Recent stem cell research could lead to a new way of treating inflammatory diseases, such as multiple sclerosis.
Multiple sclerosis (MS) causes loss of myelin, which is the fatty coating that insulates the fibers that carry electrical signals in the brain and the rest of the central nervous system (CNS).
Now, scientists from the University at Buffalo, NY, have uncovered a previously unknown mechanism that could be preventing myelin repair in MS.
The mechanism effectively stops progenitor cells from growing and developing into oligodendrocytes, which are the cells that make the myelin coating.
It does this by stopping the cell cycle of the progenitor cells. Instead, it places them in a deactivated state called pathological quiescence.
Progenitor cells are descendants of stem cells that have not yet fully matured into a final cell type. They can continue to divide as immature cells but cannot do this indefinitely like stem cells.
The journal Cell Reports has published a study paper on the research. This identifies the driver of the mechanism as a protein called Paired Related Homeobox Protein 1 (PRRX1).
The senior author of the study is Dr. Fraser J. Sim, who is an associate professor of pharmacology and toxicology in the Jacobs School of Medicine and Biomedical Sciences at the university.
MS is an unpredictable, long-term disease, the primary feature of which is the erosion of myelin. The loss of myelin disrupts the flow of electrical signals in the CNS, often causing disability.
As MS can affect any part of the CNS, symptoms vary widely. However, the most common symptoms include visual disturbance, mobility difficulties, extreme fatigue, and altered sensations.
The symptoms of MS can persist and worsen over time, or they can come and go. MS has four major forms, depending on which symptoms arise and how they progress.
Many experts are of the view that MS is an autoimmune disease, believing that the immune system launches an inflammatory attack on healthy myelin as though it were posing a threat.
MS organizations have estimated that there are around 2.3 million people worldwide living with MS.
In the United States, there is no official tracking of MS nationwide. However, the preliminary results of a National MS Society study suggest that there could be as many as 1 million people in the U.S. with MS.
In the recent study, Dr. Sim and his team focused not so much on the destruction of myelin as on what might be preventing its repair.
They found that switching on the gene that codes for PRRX1 stopped the cell cycle of the progenitor cells, effectively preventing them from dividing and differentiating into oligodendrocytes.
Dr. Sim explains that these cells are “responsible for all myelin regeneration in the adult brain.”
The researchers demonstrated this effect in a mouse model of a childhood disease called leukodystrophy, which either prevents the formation of myelin or destroys it.
Switching on PRRX1 induced pathological quiescence in human oligodendrocyte progenitor cells that they had transplanted into the mice.
This stopped the cells from colonizing white matter in the brain and effectively stopped myelin regeneration.
PRRX1 is a transcription factor, which is a type of protein that “reads” DNA code and carries it to messenger proteins that relay the information to various cell functions.
The study also revealed that blocking the transcription factor stops other signals that could be preventing myelin repair.
Most MS drug research has focused on stimulating progenitors to mature into myelin-producing cells.
The recent finding suggests that targeting the molecules that render progenitors inactive might be a promising alternative.
“The idea,” says Dr. Sim, “that pathological quiescence of progenitors could prevent regeneration in MS is distinct from the current preclinical strategies making their way into trial.”
“We plan to pursue the idea that perhaps we could identify treatments for MS that work by overcoming pathological quiescence of oligodendrocyte precursors in demyelinating lesions that characterize this disease.”
Dr. Fraser J. Sim