Researchers at the Karolinska Institute have spurred neural stem cells to produce myelin-forming oligodendrocytes, facilitating repair after spinal cord injury.
Spinal cord injury is a relatively rare occurrence. But when it does occur, it often occurs in young people, as a result of vehicle accidents, falls and, especially in the U.S., gun violence. Because almost half of all spinal cord injuries occur before the injured person turns 30, and spinal cord injury victims can live for a long time, the condition accounts for an outsize amount of morbidity.
"While neuronal is the most obvious problem in spinal cord injury, the damage is really pretty complex -- you lose many different types of cells," Jonas Frisen told BioWorld Science. And in the mammalian adult nervous system, none of them regenerate.
Insufficient regeneration of oligodendrocytes to ensure high-speed neuronal transmission are "a well-know problem" for functional recovery after spinal cord injury. After spinal cord injuries, "in many patients, there are many nerve fibers that are intact still, but malfunction to the lack of oligodendrocytes."
Frisen is professor of cell and molecular biology at the Karolinska Institutet and the senior author of the paper reporting the findings, which appeared in the October 2, 2020, issue of Science.
Cell transplantation has been a well-studied option for the replacement of both neurons and glial cells, though with limited success to date.
Promoting the regeneration of endogenous cells could be an alternative.
Oligodendrocytes have their own precursor cells, and those cells do produce new oligodendrocytes after spinal cord injury. But their numbers are typically insufficient to restore neuronal function.
Ependymal cells, the precursors to neurons in the mouse spinal cord, will produce glial cells after a spinal cord injury. But most of those cells are astrocytes and contribute to the formation of the astrocytic scar.
Scar formation is important -- "without it the injury will expand," Frisen pointed out. "But it's not really promoting repair or regeneration, it's just limiting the damage."
However, ependymal cells can also spontaneously differentiate into oligodendrocytes, though they do so quite rarely when left to their own devices.
That finding prompted Frisen and his colleagues to look at whether ependymal cells could be coaxed towards an oligodendrocytic fate in larger numbers.
In their work, the team looked at single ependymal cells, to determine whether such cells could, in principle, run the genetic programs necessary to differentiate into oligodendrocytes.
They found that ependymal chromatin was in a state that allowed the binding of transcription factors OLIG2 and SOX10, which orchestrates the production of oligodendrocytes by oligodendrocytic precursors.
Next, Frisen and his colleagues genetically engineered mice to express OLIG2 in their ependymal cells. In healthy animals, that expression had little discernible effect. But after an injury, OLIG2-expressing ependymal cells were able to produce large numbers of oligodendrocytes when they proliferated. Simultaneously, the ependymal cells also continued to produce astrocytes, enabling the formation of a glial scar.
While the spontaneous generation of oligodendrocytes from ependymal cells had suggested that the production of such cells was possible, "what was really surprising was how much we could crank it up," Frisen said.
Roughly a third of the cells produced by OLIG2-expressing ependymal cells were oligodendrocytes, more than 40 times as many as they would normally produce. The cells behaved normally, integrating with oligodendrocyte precursor-derived cells and contributing to the remyelination of neurons after injury.
If clinical translation succeeds, it could be useful not just for spinal cord injury but other neurological diseases as well. Stroke patients, too, might benefit from increased oligodendrocyte production, and Frisen said that "the most obvious disease" that results from damage to the myelin sheath is multiple sclerosis (MS), which, like spinal cord injury, often affects young individuals. The typical age of onset for MS is between 20 and 40 years of age.
For such translation, "one would need to establish that the same general mechanisms exist in humans," he said. "My guess would be that it's pretty likely."
More challenging could be the question of how to target the ependymal cells in a patient in need of myelin regeneration.
"We would need to come up with a pill that does the job that we do with genetics here," he said -- a task that "is obviously not low-hanging fruit at all." (Llorens-Bobadilla, E. et al. Science 2020, 370(6512): eabb8795).