Science Editor

By transplanting human stem cells into mutant mice that lack the insulation necessary for neural transmission to occur, researchers have been able to cure roughly a quarter of the animals of their normally fatal neurological disease. The findings are reported in the June 2008 issue of Cell Stem Cell.

Neurons can transmit information quickly because of their myelin sheath, a fatty insulation that allows signals to travel rapidly down an axon. But there are many ways for that myelin sheath to break down. Myelination disorders "represent a pretty large chunk of neurological disease," senior author Steven Goldman, of the Center for Translational Neuromedicine and professor of neurosurgery and neurology at the University of Rochester, told BioWorld Today. Problems with myelination can be genetic, resulting in the so-called leukodystrophies, a set of congenital disorders where myelin does not form properly. But myelin also is vulnerable to conditions of low oxygen, meaning that the myelin sheath is preferentially lost in a number of conditions including hypertension, diabetes and as a result of smoking.

In their study, the researchers transplanted glial progenitor cells into shiverer mice, which are deficient in myelin formation and do not usually live beyond 5 months of age. Previous attempts to treat shiverer mice by transplanting glial progenitor cells - the cells that differentiate into myelin-forming oligodendrocytes, as well as another type of brain support cell called astrocytes - had shown no improvement in the animals' condition, and so in their Cell Stem Cell paper, the authors used what they termed a "newly developed set of approaches to cell acquisition and transplantation" to transplant greater numbers of cells, and enable those cells to engraft in a wider area of the brain than had been possible previously.

Out of 26 transplanted animals, 20 did not fare noticeably better than controls. But the other six did. Four appeared to be completely cured, showing no motor dysfunction and surviving for 13 months, when the researchers killed them to look at their brains in detail. Two others ultimately died, but survived longer than any of the untreated or sham-treated controls. Anatomically, the treated mice showed myelination throughout much of the brain, which enabled normal neural transmission speed.

Goldman and his team, who are from the University of Rochester, Baylor College of Medicine, Weill Cornell Medical College and the University of California at Los Angeles, hope to ultimately take their findings into the clinic, where the approach could be useful for congenital leukodystrophies, but possibly also in other myelination disorders.

In their paper, the researchers transplanted the mice when they were only a few days old, but that is mainly due to the developmental biology of mice. "Mice start to myelinate within days of birth," Goldman said, making it necessary to transplant human progenitor cells almost immediately to give them a head start over the dysfunctional ones in the shiverer mice.

Humans, on the other hand, have a much more drawn-out period of myelination, with some areas of the forebrain not being myelinated until the age of 2 - "that's why babies are babies," Goldman said. The slower rate of myelination means that the time window in which stem cell treatment could be effective is broader in humans than in mice. While that would be too late for some leukodystrophies - the recently deceased Lorenzo Odone, who was the subject of the 1992 movie "Lorenzo's Oil," was not diagnosed until he was 5 - many leukodystrophies are diagnosed quickly enough so that cell transplants might be an option.

The researchers found that cells appeared to continue to divide and increase myelination of the brain long after the initial transplant. Epilepsy is one of the symptoms that shiverer mice develop, and in their experiments, both transplanted and untransplanted mice had seizures when picked up by the tail at the age of 3-4 months. But transplanted mice showed fewer epileptic fits at 5 months of age, than at 4, and "by 8 months, none of the four surviving mice could be induced to seize" when they were picked up, Goldman said.

Goldman said that his team still was working out the details of why the mice stopped seizing, but the researchers believe that it is a mix of factors. The myelin sheath organizes ion channels in the cell membrane, preventing neurons from firing at random; but Goldman believes that the progenitor cells also differentiate into astrocytes, and those astrocytes secrete an antiepileptic neurotransmitter. If the latter is the case, he said, his team's findings "would have implications for epilepsy broadly."

Transplantation also could be useful in adult demyelination diseases that are characterized by focal rather than diffuse damage. In such cases, Goldman said, "we would expect [transplantation] to work into and throughout adult life" as long as patients are carefully selected so that certain conditions are met.

A lack of inflammation is one important prerequisite for a transplant, as is a disease or injury that has not progressed to the point where the axons protected by the myelin sheath have themselves died off. Otherwise, he said, even if the cells engraft successfully, there are no axons left to protect. "They get all dressed up with no place to go."