Key News in Family Medicine March 26, 2019 (12 of 26)

Brain stem cells in people with the most severe form of multiple sclerosis (MS) seem much older than they actually are, according to a study conducted by UConn Health and published in the Proceedings of the National Academy of Sciences (PNAS). Prematurely old cells act differently in the brain than normal cells and could be key to new treatments for the disease.

MS disrupts the ability of the nerves to transmit signals throughout the body. MS can make it difficult to walk or hold a pen, for example. The problem is caused by inflammatory and degenerative isolation around the nerves, called myelin. Just like a wire with frayed insulation, nerves with damaged myelin can cause a short circuit or pick up spurious signals. Fortunately, most people with MS have long periods of remission, recover and can walk and live as before the disease develops.

But ultimately, most people with MS develop a progressive illness, in which their symptoms progressively worsen. And some people actually start with a progressive illness, called primary progressive MS. Currently, there is only one drug for progressive disease, and this slows progression but does not stop it.

Stephen Crocker, a neuroscientist at UConn Health, wants to better understand progressive MS to find new treatments. In the past, he and his colleagues had shown that brain cells from people with primary progressive MS prevented oligodendrocytes, the cells that make up myelin, from maturing. It's something that brain cells do, and that's probably why people with primary progressive MS are never in remission – the isolation of their nerve cells is never fixed.

Now, Crocker and his colleagues report that brain cells from patients with primary-progressive multiple sclerosis seem prematurely old. The brain stem cells examined by neurologist Anna Williams of the University of Edinburgh, Valentina Fossati of the New York Stem Cell Foundation, and Crocker's lab all seemed to be decades older than cells elsewhere. similar to healthy people of the same age, judging by standard age marker cells.

And the team discovered that not only did the stem cells of the brains of patients with progressive primary sclerosis look old, but they also acted. An badysis by Paul Robson at the UConn – Jackson Laboratory of Genomic Medicine showed that oligodendrocytes exposed to the stem cells of patients begin to express different genes. This may explain why myelin is compromised.

Curiously, the research group discovered that a large number of activated genes in oligodendrocytes were stimulated by a specific protein, a protein produced at high levels by stem cells from patients with MS. Crocker's laboratory demonstrated that, when they blocked this protein, HMGB1, oligodendrocytes then developed normally.

"This protein actively blocks the ability of oligodendrocytes to mature – we did not know it before – it was found in lesions and it was badociated with inflammation, but it was thought that she was only doing that." "Exciting the immune system We can now see if we block this protein, we significantly improve the growth of the oligodendrocyte," says Crocker.

"Primary progressive MS is a devastating disease for which we still lack effective treatments, and myelin regeneration is a major need that current treatments have not satisfied," Dr. Fossati said. "We are delighted that the study of human stem cells in a dish has led to the discovery of a new pathological mechanism that could be targeted as part of essential therapies for patients with progressive MS."

"We believe that understanding the differences between brain stem cells from people with MS and those from healthy people will be an essential part of the development of much-needed treatments," said Williams.

Crocker's lab also found that treating brain cells with rapamycin helped the cells to develop normally. Rapamycin is a medicine that can be used to suppress the immune system. Rapamycin had previously been tested in patients with relapsing remitting multiple sclerosis and was of no benefit. But this could help patients with the progressive form of the disease.

"Recent studies have shown that drugs designed to combat aging processes, such as senescence, could slow the onset and progression of many chronic diseases, such as cancer, atherosclerosis, Stroke and Alzheimer's disease, for which aging was a major risk factor – a significant impact on the clinical treatment of MS as it opens up a whole new direction to explore as a possible approach to slowing down MS. progression of the disease, "said George Kuchel, director of UConn Health's Center on Aging.

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

"Brain regeneration treatments are already undergoing clinical trials," says Crocker, and could eventually be adapted to help regenerate myelin in the nervous system of MS patients. "We know that MS is not a disease of the elderly, but perhaps also aging.With this in mind, we now want to know how to target this process to improve myelin repair in patients."