Cellular Senescence Implicated in MS Development, Study Suggests

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Cellular senescence — the process of aging at the cellular level — may play a role in the development of primary progressive multiple sclerosis (PPMS) by limiting the ability of myelin-producing cells (oligodendrocytes) to renew and mature.

The study with that finding, “Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis,” was published in the journal PNAS.

As MS is characterized by the loss of myelin on neurons — demyelination —  therapeutic strategies to reverse this process (and promote remyelination) make sense intuitively. However, such strategies are inherently limited by the body’s capacity to produce new myelin. This, in turn, is limited by whether oligodendrocyte precursors cells (OPCs) can differentiate into mature, myelin-producing oligodendrocytes.

The team behind this study previously had used induced pluripotent stem cells (iPSCs) — stem cells reverse-engineered from other cell types, such as  skin cells — from both PPMS patients and healthy controls to make neural progenitor cells (NPCs). Through these experiments, they obtained preliminary evidence that cells from PPMS patients were less capable of promoting OPC maturation.

Researchers hypothesized this difference might be due to cellular senescence, which, according to the team, “causes a pro-inflammatory cellular phenotype that impairs tissue regeneration, has been linked to stress, and is implicated in several human neurodegenerative diseases.”

To test their hypothesis, researchers first analyzed brains from deceased patients with and without progressive MS, including PPMS and secondary progressive MS (SPMS). They tested for the presence of molecular markers of precursor cells, and markers of senescence.

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Results showed that in the progressive MS brains — specifically within demyelinated lesions — there were fewer progenitor cells, and those that were present had higher levels of senescence markers.

Researchers then returned to their iPSC/NPC model. They confirmed that NPCs derived from iPSCs from PPMS patients had more markers of senescence, compared to NPCs derived from iPSCs from healthy controls. However, both iPSCs from PPMS patients and controls had similar levels of senescence markers, suggesting that the difference occurred only after some differentiation.

The team next wondered whether reversing senescence might improve the ability of PPMS NPCs to support OPCs maturation into full-fledged oligodendrocytes. To test this, they treated NPCs with rapamycin, which, among its many effects, can prevent cells from secreting senescence-related signals.

Researchers then took the medium these cells were grown in,  which contained all the signals they had secreted, and tested its effect on OPCs in a separate culture. Medium from untreated NPCs from PPMS patients did little to promote the differentiation of OPCs, but medium from rapamycin-treated PPMS NPCs promoted OPCs’ growing and differentiation into myelin-producing oligodendrocytes.

This shows, at least conceptually, that the senescence phenotype is somewhat reversible, and might be able to be therapeutically targeted in MS patients.

Finally, the researchers analyzed the components secreted by NPCs to try to find the molecules most responsible for preventing OPCs from maturing. They honed in on the protein HMGB1, which, they found, could alter the genes active in OPCs to inhibit maturation.

Overall, the “findings provide evidence that cellular senescence is an active process in progressive MS that may contribute to limited remyelination,” the researchers wrote.

“Although MS is not typically considered a disease of aging, because it is generally diagnosed in early-to-middle adulthood, the functional impact of cellular senescence in progenitor cells … may indicate that premature cellular aging is an important component of this disease,” the team concluded.

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