Researchers at the University at Buffalo say they have identified the single transcription factor or “master switch” that initiates the critical myelination process in the brain. Their study (“Transcription factor induction of human oligodendrocyte progenitor fate and differentiation”) is published online in the Proceedings of the National Academy of Sciences (PNAS).
The identification of this factor, SOX10, in human brain cells brings scientists closer to the goal of treating multiple sclerosis (MS) by transplanting into patients the brain cells that make myelin, according to one of the authors of the paper.
“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,” said Fraser Sim, Ph.D., senior author on the paper and assistant professor in the UB department of pharmacology and toxicology in the School of Medicine and Biomedical Sciences. “If we could create a small molecule drug that would switch on SOX10, that would be therapeutically important.”
Stem cell therapy is seen as having dramatic potential for treating MS, but there are key obstacles, especially the length of time it takes for progenitor cells to turn into oligodendrocytes, the brain's myelin-making cells. Using currently available methods, added Dr. Sim, it can take as long as a year to generate a sufficient number of human oligodendrocyte cells to treat a single MS patient.
That's partly because there are so many steps: the skin or blood cell must be turned into induced pluripotent stem cells, which can differentiate into any other type of cell and from which neural progenitor cells can be produced. Those progenitor cells then must undergo differentiation to oligodendrocyte progenitors that are capable of ultimately producing the oligodendrocytes.
“Ideally, we'd like to get directly to oligodendrocyte progenitors,” continued Dr. 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.”
Using fetal (not embryonic) brain stem cells, the UB researchers searched for transcription factors that are absent in neural progenitor cells and switched on in oligodendrocyte progenitor cells. While neural progenitor cells are capable of producing myelin, they do so very poorly and can cause undesirable outcomes in patients, so the only candidate for transplantation is the oligodendrocyte progenitor.
“The ideal cell to transplant is the oligodendrocyte progenitor cell,” said Dr. Sim. “The question was, could we use one of these transcription factors to turn the neural progenitor cell into an oligodendrocyte progenitor cell?”
To find out, they looked at different characteristics, such as mRNA expression, protein and whole gene expression, and functional studies. The team narrowed it down to a short list of 10 transcription factors that were made exclusively by oligodendrocyte progenitor cells.
“We describe, to our knowledge, the first comprehensive study of transcription factor expression and function by purified neural and oligodendrocyte progenitors obtained directly from human brain tissue,” wrote the investigators. “We have identified those transcription factors capable of regulating oligodendrocyte progenitor fate and establish that among these, only SOX10 was capable of comprehensively inducing oligodendrocyte fate both in vitro and following transplantation into a model of human leukodystrophy. Thus, viral and pharmacologic approaches to increasing SOX10 expression likely will improve the outcome of human transplant therapy.”
“In MS, first the immune system attacks the brain, but the brain is unable to repair itself effectively,” noted Dr. Sim. “If we could boost the regeneration step 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 of disease than the later, progressive stage.”