Stem cells repair damaged circuits in mice with Parkinson’s

A study suggests a type of nerve cell derived from stem cells can make the right connections when implanted into the brain, restoring lost motor function.

Parkinson’s disease is a progressive degenerative disorder that affects muscular control.

Its symptoms include tremor, rigidity, slowness of movement, and impaired balance. Difficulties with swallowing and speaking are also common, particularly later in the course of the disease.

The National Institutes of Health estimate that about 50,000 people are diagnosed with Parkinson’s every year in the United States, and around half a million people live with the condition.

In the disease’s early stages, before symptoms appear, certain brain cells called the “substantia nigra” start to die. These cells produce dopamine, a nerve signaling molecule, or neurotransmitter, which is essential for the smooth movement of muscles.

There is currently no cure for Parkinson’s, but one promising line of research involves transplanting nerve cells into the brain to replace lost functions. Experts could potentially use the same approach to repair damage caused by other neurodegenerative disorders and trauma.

However, for such therapies to succeed, the transplanted nerve cells must make the right connections.

“Our brain is wired in such an accurate way by specialized nerve cells in particular locations so we can engage in all our complex behaviors. This all depends on circuits that are wired by specific cell types,” says Su-Chun Zhang, a professor of neuroscience and neurology at the Waisman Center in the University of Wisconsin-Madison.

“Neurological injuries usually affect specific brain regions or specific cell types, disrupting circuits,” he says. “To treat those diseases, we have to restore these circuits.”

To repair the lost neural circuitry, implanted cells would need to send out projections or “axons” to transmit signals to the correct targets in distant regions of the brain. They would also need to receive the appropriate signals from other nerve cells.

One major unanswered question is whether it is the exact location in the brain where the cells are implanted or the identity of the cells themselves that determine these connections.

It is also unknown whether such new connections would restore lost brain functions.

Zhang and his colleagues set out to find the answers through experiments on mice with Parkinson’s.

They report their results in the journal Cell Stem Cell.

Scientists can now create particular human cells to order from embryonic stem cells, which, given the right conditions, can produce virtually any cell type in the body.

Zhang and his team used this technique to make dopamine-producing neurons, the cells that die in Parkinson’s. For comparison, they also created neurons that produce another neurotransmitter called glutamate.

When they transplanted either cell type into the mice’s substantia nigra, both neuron types sent out long-distance projections. But the projections followed different routes and connected to other targets in the brain.

The majority of implanted dopamine-producing cells sent axons to a part of the brain called the dorsal striatum, which is crucial for coordinating movement. In a healthy brain, “native” dopamine cells target the same region.

The researchers believe this shows that the identity of transplanted nerve cells — rather than their location — determines the path their axons will take through the brain and their ultimate destination.

Just as importantly, the two types of implanted nerve cells started to receive distinctive inputs from other nerve cells. The glutamate cells were more likely to receive stimulatory inputs, whereas the dopamine cells were more likely to receive inhibitory inputs that prevented them from being overstimulated.

Between 4 and 5 months after the transplantation of dopamine cells into their brains, the mice showed improved motor skills. By contrast, the mice that received glutamate cells showed no such improvements.

Finally, the researchers demonstrated that it was the implanted dopamine-producing cells that restored the mice’s motor abilities.

Before implanting them into the brain, they inserted genetic “on-off” switches into the dopamine cells. These increase or decrease the cells’ activity in response to drugs in the animals’ feed or injections.

When the team switched off the cells, improvements in the animals’ motor skills disappeared, proving that the new circuitry created by them had been responsible.

The researchers speculate that specialists could use the same technique to fine-tune the activity of implanted dopamine cells in Parkinson’s patients.

The authors conclude:

“These findings reveal cell-type-dependent functional circuit integration by transplanted neurons, highlighting the prospect of using specialized neuronal types from stem cells to repair the neural circuit to treat neurological conditions.”

However, they note some important limitations of their work.

The distance between the substantia nigra and dorsal striatum is considerably greater in humans than mice, so axons from implanted nerve cells will have further to grow.

They write that further studies in non-human primates will be needed to test the therapy for larger brains. To make the technique work in people, scientists may also have to find ways to speed up the axons’ growth.

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