view of human neural progenitors induced to differentiate as oligodendrocytes following SOX10 over-expression.

Human neural progenitors were induced to differentiate as oligodendrocytes following SOX10 over-expression. “We found that SOX10 was the critical transcription factor for specification of oligodendrocyte lineage fate in human cells,” says Fraser J. Sim, PhD. Oligodendrocytes, labeled in green, expressed OLIG2, another important oligodendrocyte transcription factor, shown in red. Photo: Jing Wang

Study IDs ‘Master Switch’ for Myelination in Brain Stem Cells

Published July 15, 2014

Scientists in the University at Buffalo’s Department of Pharmacology and Toxicology have identified SOX10 as the single transcription factor or “master switch” that initiates myelination in the brain.

“If we could create a drug that would switch on SOX10, that would be therapeutically important.”
Fraser J. Sim, PhD
Assistant professor of pharmacology and toxicology

The finding brings researchers closer to the goal of treating multiple sclerosis (MS) with transplanted brain cells that produce myelin — the nerve sheath destroyed by the disease.

Goal is to Induce SOX10 in MS Patients

Fraser J. Sim, PhD.

Fraser J. Sim, PhD.

“Now that we have identified SOX10 as an initiator of myelination, we can work on developing a viral or pharmaceutical approach to inducing it in MS patients,” says Fraser J. Sim, PhD, assistant professor and senior author of the paper.

Transcription factors are proteins or molecules that bind to DNA and alter which genes are turned on, or expressed.

“If we could create a drug that would switch on SOX10, that would be therapeutically important,” Sim explains.

Removing Barriers to MS Stem Cell Therapy

Targeting SOX10 offers hope for a viable stem cell treatment for MS.

Long seen as having dramatic potential for treating MS, stem cell therapy has been impractical largely due to the time needed to produce the necessary oligodendrocyte cells.

“Today, it could take up to a year to generate enough cells to treat a single MS patient,” Sim explains.

The lengthy process involves producing pluripotent stem cells from skin or blood cells, then generating neural progenitor cells, which must then undergo differentiation to oligodendrocyte progenitors.

Although neural progenitor cells also can produce myelin, they do so poorly and may cause undesirable outcomes in patients.

“Ideally, we’d like to get directly to oligodendrocyte progenitors,” says Sim. “The new results are a stepping stone to the overall goal of being able to take a patient’s skin cells or blood cells and create from them oligodendrocyte progenitors,” he says.

Only SOX10 Makes the Switch

Using fetal (not embryonic) brain stem cells, the UB researchers searched for transcription factors that are switched on in oligodendrocyte progenitor cells, but are absent in neural progenitor cells.

They asked: “Could we use one of these transcription factors to turn the neural progenitor cell into an oligodendrocyte progenitor cell?”  

To find out, the research team looked at characteristics such as mRNA expression, protein and whole-gene expression as well as functional studies.

“We narrowed it down to 10 transcription factors made exclusively by oligodendrocyte progenitor cells,” says Sim.

“Of those, only SOX10 was able to make the switch from neural progenitor to oligodendrocyte progenitor cell.”

Potential to Stall MS at Earlier Stage

The researchers also found that SOX10 could expedite the transformation from oligodendrocyte progenitor cell to differentiation as an oligodendrocyte.

“That’s tantalizing,” says Sim, “because one of the biggest problems with MS is that cells get stuck in between these steps.”

“First the immune system attacks the brain, but the brain can’t repair itself effectively,” explains Sim.

“If we could boost regeneration by facilitating formation of oligodendrocytes from progenitor cells, then we might be able to keep patients in the relapsing remitting stage of MS — a far less burdensome stage than the later, progressive stage.”

Doctoral Candidate is First Author

Co-authors on the paper are:

  • first author Jing Wang, doctoral candidate
  • Suyog U. Pol, doctoral candidate
  • Alexa Keller Haberman, BS/MS ’12
  • Chunming Wang, PhD, postdoctoral researcher
  • Melanie A. O’Bara, PhD, research scientist

The study, “Transcription Factor Induction of Human Oligodendrocyte Progenitor Fate and Differentiation,” has been published in Proceedings of the National Academy of Sciences.