Stroke damage has traditionally been considered permanent

Stroke is extremely common, affecting approximately one in four adults during their lifetime. About half of people who experience a stroke are left with permanent problems, including paralysis and difficulty speaking.

These disabilities can occur when a stroke deprives parts of the brain of oxygen or causes bleeding that destroys brain cells. Once these cells are lost, the resulting damage has traditionally been considered permanent because there are currently no treatments that can rebuild affected brain tissue.

“That is why it is important to pursue new treatments for the possibility of brain regeneration after disease or injury,” says Christian Tuckenberg, scientific director of the Neurodegeneration Group at the Institute for Regenerative Medicine at the University of Zurich (UZH).

Neural stem cells may help rebuild damaged brain tissue

One possible approach involves neural stem cells, which can develop into multiple types of cells found in the nervous system.

Tuckenberg and a research team led by postdoctoral researcher Rebecca Weber tested this approach in two studies conducted in collaboration with a group led by Ruslan Rust at the University of Southern California.

The findings suggest that transplanted cells do more than simply replace neurons lost after a stroke.

“Our findings show that neural stem cells not only form new neurons, but also induce other regenerative processes,” Tuckenberg says.

Human stem cells developed into new neurons in mice

The researchers used human neural stem cells capable of generating different types of nervous system cells. The cells were created from induced pluripotent stem cells, which are produced by reprogramming normal human somatic cells so they regain the ability to differentiate into many different cell types.

The team then induced permanent strokes in mice. The resulting brain damage was designed to closely resemble key features of human stroke.

Because the transplanted cells were human, the researchers genetically modified them to prevent the mice’s immune systems from rejecting them.

One week after inducing the stroke, the researchers transplanted the neural stem cells directly into the damaged area of the brain. They used imaging techniques and biochemical analysis to monitor what happened.

“We found that the stem cells survived throughout the five-week analysis period, and most of them turned into neurons and were actually even communicating with existing brain cells,” Tuckenberg said.

The ability to connect with existing brain cells is especially important because simply generating new neurons does not necessarily restore function. The new cells must also become part of a functioning neural network.

Stem cell treatment triggered multiple signs of brain repair

The researchers found evidence that the treatment caused a broader healing response in the damaged brain tissue.

• New blood vessels formed in the damaged brain tissue.
• Inflammation was reduced.
• The integrity of the blood-brain barrier improved.

The blood-brain barrier is a tightly regulated protective boundary that separates circulating blood from brain tissue. Damage to this barrier can contribute to inflammation and further injury after a stroke.

“Our analysis goes well beyond other studies that focus on immediate effects immediately after transplantation,” Tuckenberg explains.

Most importantly, these biological changes were accompanied by improvements in the animals’ movement.

The stem cell transplant reversed stroke-related motor deficits in the mice. Researchers measured the improvements partly through artificial intelligence-assisted analysis of the animals’ gait patterns.

Delaying treatment by one week may improve stroke stem cell therapy

The researchers designed the experiment with potential human treatment in mind.

For example, the stem cells were generated without animal-derived reagents. Avoiding animal-derived materials may be important when developing treatments for human use because it can reduce potential safety and regulatory complications.

The University of Zurich team collaborated with the Kyoto University Center for iPS Cell Research and Applications (CiRA) to create a defined production protocol.

The second study also provided important information about treatment timing. Researchers found that stem cell transplants were more effective when performed one week after the stroke than when performed immediately afterward.

This delay could make the approach considerably easier to use in clinical practice. Physicians would not need to provide the treatment immediately during the emergency phase of a stroke and could have more time to prepare.

Researchers are preparing for potential human clinical trials

Despite the encouraging findings, the researchers stress that several challenges must be addressed before the treatment can be widely tested in people.

“We need to minimize risk and simplify potential applications in humans,” Tuckenberg says.

One concern is the uncontrolled proliferation of stem cells in the brain. Tuckenberg’s group is working with Ruslan Rust to develop a safety switch intended to prevent this from occurring.

The researchers are also exploring less invasive ways to deliver the cells.

Rather than transplanting stem cells directly into brain tissue, the team is developing an intravascular injection approach that would deliver the cells through blood vessels. This could be more practical than performing a direct brain transplant.

There is already precedent for moving guided stem cell therapies into human trials. Early clinical trials using engineered stem cells to treat Parkinson’s disease are underway in Japan, Tuckenberg said.

“Stroke could be one of the next diseases to be tested in clinical trials.”