Electrically stimulated stem cells aid stroke recovery in rodents, Stanford researchers find

More than 10 million strokes occur worldwide every year, leaving at least half of patients with life-altering disabilities. Yet therapies for stroke are limited, and many patients have only modest improvements in motor and cognitive function. The need for better treatments has sparked interest in two therapies in particular: transplanted stem cells and electrical current.

Although hundreds of studies in animals — and a handful in humans — have demonstrated that stem cells transplanted into the brain can improve stroke outcomes, the challenge has been finding the best way to deliver and use the cells. Another challenge: how to use electricity to stimulate those cells and the brain.

Now, Stanford Medicine researchers have developed a tool that solves both problems. It can deliver and electrically stimulate transplanted stem cells and stimulate injured brain tissue. It also helped the researchers identify a protein that encourages the brain to heal.

The device is a tiny conductive polymer implant that’s 1 millimeter wide by 3 millimeters long and about a quarter as thick as a credit card. Conductive polymer is a dark-colored organic compound with the consistency of flexible plastic and the ability to conduct electrical current. The electricity that powers the device comes from an external generator that’s attached with wires. The charge and surface interactions of the polymer hold the stem cells in place.

“Conductive polymers have all the advantages of a polymer,” said Paul George, MD, PhD, assistant professor of neurology and neurological sciences. “You can load cells onto them, deliver drugs with them. It’s the perfect platform to load cells onto and into the body. They also act in a way similar to a semiconductor to conduct electricity.”

Not only did the conductive polymer system work as intended, it helped rodents recover faster and better after a stroke.

“We found that if we electrically modulate transplanted human stem cells in our rodent stroke model, we nearly double the treatment effect from stem cells alone,” George said.

A paper describing the conductive polymer system was published online March 15 in Nature Communications. George is the paper’s senior author. Matine Azadian, a graduate student in George’s lab, and postdoctoral fellows Sruthi Santhanam, PhD, and Byeongtaek Oh, PhD, share lead authorship.

Boosting the brain

George’s team started by looking at the way the body uses electrical cues to develop its own stem cells. They were interested in how electrical stimulation ramps up substances the brain naturally produces after an injury and the role those substances play in healing. And they wanted to replicate that process as much as possible using transplanted stem cells stimulated with electric current.

Once they developed a tool that could accomplish this, the team tested it in rats that had experienced strokes. The scientists implanted the conductive polymer system on the brain surface near the edge of damaged tissue without harming the brain.

Some rats underwent stem cell transplants. The cells were electrically stimulated for one hour a day for the first three days. Other rats received transplanted cells but no electrical stimulation. A control group received conductive polymer implants and another control group received sham implants.

As hoped, animals receiving stem cells combined with electrical stimulation experienced earlier and longer-lasting recovery compared with the other groups.  

The benefits didn’t seem to result entirely from the stem cells, however. Electrically stimulated or not, the cells survived a few weeks with only a tiny fraction integrating with surrounding brain tissue. The scientists think electrical stimulation combined with cues from the transplanted stem cells acted like a call to action, revving up the brain’s repair processes and recruiting the brain’s own stem cells from other parts of brain to help heal stroke-damaged tissue.

“We’re trying to understand the right stimulation patterns and how to manipulate the system to see if we can optimize the body’s own repair mechanisms even more — how to make the process more effective,” George said.

The role of STC2

George’s team also wanted to understand exactly how neural regeneration works. They discovered that electrical stimulation alters the brain’s repair mechanisms and profoundly changes gene expression in stem cells. They found nearly 600 upregulated genes and 168 downregulated genes in the transplanted cells. Upregulated genes increase their response to signals outside the cell, and downregulated genes decrease it. One of the most upregulated genes gave instructions to produce stanniocalcin 2 (STC2), a protein associated with cell growth.

When the scientists used a type of virus to reduce levels of STC2 in the transplanted stem cells, the positive effects of electrical stimulation disappeared and healing stalled. When they administered STC2 directly to the animals, their brains pumped out more stem cells, leading to better outcomes. George said studies are needed to figure out how and why increased STC2 causes the brain to produce more of its own stem cells.

The human brain loses some resiliency over time. And though it can still produce new stem cells throughout life, the numbers decline with age. Stroke sharpens that decline. Since stroke often affects older adults, devices such as the conductive polymer may increase the brain’s ability to heal at critical points in the recovery process.

“After a stroke, the brain got about 20% better on its own in our rodent model,” George said. “Other groups using stem cells have gotten a 50% to 60% recovery rate. Our recovery rate was 80% to 90%. This has important treatment considerations for the numerous completed and ongoing clinical stem cell trials and may be a new avenue to optimize this treatment method.”

George is a member of Stanford Bio-X and of the Wu Tsai Neurosciences Institute at Stanford.

Other Stanford co-authors of the study are research assistants Kelly McConnell, Vishal Swaminathan and Alexa Levinson; postdoctoral scholar Shang Song, PhD; and undergraduate students Jainith Patel and Emily Gardner.

Former Stanford postdoctoral scholar Alex Lee, PhD, who is now a researcher at UC-San Francisco, also contributed to the work.

The study was supported by the National Institutes of Health (grant K08NS089976), the Selavy Foundation and a Stanford School of Medicine dean’s postdoctoral fellowship.