Faster aging prevents remyelination of stem cells in MS patients

Faster aging prevents remyelination of stem cells in MS patients

Brain stem cells in people with the most severe form of multiple sclerosis look much older than they really are, according to a study published in the Proceedings of the National Academy of Sciences (PNAS). The prematurely old cells act differently in the brain than normal ones, and could be the key to new treatments for the disease.

Currently, there is only one drug for progressive disease, and it slows the progression but does not halt it.

In the past, the authors had shown that the brain stem cells from people with primary progressive MS prevent oligodendrocytes, the cells that form myelin, from maturing. It's something the brain stem cells are doing and it was likely why people with primary progressive MS never have remissions--the insulation around their nerve cells never gets repaired.

Now, the authors report that brain stem cells from primary progressive MS patients look prematurely old. Brain stem cells examined all looked to be decades older than otherwise similar cells from healthy people of the same age, as judged by standard cell age markers.

And the team found that not only do the brain stem cells from primary progressive MS patients look older--they also act older. An analysis showed that oligodendrocytes exposed to the patients' stem cells start expressing different genes. This may explain why the myelin is compromised. 

Intriguingly, the research group figured out that many of the genes activated in the oligodendrocytes were being prodded by a specific protein, a protein that the MS patients' stem cells were producing at high levels. The lab demonstrated that when they blocked this protein, HMGB1, the oligodendrocytes then developed normally.

"This protein actively blocks the ability of oligodendrocytes to mature. We did not know that before. It had been found in lesions, and it has been associated with inflammation, but it was thought to be just exciting the immune system. Now we can see if we block that protein, we dramatically improve the oligodendrocyte's growth," the author says.

The lab also found that treating the brain stem cells with rapamycin helped the cells develop normally. Rapamycin is a drug that can be used to suppress the immune system. Rapamycin had already been tested in relapsing-remitting MS patients and found not to help. But it might help patients with the progressive form of the disease.

"Recent studies have shown that drugs designed to target aging processes such as senescence may slow the onset and progression of many different chronic diseases, including cancer, atherosclerosis, stroke and Alzheimer's disease, for which aging is a major risk factor. This work could have a great impact on the clinical treatment of MS since it opens up an entirely new direction to explore as a possible approach to slowing the progression of the disease," says another author.

The next step will be to look at brain stem cells from people with the relapsing-remitting form of MS to see if, and when, these changes associated with aging begin. And to see if they can be avoided, slowed, or reversed.

"Brain regenerative therapies are already in clinical trials," the author says, and could potentially be tuned to help regrow the myelin in MS patients' nervous systems. "We know MS is not a disease of the aged, but it may be a disease of aging. Knowing this, we now want to know how this process can be targeted to enhance myelin repair in patients."