July 17, 2005 Researchers at the San Raffaele Hospital (Milan, Italy) published unexpected results of studies in which immature nerve cells (adult mouse neural stem cells) injected into the blood of mice with MS-like disease were able to suppress the immune attacks that damage the brain and spinal cord tissues. The study, funded in part by the National MS Society, is being reported by Drs. Stefano Pluchino, Gianvito Martino and colleagues in the July 14, 2005 issue of Nature. These surprising findings, if confirmed, suggest that neural stem cells that reside in the adult brain may not only serve as replacement cells for tissue repair, but in some circumstances may also protect the brain from inflammation. Further research is needed to confirm these results and to address multiple issues involved in translating such experiments into finding ways to fight the immune attack and protect and repair brain tissues in people with MS.
Background: In recent years, scientists have been exploring ways to repair the damage of brain and spinal cord tissues during the course of the immune attack in MS. Evidence suggests that the body successfully repairs some myelin damaged in MS, but not enough to keep up with its loss. Research has shown that adult brains contain stem cells – also known as precursors or progenitors – that might serve as replacement cells. It has been hoped that, given the right signals, these may be stimulated to grow into viable new tissue. The search for these signals is an active area of research. Another possibility being explored is cell transplantation.
Studies involving transplantation of immature myelin-making cells (oligodendrocyte precursors) have been to some degrees successful in rodent models, triggering recovery of function and restoring nerve conduction. However, such repair has only been successful in isolated areas of the brain, whereas MS and MS-like diseases in animal models involve lesions scattered throughout the brain and spinal cord. Finding a way to introduce potential replacement cells that can migrate throughout the central nervous system and home in on damaged areas has presented a significant hurdle in this field.
The San Raffaele Hospital team and others have been investigating transplantation of neural stem cells, which have the potential to develop into various types of brain cells – including nerve cells and myelin-making cells – and which appear capable of expanding their numbers extensively, and moving to distant sites of injury within the brain. In 2003, they reported that neural stem cells transplanted into mice with an MS-like disease were able to migrate to multiple areas of myelin and nerve fiber damage in mice with an MS-like disease, repair this damage, and restore clinical function. (Nature 2003;422:688-694). In the current study, the team attempted to define the mechanisms responsible for the migration of these cells into the brain and to sites of injury. This study was funded in part by the National MS Society (USA), the Myelin Project, the Italian MS Foundation and the Italian Minister of Health.
The Study: Dr. Pluchino and colleagues injected neural stem cells, taken from the brains of adult mice, into the blood of mice with a relapsing-remitting form of EAE, an MS-like disease. Relapsing-remitting disease involves clearly defined flare-ups followed by partial or complete remissions. Some mice were injected at the onset of disease, and others at the onset of the first relapse.
Mice in which neural stem cells were injected at disease onset started to recover between 30 and 60 days, and experienced a twofold reduction in relapses compared with untreated mice. Mice injected at the first relapse started to recover later, but showed a threefold reduction of the relapse rate between 60 and 90 days, compared with untreated mice. Both groups showed a significant reduction in the extent of myelin damage and nerve fiber loss compared to untreated mice.
The team then explored the mechanism by which the neural stem cells entered the brain from the bloodstream. They reported that a protein on their surface called VLA-4, which is also found on immune cells and allows them to cross from the blood into the brain, facilitated their movement into the brain. In addition, the investigators reported finding a wide range of immune proteins to be active on the transplanted neural stem cells; these proteins serve as “docking sites” to receive signals from immune cells active in the attack. Furthermore, they reported that a portion of the transplanted cells remained in an immature state and accumulated in the brain around blood vessels (perivascular areas) where immune cells enter the brain during active disease. These transplanted cells showed signs of being able to turn off activated immune cells and reduce inflammation, thus protecting brain tissues from immune-mediated damage.
Conclusion: These exciting and unexpected findings from a respected group of investigators, if confirmed, suggest that transplanted neural stem cells may serve not only as replacement cells for tissue repair, but in some circumstances may also protect the brain from inflammation. Further research is needed to confirm these results and to address multiple issues involved in translating such experiments into finding ways to fight the immune attack and protect and repair brain tissues in people with MS.
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