Insights about brain cell damage after stroke and repair after transplant could pave the way for therapies that extend the treatment window, as revealed in a lab study led by the Keck School of Medicine of USC.
When someone has a stroke — a leading worldwide cause of death and disability — time is of the essence. Almost nine out of 10 cases are ischemic strokes, caused by restricted blood flow in the brain, and the current gold-standard treatment that breaks up blood clots must be delivered within four and a half hours of symptoms appearing.
Researchers are on the hunt for ways to extend that ticking clock and enable better stroke recovery. One promising prospect is an experimental stem cell therapy to help repair damaged brain tissue, co-developed by scientists at the Keck School of Medicine of USC, the University of Zurich and ETH Zurich in Switzerland. A study in the journal Nature Communications showed that a stem cell transplant performed one week after an ischemic stroke in mice led to recovery.
“There are a lot of patients who cannot get the acute treatment, and their blood vessels remain blocked,” said co-corresponding author Ruslan Rust, PhD, assistant professor of research physiology and neuroscience at the Keck School of Medicine of USC. “If we can bring this treatment to the clinic in the future, it may help patients who have long-term symptoms or large strokes see recovery.”
Employing stem cells to heal damaged brain tissue
Rust and his colleagues reprogrammed human blood cells into neural stem cells — which can mature into neurons — and transplanted them into the damaged brain tissue of mice that had strokes. After five weeks, the researchers compared their recovery to a group of mice from the same litter that had strokes but underwent surgery without transplantation.
The brains of the mice that received transplanted neural stem cells showed more robust signs of recovery than those of untreated mice. The transplant recipients’ brains had less inflammation, more growth of neurons and blood vessels, and more connectivity among neurons than the brains of the mice that did not receive transplanted cells. The treated mice also had less leakage from the blood-brain barrier, which is important for normal brain function and acts as a filter to keep harmful substance out of the brain.
To measure function, the researchers used artificial intelligence to closely track the movement of the animals’ limbs while walking and climbing up a ladder with irregular rungs.
“Recovery can be hard to determine in mice, so we needed to see these little differences,” Rust said. “The unbiased view we got through this deep learning tool gave us a lot more detail about this complex process.”
The team found that treated mice fully recovered the fine motor skills tested in the climbing task five weeks after the transplants. By the end of the study, their gait also improved significantly compared to mice that received sham surgery.
Clues among the new brain cells that develop
When the researchers looked at which types of cells died off due to stroke, they found roughly a 50% reduction in neurons that secrete gamma-aminobutyric acid (GABA), which decreases activity in the brain cells to which it binds. These GABA-secreting neurons, known as GABAergic neurons, have previously been shown to assist stroke recovery.
The team also explored the fate of the transplanted stem cells, finding that the majority had become GABAergic neurons. This is a possible indication that the local environment where the stroke injured the brain may help steer the development of the neural stem cells.
Rust and his colleagues also analyzed the interactions between the transplanted cells and other cells in the brains of the mice. They found strong activity in several signaling pathways that were shown in prior studies to be associated with regenerating neurons, forming connections between neurons, and guiding how neurons branch out.
“Mechanistic insight can be quite important if we seek to inform new therapies or improve emerging ones,” Rust said. “Understanding the mechanisms allows us to think about adapting a drug that regulates them — perhaps one that’s already clinically approved for a different disease. It could open up a whole new wave of therapies.”
The team is currently investigating other ways to increase activity in the pathways identified in the study and evaluating the results of the transplant in mice for periods longer than five weeks.
“If we can help people by transplanting stem cells into a human stroke patient, we want the cells to be there for the rest of their life,” Rust said. “So our aim would be to look across the whole lifetime of a mouse and see what happens with the cells, and also see whether this recovery is sustained or even improves.”
About this study
The study’s first author is Rebecca Weber of the University of Zurich and ETH Zurich. The co-corresponding author is Christian Tackenberg of the University of Zurich and ETH Zurich. Other co-authors are Beatriz Achón Buil, Nora Rentsch, Patrick Perron, Stefanie Halliday, Chantal Bodenmann, Kathrin Zürcher, Daniela Uhr, Debora Meier, Siri Peter, Melanie Generali of the University of Zurich and ETH Zurich; Allison Bosworth, Mingzi Zhang and Kassandra Kisler of the Keck School of Medicine; Shuo Lin and Markus Rüegg of the University of Basel in Switzerland; and Roger Nitsch of Neurimmune, a Swiss biopharmaceutical company.
The study received support from the Swiss 3R Competence Center; the Swiss National Science Foundation; the Neuroscience Center Zurich at the University of Zurich and ETH Zurich; and the Maxi Foundation.