Study Reveals Increased Cellular Stress in MS Skin Fibroblasts

In people with multiple sclerosis (MS), skin cells show increased amounts of cellular stress in a manner that is distinct from people without MS and from other neurological diseases, new research shows.

The findings were published in the journal Aging, in the study “Signatures of cell stress and altered bioenergetics in skin fibroblasts from patients with multiple sclerosis.”

Although MS primarily is considered a neurological disease, people with the disease commonly have abnormalities in many of the body’s systems. For instance, previous research has indicated that MS results in specific changes to skeletal muscle, urine, and blood.

These findings suggest that MS is, at least to some extent, a systemic disease. As such, studying cells from MS patients could provide insight into disease processes or possible treatment strategies.

Skin fibroblasts are a type of skin cell that is convenient for such studies because they can be collected easily from patients and cultured in a lab for experimentation. Previous research has indicated that skin fibroblasts are abnormal in other neurological diseases — including Parkinson’s and Huntington’s diseases — but these cells have not been thoroughly researched in the context of MS.

In the new study, researchers at the Mayo Clinic in Rochester, Minnesota, collected skin fibroblasts from 30 MS patients: 27 with relapsing-remitting MS, two with secondary progressive MS, and one with clinically isolated syndrome. For comparison, the team collected skin fibroblasts from 10 people with amyotrophic lateral sclerosis (ALS) — a neurological disease characterized by the death of motor neurons — and from 24 people without any sign of neurological disease (the control group).

The three groups all included a roughly even split between men and women.

Researchers analyzed the gene expression profiles of fibroblasts — essentially, which genes are “off” (inactive) or “on” (active). This analysis indicated that, compared to both control fibroblasts and ALS fibroblasts, MS fibroblasts had increased levels of endoplasmic reticulum (ER) stress.

The ER is a cellular organelle that aids in the production of proteins. ER stress refers to conditions in which the ER is not working properly, and usually is a sign of disease or dysfunction in cells.

Additional analyses suggested that MS fibroblasts also had increased levels of other types of cellular stress markers. For example, following irradiation, MS fibroblasts had higher expression levels of the gene P21, which is associated with DNA damage.

“These results suggest that MS skin fibroblasts have an underlying stress phenotype that may be distinct from normal controls and ALS,” the researchers wrote.

To test whether these cells had a corresponding inability to respond to outside stress triggers, the researchers treated fibroblasts with hydrogen peroxide, a powerful inducer of oxidative cell stress. Compared to control and ALS fibroblasts, MS fibroblasts were less resilient to this treatment; that is, more MS fibroblasts died upon treatment.

“Given MS skin fibroblasts have reduced viability compared to ALS and control cells when treated with hydrogen peroxide, our findings may suggest cell survival mechanisms are altered in MS fibroblasts and may be disease specific,” the researchers wrote, adding that this finding “supports the notion that an underlying stress phenotype in MS skin fibroblasts renders them more susceptible to additional cytotoxic events.”

A subsequent suite of experiments assessed the metabolism of fibroblasts. Generally, cellular metabolism is markedly affected by cellular stress. Several differences were noted, including differences in the glycolytic reserve (the amount of energy a cell has ready) and increased production of lactate (a metabolic waste product).

“Our data suggests that the bioenergetics in MS skin fibroblasts is altered compared to controls,” the researchers wrote.

“Taken together, we determined that the skin fibroblasts derived from MS patients have an underlying cell stress phenotype, which likely predisposes the cells to altered bioenergetics. Furthermore, comparison of MS skin fibroblasts to ALS cells demonstrates that these changes are likely disease specific,” they concluded.

The team noted that its results demonstrate “that skin fibroblasts could serve as an additional model to study MS branching important aspects that are missing from animal models.”