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Nerve Regeneration: Another Piece of the Stem Cell Puzzle

rat lab

Almost everyone regenerates nerves, but you! Sure, yesterday we talked about how other animals in the kingdom regenerate damaged nerves and how we got left in the dust. But we forge ahead and we have more good news in the race to catch up to some other animals. Building upon previous research, a team of scientists report that neurons which were derived from human induced pluripotent stem cells [ or iPSC for short] and grafted into rats after a spinal cord injury produced cells with tens of thousands of axons extending virtually the entire length of the animals’ central nervous system.

Crazy I know, yet the researchers say the human iPSC-derived axons extended through the white matter of the injury sites, frequently penetrating adjacent gray matter to form synapses with rat neurons. Similarly, rat motor axons pierced the human iPSC grafts to form their own synapses.

Now for the kicker, the iPSCs used were developed from a healthy 86-year-old human male, yep 86. Maybe they have a better grip on the cancer problem typically caused by iPSCs.

“These findings indicate that intrinsic neuronal mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons reprogrammed from very aged human cells,” said senior author Mark Tuszynski, MD, PhD, professor of Neurosciences and director of the UC San Diego Center for Neural Repair.

The team has been steadily chipping away at the notion that a spinal cord injury purposefully results in permanent dysfunction of the damaged area and paralysis. Earlier work from the team has shown that grafted stem cells reprogrammed to become neurons can, in fact, form new, functional circuits across an injury site, with the treated animals experiencing some restored ability to move affected limbs.

This would be a huge step forward if it can be translated to humans and the new findings underscore the potential of iPSC-based therapy. It suggests a host of new studies to be done and questions to be asked — questions like whether axons can be guided [I would venture to say yes] and how will they develop, function and mature over longer periods of time. As I mentioned before, cancer caused by iPSC is always a worry as well as the functionality of the nerves over time.

While neural stem cell therapies are already advancing to clinical trials, this research raises cautionary notes about moving to human therapy too quickly, said Tuszynski.

“The enormous outgrowth of axons to many regions of the spinal cord and even deeply into the brain raises questions of possible harmful side effects if axons are mistargeted. We also need to learn if the new connections formed by axons are stable over time, and if implanted human neural stem cells are maturing on a human time frame – months to years – or more rapidly. If maturity is reached on a human time frame, it could take months to years to observe functional benefits or problems in human clinical trials.”

In the latest work, the researchers converted skin cells from a healthy 86-year-old man into iPSCs — these cells possess the ability to become almost any kind of cell. The iPSCs were then reprogrammed to become neurons. Then those new human neurons were embedded in a matrix containing growth factors to allow them to mature, after they were grafted into two-week-old spinal cord injuries in rats [rats have a shorter lifespan so a two-week-old spinal cord injury when translated to a human timeline would be much longer].

Three months later, researchers examined the post-transplantation injury sites [again three months on a rat timeline would translate to much longer in human terms]. They found biomarkers indicating the presence of mature neurons and extensive axonal growth across long distances in the rats’ spinal cords. Most shockingly the nerve cells even extended into the brain. The axons traversed wound tissues to penetrate and connect with existing rat neurons. Similarly, rat neurons extended axons into the grafted material and cells. Most importantly the transplants produced no detectable tumors.

Unfortunately, while numerous connections were formed between the implanted human cells and rat cells, a actual functional recovery was not found. However, researchers are quick to point out that the tests only assessed the rats’ skilled use of the hand. Simpler assays of leg movement could still show benefit.

Also, several iPSC grafts contained scars that may have blocked beneficial effects of new connections. The team says that continuing research will seek to optimize transplantation methods to eliminate scar formation.

Tuszynski said he and his team are attempting to identify the most promising neural stem cell type for repairing spinal cord injuries. They are testing iPSCs, embryonic stem cell-derived cells and other stem cell types.

“Ninety-five percent of human clinical trials fail. We are trying to do as much as we possibly can to identify the best way of translating neural stem cell therapies for spinal cord injury to patients. It’s easy to forge ahead with incomplete information, but the risk of doing so is greater likelihood of another failed clinical trial. We want to determine as best we can the optimal cell type and best method for human translation so that we can move ahead rationally and, with some luck, successfully.”

Personally I am all for slowing down and working out all the nuances of stem cell transplant, after all you don’t want to be like the woman who had a nose growing on her spinal cord. Or maybe you do want to be that person, I’m not one to judge. I just think that we should be putting actual nerve cells back there instead.

Want more? Of course you do, you can find the full study —here!

Lu, P., Woodruff, G., Wang, Y., Graham, L., Hunt, M., Wu, D., Boehle, E., Ahmad, R., Poplawski, G., Brock, J., Goldstein, L., & Tuszynski, M. (2014). Long-Distance Axonal Growth from Human Induced Pluripotent Stem Cells after Spinal Cord Injury Neuron DOI: 10.1016/j.neuron.2014.07.014

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