Targeting Brain Stem Cell Aging in Progressive MS May Enhance Remyelination

Brain stem cells of individuals with primary progressive multiple sclerosis (PPMS) appear to age prematurely compared with similar cells from healthy individuals, according to a new study from the Proceedings of the National Academy of Sciences. The research provides vital insights that could help in the development of new MS therapies, the study authors noted.

Due to chronic demyelination and neurodegeneration, PPMS represents the phase of irreversible neurological disability for patients. Current treatments for PPMS can suppress inflammation and block access of immune cells into the central nervous system, but do not fully prevent demyelination and axonal degeneration, indicating a need for therapeutic targets that can restore myelin repair, according to the study.

Cellular senescence, a form of adaptive cellular physiology associated with aging, causes a proinflammatory cellular phenotype that impairs tissue regeneration and has been linked to neurodegenerative diseases.

“Senescence can be induced from natural aging (termed replicative senescence) or can be induced by stressors, including inflammation and oxidative stress,” the researchers wrote in the study. “Persistent signs of oxidative stress and inflammation are associated with demyelination, and both are measurable in the brain and in the blood in PMS.”

Previous studies have shown that the brain stem cells in MS prevent oligodendrocytes from maturing, which is likely why individuals with PPMS never have remissions, according to the researchers. In the current study, the authors found that the brain stem cells from patients with PPMS both look and act prematurely aged, as judged by standard cell age markers.

The analysis showed that oligodendrocytes exposed to a patients’ stem cells started expressing different genes. Particularly, the researchers found that a specific protein, called HMGB1, blocked the ability of oligodendrocytes to mature normally and blocking this protein could improve the oligodendrocyte’s growth.

To test this potential therapeutic target, the researchers treated the brain stem cells with rapamycin, which helped the cells develop normally. The findings indicate that targeting the aging processes such as senescence to promote myelin repair could be effective in slowing the onset and progression of PPMS.

The researchers noted that it is unclear whether cellular aging is present in other types of MS and that the next step would be to examine the brain stem cells from patients with the relapsing-remitting form of MS.

“Brain regenerative therapies are already in clinical trials,” Stephen Crocker, PhD, neuroscientists at UConn Health, said in a press release about the study. “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.”

References

Nicaise AM, Wagstaff LJ, Willis CM, et al. Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Proceedings of the National Academy of Sciences. March 25, 2019. https://doi.org/10.1073/pnas.1818348116

Study: Brain Stem Cells Age Faster in MS Patients [news release]. University of Connecticut. https://today.uconn.edu/2019/03/ms-sufferers-brain-stem-cells-age-faster/. Accessed March 25, 2019.