See how they run
Mice with MS-like virus recover after human stem cell injections, offering hope for human cure
LA JOLLA, Calif.—When a team of scientists at The Scripps Research Institute (TSRI), the University of Utah and the University of California (UC) injected human stem cells into the spines of mice crippled by a version of multiple sclerosis (MS), the improbable happened: less than two weeks later, the mice arose from paralysis and began to walk—then run. Six months later, the same mice showed no sign of relapsing.
The story of this discovery appeared in the online version of Stem Cells Report, May 15, 2014. These findings could open the door to new pathways toward treating humans with MS, a debilitating disease of the central nervous system, with symptoms ranging from numbness and tingling to blindness and paralysis—and a condition for which there is no cure.
“The progress, severity and specific symptoms of MS in any one person cannot yet be predicted, but advances in research and treatment are moving us closer to a world free of MS,” according to the National Multiple Sclerosis Society website. “Most people with MS are diagnosed between the ages of 20 and 50. MS affects more than 2.3 million people worldwide.”
The study was actually done in 2010 by UC researchers, who, after injecting human stem cells into genetically engineered mice with MS-like symptoms, actually expected the mice to reject the cells like they might an organ transplant.
Dr. Thomas Lane, an immunologist and professor in the Department of Pathology at the University of Utah School of Medicine, was just as surprised as anyone when about 10 days later, postdoctoral fellow Dr. Lu Chen announced, “The mice are walking.”
He thought she was joking. So did co-leader Jeanne Loring, a professor of developmental neurobiology at TSRI.
“Tom called me up and said, ‘You’re not going to believe this.’ He sent me a video, and it showed the mice running around in the cages. I said, ‘Are you sure these are the same mice?’”
The transformation that took place in the paralyzed mice after the human neural precursor cells were injected into the animals’ damaged spinal cords was dramatic, the researchers reported.
Even more remarkable, the mice continued walking even after the human cells were rejected, which occurred about a week after implantation. This suggests that the human stem cells were secreting a protein or proteins that had a long-lasting effect on preventing or impeding the progression of MS in the mice, said Ron Coleman, a TSRI graduate student in Loring’s lab who was first author of the paper with Lu Chen of UC Irvine.
“Once the human stem cells kick that first domino, the cells can be removed and the process will go on because they’ve initiated a cascade of events,” Coleman stated in a news release.
The scientists showed in the new study that the implanted human stem cells triggered the creation of white blood cells known as regulatory T cells, which are responsible for shutting down the autoimmune response at the end of an inflammation, he said. In addition, the implanted cells released proteins that signaled cells to re-myelinate the nerve cells that had been stripped of their protective sheaths.
“We’ve been studying mouse stem cells for a long time, but we never saw the clinical improvement that occurred with the human cells that Dr. Loring's lab provided,” Lane said. “And I’ve been doing MS research for 20 years.
“Other studies have shown either the effects on neuroinflammation or demyelination, while ours is one of a select few to show that stem cells influence both,” Lane said. “The aspect I am most interested in is to define what is being secreted from the human cells that influence demyelination.”
Co-author Craig Walsh, a UC Irvine immunologist, stated, "This is a great step forward in the development of new therapies for stopping disease progression and promoting repair for MS patients.”
Current therapies, such as interferon beta, aim to suppress the immune attack that strips the myelin from nerve fibers, according to the researchers. But they are only partially effective and often have significant adverse side effects.
Loring’s group at TSRI has been focused on turning human stem cells into neural precursor cells, which are an intermediate cell type that can eventually develop into neurons and other kinds of cells in the nervous system.
The particular line of human neural precursor cells used to heal the mice was the result of a lucky break, said Coleman. During the experiment, he was using a common technique for coaxing human stem cells into neural precursor cells, but decided partway through the process to deviate from the standard protocol, and transferred the developing cells to another Petri dish.
“I wanted the cells to all have similar properties, and they looked really different when I didn’t transfer them,” said Coleman, who was motivated to study MS after his mother died from the disease. This step, called “passaging,” proved key since passaging alters the types of proteins that the cells express.
Loring called the creation of the successful neural precursor cell line a “happy accident.”
“If we had used common techniques to create the cells, they wouldn’t have worked,” Loring said. “There are a dozen different ways to make neural precursor cells, and only this one has worked so far. We now know that it is incredibly important to make the cells the same way every time.”
The team is now working to discover the particular proteins that its unique line of human precursor cells release, according to TSRI. One promising candidate is a class of proteins known as transforming growth factor beta, or TGF-B, which other studies have shown is involved in the creation of regulatory T cells.
Experiments by the scientists showed that the human neural precursor cells released TGF-B proteins while they were inside the spinal cords of the impaired mice. But the team says it’s also likely that as-yet-unidentified protein factors may also be involved in the mice’s healing.
If the team can pinpoint which proteins released by the neural precursor cells are responsible for the animals’ recovery, it may be possible to devise MS treatments that don’t involve the use of human stem cells.
“Once we identify the factors that are responsible for healing, we could make a drug out of them,” said Lane. “Another possibility might be to infuse the spinal cords of humans affected by MS with the protein factors that promote healing.”
Ultimately, the information from the “happy accident” could contribute to the development of stem cell therapies and even cell-free therapies that stimulate recovery in people with MS, the researchers say. And although these are early results and further work is needed, the team believes its findings show some promise for strategies to repair damage and restore function for people with multiple sclerosis.
Lane is cautiously optimistic.
“Cure is a word I try to avoid,” Lane said. “I believe that this work complements other studies in the field and hopefully leads to effective treatments for MS patients.”