Physicians and research scientists at the Oregon Health Science University in Portland, Oregon have used banked neural stem cells to make myelin in mice that have a severe disease that prevents the synthesis and deposition of myelin around nerves. This proof-of-concept experiment shows that such a treatment strategy is feasible for human patients.
In previous posts on this blog site, I have discussed the importance of the myelin sheath that surrounds and insulates certain nerves. I will not reiterate those points here, but simply refer you to those older posts.
In humans, myelin loss is not noticed until the patient begins to show symptoms. Myelin disorders are quite disabling and even fatal in some cases. Such disorders include cerebral palsy in children born prematurely, multiple sclerosis, and others.
Myelin loss has also been found to play an important role in age-related senility. Researchers at the Oregon Health and Science University Doernbecher Children’s Hospital used very advance Magnetic Resonance Imaging to study myelin (white matter) in the brains of adults of all stages. They discovered that widespread changes in the white matter, and damage to the myelin of the brain were highly correlated with progressive senility (See Black SA, et al., “White matter lesions defined by diffusion tensor imaging in older adults.” Annals of Neurology, 2011 Volume 70, Issue 3, pages 465–476).
Stephen Back and his colleagues at OHSU examined the ability of human stem cells to make myelin and heal the sick animals. To test this possibility, Back used a mouse called the “Shiverer immunodeficient” mouse, that develops progressive neurological damage because of its inability to make myelin. Remember that small regions of demyelination that cover particular segments or even patches of nerves are followed by repair, regeneration, and complete recovery of neural function. However, extensive demyelination or myelin loss is typically followed by degeneration of the axon (the extension of the neuron that conducts nerve impulses to other neurons) and also the neuron cell body. Neuron death and axonal death are often irreversible.
The use of the Shiverer mouse presented some unique challenges. Most neural stem cell experiments utilize newborn rather than adult mice. Back explained: “Typically, new-born mice have been studied by other investigators because stem cells survive very well in the newborn brain. We, in fact, found that the stem cells preferentially matured into myelin-forming cells as opposed to other types of brain cells in both newborn mice and older mice. The brain-derived stem cells appeared to be picking up on cues in the white matter that instructed the cells to become myelin-forming cells.”
Back collaborated with StemCells Inc., to make use of their proprietary neural stem cell line. His initial experiments showed that implanting these neural stem cells made myelin sheaths in presymptomatic newborn animals. However, these experiments did not indicate whether or not these stem cells would survive after transplantation into older animals that were already showing symptoms and declining in health. Black, therefore, wanted to perform a much more difficult experiment by transplanting the neural stem cells into very sick adult animals that showed the horrific symptoms of demyelination.
MRI studies confirmed that implanted neural stem cells did in fact make new myelin within weeks after transplantation. However, the detection of something such as myelin in mice usually requires the use of dyes of some other agent that fills the thing you want to detect in order to see it. Many of these Shiverer animals are so sick that they cannot survive MRI experiments. Therefore OHSU used a very sophisticated piece of equipment to solve this problem: ultra-high field MRI scanners that could detect myelin without the use of dyes.
Back further explained: “This is an important advance because it provides proof of principle that MRI can be used to track the transplants as myelin is being made. We actually confirmed that the MRI signal in the white matter was coming from human myelin made by the stem cells.”
This study is in combination with a clinical study at the University of California, San Francisco that examines the use of this same neural stem cell to myelinate the nerves of children with severe demyelination diseases. Back’s group provides the crucial pre-clinical work that serves as the foundation for this clinical study.
Back noted: “These findings provide us with much greater confidence that going forward, a wide variety of myelin disorder might be candidate for therapy. Of course, each condition varies in terms of severity, how fast it progresses and the degree of brain injury it causes. This must all be taken into consideration as neurologists and stem cell biologist [sic] work to make further advances for these challenging brain disorders.”