researchupdateH E A T H E R B U S C H M A N , P H D

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Stroke Drug Boosts Stem Cell TherapyFour months after treating his rats, Yasuhiro Shiga, MD, PhD, checked on them.

Walking into the lab, Shiga, a visit-ing scholar at the University of Califor-nia (UC) San Diego School of Medicine in San Diego, carried minimal expecta-tions. Treating spinal-cord injuries (SCI) with stem cells had been tried by many people, many times before, with modest success at best.

The endpoint he was specifically there to measure — pain levels — hadn’t seemed to budge in past efforts.

“Well, it doesn’t seem to be work-ing. I don’t see any real change in pain behavior in any of the groups,” Shiga recalls saying, apologetically, as he walked into the office of his supervisor, Wendy Campana, PhD, professor in the Department of Anesthesiology and Pro-gram in Neuroscience. But to Campa-na’s surprise, Shiga continued, almost as an after-thought, “although … some rats are actually really moving.”

The difference for those rats was this: Before delivering them into the SCI site, Shiga and Campana had condi-tioned stem cells with a modified form of tissue-type plasminogen activator (tPA), a drug commonly used to treat nonhemorrhagic stroke.

Their findings were published Dec. 17 in Scientific Reports.

Big ImprovementsThe drug tPA is used to break up blood clots, allowing blood to more freely flow back into the brain following a stroke.

But tPA is also a naturally occurring enzyme known to boost neuron growth and dampen inflammation.

So the researchers used an enzy-matically inactive form of tPA, still anti-inflammatory and pro-neuron growth but without effects on blood clotting,

which could be a dangerous side effect in a person not having a stroke.

In a laboratory dish, the research-ers added the modified tPA to neural progenitor cells — the precursors to

neurons. They had generated these pre-neurons from induced pluripotent stem cells, a special kind of stem cell that can be derived from a person’s skin cells.

After 15 minutes, the researchers transferred either tPA-conditioned or unconditioned neural progenitor cells to the injury site in a rat model of severe SCI.

Two months after treatment, the researchers found 2.5-fold more tPA-conditioned neural progenitor cells than unconditioned cells still present in the rats. What’s more, the tPA-con-ditioned cells had begun specializing into full-fledged neurons, with axons (branches) emerging from the site of transplantation and extending as far as four vertebrae away. According to Campana, that’s unusual.

“It was striking to see at two and four months the tremendous improve-ments in the ability of those progenitor cells to survive in the injury cavity,” she says. “Just keeping these cells alive has been very difficult in past studies.”

Even more surprisingly, it turned out that what Shiga had observed in the

rats with modified tPA was a three-fold increase in motor activity after four months, as measured using a well-established scoring system that quanti-fies a combination of rat joint and limb

movements, trunk stability, paw and tail positioning, stepping and coordination.

Pain is a special focus of Campana’s lab, and the team was initially most interested in that aspect of SCI treat-ment. They measure pain in rat models based on how they lift their front paws in response to added weights.

“The addition of tPA-treated neural precursors didn’t reduce pain in this model,” Campana says. “But we also didn’t exacerbate it — and to not see increased pain is important safety information for clinical trans-lation to improve motor outcomes. We also don’t want worsen the pain burden of patients living with spinal-cord injuries.”

One limitation of this SCI model is that the rats don’t live long enough to truly recapitulate what for humans is a long-term condition — or long enough to measure potential changes in gene expression over time. But it is currently the best available non-human primate model for the human situation, Campana says.

In this microscopic view of rat spinal-cord injury models, there is an abundance of

neural progenitor cell-derived axons emerging when the cells are preconditioned with a

modified stroke drug, right, compared to those that received unconditioned cells, left.


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Additional StudiesWhile Campana’s work may be many years away from testing in patients, her approach has two potential advan-tages compared to other studies.

First, the use of induced pluripotent stem cells means a patient’s own cells would be the source of treatment, rather than a transplant of donated cells from another person. Second, tPA is already approved by the Food and Drug Admin-istration (FDA) for use in humans.

The team next plans to dive into exactly what modified tPA does to neural progenitor cells on a molecu-lar level that stimulates their growth and allows them to help repair SCIs.

Meanwhile, other UC San Diego School of Medicine researchers are

testing other approaches to treating SCI with stem cells in clinical trials. For example, in June 2018, a team reported that a first-in-human phase 1 clinical trial in which neural stem cells were transplanted into par-ticipants with chronic SCI produced measurable improvement in three of four subjects, with no serious adverse effects.

There are currently an estimated 291,000 people living with SCI in the U.S. and approximately 17,730 new cases each year, according to 2019 sta-tistics provided by the National Spinal Cord Injury Statistic Center at the Uni-versity of Alabama at Birmingham.

There are no FDA-approved stem cell-based therapies available for SCI.

Additional co-authors in this research include: Akina Shiga; Seiji Ohtori, Chiba University; Pinar Mesci; HyoJun Kwon; Coralie Brifault; John H. Kim; Jacob J. Jeziorski; Chanond Nasamra; Alysson R. Muotri; and Ste-ven L. Gonias, UC San Diego.

The research was funded, in part, by the National Institutes of Health, Department of Defense, International Rett Syndrome Foun-dation and National Cooperative Reprogrammed Cell Research Groups to Study Mental Illness.

Heather Buschman, PhD, is a senior public information officer at UC-San Diego Health. n

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