In experiments with mice, Johns Hopkins Medicine scientists report new evidence that precursors of myelin-producing cells - one of the few brain cell types that continue to be produced in the adult brain - undergo differentiation widely and at a constant pace, rather than "as needed" in response to injury or advancing age. The findings, say the scientists, suggest that treatments to combat myelin-damaging diseases such as multiple sclerosis may benefit from maximizing this intrinsic potential.

The new study, funded by the National Institutes of Health and described Jan. 22 in Science, centers on cells in the brain called oligodendrocytes. These cells produce a fatty-rich, insulating coating called myelin that wraps around nerve cell axons to speed transmissions of electrical signals in the central nervous system.

Demyelinating disorders, generally caused by autoimmune attacks, infections or genetic factors, produce vision problems, weakness, numbness, pain, and lack of coordination and balance in people.

Unlike neurons, oligodendrocytes are produced for many decades in the human brain, made possible by a population of oligodendrocyte precursor cells (OPCs) that can transform into new oligodendrocytes.

Bergles adds that because OPCs are capable of self-renewal, they are one of the longest lasting types of precursor cell in the nervous system.

In people with multiple sclerosis, trauma-related brain inflammation or other demyelinating diseases, myelin is stripped away. "Loss of myelin disrupts the ability of nerve cells to transfer information and alters the function of neural circuits," says Bergles. However, the persistence of OPCs allows regeneration of oligodendrocytes and - at least partial - restoration of myelin, Bergles notes.

For the current study, the Johns Hopkins team took a closer look at how OPCs differentiate into new oligodendrocytes. This process, say the researchers, is strikingly inefficient, as most OPCs that attempt to differentiate fail to successfully make new oligodendrocytes.

To understand how oligodendrocyte formation is controlled, the team looked in existing mammalian gene databases to see if there was a common molecular marker that offered a way to identify when OPCs start their transformation into oligodendrocytes in different mammalian species, including mice, marmosets and humans. They found that when OPCs attempt to differentiate, they change their gene expression to alter the extracellular matrix, a kind of protein meshwork surrounding them. They found that this molecular change resulted in the formation of "dandelion clock-like structures," or DACS, named because of their resemblance to the spherical seed head of a dandelion, specifically around differentiating OPCs. This knowledge provided a new means to track the differentiation of OPCs in the brain.

The team, led by Bergles and research associate Yevgeniya Mironova, Ph.D., was able to track DACS in the brains of mice, and used genetic labeling and imaging tools to validate evidence that each differentiating OPC produces a DACS that persists until precursor cells matured into oligodendrocytes.

With this new tracking tool, the scientists say they had a eureka moment when they found that OPCs were attempting to differentiate in every part of the mouse brain, even in regions where there are no oligodendrocytes and no myelination of neurons.

"It showed us that OPC differentiation was constantly happening all over the brain. They seem to have this intrinsic drive to continually try to make new oligodendrocytes," says Bergles. "Although this may seem very inefficient, we think this process evolved to provide equal potential to make new oligodendrocytes and myelin anywhere in the brain. It is then left to the neurons to help decide which of these differentiating cells survives to make myelin."

In a final series of experiments, the scientists stripped away oligodendrocytes and myelin in mouse brains to mimic myelin-related diseases, damage and aging. Unexpectedly, they found that OPCs carry on as usual with their steady differentiation process, regardless of whether there was an urgent need for new myelin. Although there was no increase in OPC differentiation, more of these cells survived to make new oligodendrocytes, showing how changes in integration, rather than direct mobilization of the precursor cells, are responsible for the increase in appearance of new myelin after injury.

"It seems that this constant OPC differentiation was designed for brain development, not for repair," says Bergles, who suggests that finding treatments that harness the developmental aspects of the oligodendrocyte production process may increase the chances of rapid myelin repair.

In addition to Bergles and Mironova, other contributors to the research are Brendan Dang, Dongeun Heo, Yu Kang Xu, Angela Yu-Huey Hsu, Jaime Eugenin von Bernhardi, Gian Carlo Molina-Castro, Anya A. Kim and Jing-Ping Lin from Johns Hopkins and Daniel Reich from the National Institutes of Health. 

Funding for the research was provided by the National Institutes of Health (AG072305, NS041435), the intramural research program of the National Institutes of Neurological Disorders and Stroke, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the National Multiple Sclerosis Society.