Stem cell therapy is very attractivein its intuitive simplicity: you cleanse damaged cells, launch a gang of healthy cells in their place, sit back and wait until the body heals itself. In the case of spinal cord injuries, the potential of stem cells to restore mobility promises fantastic prospects. However, the human body is not a machine and is not a simple system that allows you to replace parts on the go. After transplantation, stem cells are often rejected, they die in a hostile environment of the host organism before they even get a chance to recover.
Over the past thirty years neuroscientiststried a lot of ways, tried a cocktail after a cocktail of special molecules that can accelerate the survival of stem cells. And although it was a great success on models with rodents, it did not work out to scale this therapy to work with primates - and this is important for human trials.
Or it didn’t work out. Last month, an important study was published in the journal Nature Medicine, detailing the recipe for a human stem cell transplant that survived and integrated into the damaged spines of monkeys.
Nine months after cell surgerydismissed hundreds of thousands of branches that formed synapses with the surviving neurons of the spinal cord of monkeys. Moreover, the spinal neurons of the carriers recognized human cells as their own, formed new compounds that restored the animal's ability to grab objects.
"The growth that we observed in these cells,impressive, and ten years ago I would have thought it was impossible, ”says lead author Dr. Mark Tushinsky of the University of California, San Diego Transplant Neuroscience Institute. “We definitely added confidence that this treatment would work for people as well.”
Spinal cord injury cuts long, thinneural branches - axons - that the brain uses to communicate with the rest of the body. To restore motor function, scientists need to convince the body to restore or grow these compounds.
But here is the problem. After damage, the spinal cord quickly reorganizes the extracellular matrix - a complex network of structural molecules - around the site of damage. Like “bricks” on the road, these proteins effectively block transplanted stem cells from stretching their long axon branches. Moreover, the site of damage is also devoid of supporting growth factors and other beneficial molecules that act as a nutritional cocoon for stem cells.
To get around this double defense, scientists have formed dozens of growth-provoking cocktails that could give a boost to transplanted cells. And this strategy seems to have worked.
Back in 2014, Tushinsky transformed cellsskin of a healthy human donor, transformed them into iPSC cells (induced pluripotent stem cells) and introduced these artificial stem cells into a matrix containing growth factors.
After placing the graft to two rats withBy two-week spinal injuries, human cells matured into new neurons and extended axons in the rat spinal cord. But strangely, scientists did not see any improvement in function, partly due to scarring at the site of transplantation.
“We are trying to do our best to determine the best way to transfer treatment methods involving neural stem cells in patients with spinal cord injury,” Tushinsky said at the time.
True to his word, Tushinsky tested his transfer protocol on monkeys that are better suited as models for the human spinal cord.
Team crashed into spinal cord sectionmonkeys and after two weeks - enough time for the patients to stabilize - introduced human stem cells into the damaged areas along with growth factors.
Did not work. In the first four monkeys, the injections were not even fixed in place.
“If we tried to perform a human transplant without a preliminary animal test, there would be a significant risk of failure of the clinical trial,” says Tushinsky.
Scientists quickly realized that they needed to increasethe amount of important protein ingredient in your recipe to better “stick” the graft in place. The team also found problems with immunosuppression, timing, and a surgical procedure. For example, they had to tilt the surgical table during surgery so that the cerebrospinal fluid did not wash away the graft. In addition, the monkeys needed a high dose of immunosuppressants so that the body did not attack human cells.
With the help of some lotions, grafts, each of which contained about 20 million human stem cells, were kept in place in the remaining five monkeys.
The results were incredible. Two months after the transplant, scientists discovered an explosion of new neural branches. The stem cells at the lesion site developed into mature neurons, and bred up to 150,000 axons that stretched along the monkey’s spinal cord.
Some of the branches passed at a distance of 50millimeters from the graft site, approximately the length of two spinal fragments in humans. Along the way, they established extensive connections with intact monkey cells.
What's even cooler is the monkey’s own axons.also formed synapses with a human neural graft, forming interconnections. These connections are extremely important for free hand movements in humans and this is one of the first striking evidence that transplanted stem cells can form such patterns.
Nine months later, new neural connectionshelped the injured monkeys regain movement in their limbs so that they could grab soft objects (like oranges). Conversely, monkeys with poor grafts had poor control over precise movements in the palms and fingers - they could only push an orange.
The results may not seem very impressive, but the authors say that nine months is an instant for functional recovery.
“The grafts and the new schemes, of which they were a part, were still ripening towards the end of our observations, so restoration can continue,” says study author Dr. Efron Rosenzweig.
Although functional improvements were onlypartial, Dr. Gregoire Curtine of the Swiss Federal Institute of Technology (EPFL) in Geneva calls the study "a milestone in regenerative medicine."
“And this is not surprising when you consider thatthe functional integration of new cells and compounds in the nervous system will take time and specific rehabilitation procedures, ”he says, adding that the study offers valuable information for potential human research.
Dr. Steve Goldman of the University of Rochester agrees with him:
“This is a big leap from rodents to primate. This is a heroic exploration, for that matter. ”
For Tushinsky, the work is just beginning. First, not all stem cells are created the same, and his team is trying to determine which ones are most effective in restoring function.
On the other hand, he is also exploring additionalways to further enhance the functionality of regenerated neurons, so that their axons can spread through the damaged area and completely replace those that were lost during the injury.
“It's too early to move on to people,” he warns, as additional trials are needed. And this patience will pay off in full.