for ALS patients if this technique can be translated to the clinic.
Activated motor neurons triggered muscle movement in the mice
In their first experiments, over 95% of the transplanted motor neurons died because the mice’s immune system mistook the transplanted cells as a threat and attacked them.
Based on this finding, the researchers tested whether the transplant procedure could be improved by treating the mice with an immune-suppressing therapy.
They initially tried a drug called tacrolimus, which is often used to suppress the immune system prior to an organ transplant in people. While tacrolimus’ use allowed more motor neurons to survive, it had toxic effects on the mice’s bodies, so the transplanted neurons weren’t able to form healthy connections with muscle cells.
Researchers next tried a more targeted therapy called H57-597, which specifically inhibits the activity of T-cells (a type of immune cell) by blocking the receptor that these cells normally use to detect threats. With H57-597 treatment, all of the transplanted motor neurons survived and formed healthy connections with the mice’s muscles.
This procedure could be reliably replicated in dozens of individual mice, the researchers showed, and they found that similar results were obtained regardless of what subtype of motor neuron was used in the transplant.
“If this approach can be successfully translated to ALS patients, the redundancy of the motor neuron subtype used would mean that a single type of motor neuron could be produced to target a large number of different muscles in individual ALS patients. This in turn would lead to a more efficient and wide-scale treatment option,” Greensmith said.
When the motor neurons were activated via optogenetics, they could trigger movement in the mice’s muscles, experiments showed. At first the movement was very weak, but the researchers found that if they regularly activated the motor neurons — imposing muscle contractions for one hour each day — connections between the nerve and muscle cells grew stronger, allowing for about 13 times more powerful muscle movements.
Gains seen in muscle innervation, atrophy prevention, and contractile force
By the end of the experiments, mice that had undergone daily muscle stimulation in this manner had larger muscles than those that did not receive stimulation, implying that this process helps to reduce muscle atrophy in the mouse model.
“The highly significant improvements in muscle innervation, atrophy prevention and maximum contractile force, as a result of the daily [regimen of activating the motor neurons with optogenetics], confirms that stimulation-induced activity is necessary to maximize connectivity between engrafted motor neurons and their target muscles,” the researchers wrote.
The scientists stressed that there’s still more work to be done — these tests all were conducted in mice, so it will be necessary to see if human cells can be engineered for an optogenetics-controlled transplant in the same manner. They also noted that, because people are much larger than mice, it will be necessary to test whether this technique can be effective in bigger animals.
“Despite these remaining challenges, the findings of this study provide strong support for this novel cell therapy, which, if successful, could finally begin to deliver major health benefits for ALS patients,” the scientists concluded.
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