Neural Stem Cells in MS Patients Look Prematurely Old

Cellular aging in progressive multiple sclerosis (MS) may contribute to the damage caused by limited remyelination as MS advances, a new study suggested.

Senescence was found in neural progenitor cells within demyelinated white matter lesions in progressive MS autopsy tissue, according to Stephen Crocker, PhD, of the University of Connecticut School of Medicine in Farmington, and colleagues.

Moreover, induced pluripotent stem-derived neural progenitor cells from blood samples of patients with primary progressive MS (PPMS) expressed cellular senescence markers, when compared with controls, they reported in Proceeding of the National Academy of Sciences.

Targeting cellular senescence in progenitor cells may be a novel therapeutic approach to promote remyelination in MS, they added.

“We don’t know why, but in individuals who are of the same age as people without the disease, the molecular marks of advanced age seem to be already present,” Crocker told MedPage Today. “At the cellular level, the processes of aging may be at play, limiting the endogenous ability of the brain to repair the damage occurring in the disease.”

“MS is not a disease of the aged but, we now think, a disease of aging,” he added.

In previous work, Crocker’s research group found that neural progenitor cells derived from induced pluripotent stem cells from PPMS patients failed to promote oligodendrocyte progenitor cell maturation, while neural progenitor cells from age-matched controls did so efficiently. In this study, Crocker and colleagues found that many of the genes activated in the oligodendrocytes were being affected by high-mobility group box-1 (HMGB1), a protein progressive that MS stem cells were producing at high levels.

“This protein actively blocks the ability of oligodendrocytes to mature,” Crocker said. “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 oligodendrocytes’ growth.”

Crocker and colleagues demonstrated the expression of cellular senescence in PPMS neural progenitor cells was reversible by treatment with rapamycin (Rapamune), also known as sirolimus, an immunosuppressive drug used to prevent transplant organ rejection.

Distinguishing cellular aging as a process active in progressive MS opens up “a whole new cupboard of potential therapeutic options for progressive MS patients,” Crocker said.

“There are other drugs that could potentially be effective, like metformin, which is being explored as potentially having an impact on aging,” he pointed out. “There’s also a new class of drugs called senolytics, which can target and kill off senescent cells to help alleviate the impact those cells have on tissues.”

The next step is to look at induced pluripotent stem cells and the effect of reversing senescence on regeneration in more models, including ones of relapsing MS patients, and to understand the timing of the process, he noted. “When does this become active in the disease? We don’t know yet.”

“What’s driving us is hope,” Crocker added. “By identifying a new process, a process not previously attributable to remyelination failure in multiple sclerosis, it adds to the hope that we will crack this disease and find ways to reverse its course.”