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DURHAM, N.C.—Stem cells are being lauded and explored in multiple indications, one of them being multiple sclerosis (MS). Transplants of mesenchymal stem cells (MSCs) are being tested in mice in clinical trials, though their potential in humans with MS is not fully known as yet. What is known, and has been reported in a recent study in STEM CELLS Translational Medicine, is that adipose-derived stem cells from older donors are proving less effective than cells from younger donors.
MSCs are a promising therapy for MS because they travel to areas of damage caused by the disease and release trophic (cell growth) factors, in addition to exerting neuroprotective and immunomodulatory effects to inhibit T cell proliferation. MS-related clinical trials have confirmed the safety of this kind of therapy, but Bruce Bunnell, Ph.D., of Tulane University's Center for Stem Cell Research and Regenerative Medicine, says questions still remain as to the exact mechanism by which MSCs provide this benefit to MS patients.
"All of our data would indicate that the [MSC] cells are very good and very efficient at quieting the inflammatory component of the disease," says Bunnell. "When we look at a molecular, pathologic level, we see that the myelin destruction caused by the disease is nowhere near what it was prior to treatment [with the MSCs], or if we treat with other cell types, or do a mock treatment. So whatever is going on seems to be able to help preserve myelin, and when we look at the markers of disease-associated inflammation, they seem to have dropped dramatically.
"So there's this connection between the inflammation and immune cell infiltration into the spinal cord that causes this immune-mediated disruption of myelin. What we think is happening is by quieting the inflammatory component, you're reducing the amount of inflammatory cell inflammation into the spinal cord, and that results in a decrease in the amount of myelin destruction."
Bunnell served as lead author for this study, working alongside a team of his colleagues in Tulane as they tested MSCs transplants in mice. The team induced chronic experimental autoimmune encephalomyelitis in mouse models, a disease similar to MS, and treated them before the onset of the disease with human adipose-derived MSCs derived from donors who were either younger than 35 years of age or older than 60 years of age. Their results showed that the transplants provided by older donors are less effective and that the older MSCs might actually increase the proliferation of T cells and associated attacks on the central nervous system. In vitro, mice that received stem cells from older donors faced increased central nervous system inflammation, demyelination resulting in impaired movement and cognition, and an increase in splenocytes compared to mice that receive cells from younger donors.
"Aging is known to have a negative impact on the regenerative capacity of most tissues, and human MSCs are susceptible to biologic aging including changes in differentiation potential, proliferation ability and gene expression. These age-related differences may affect the ability of older donor cells to migrate extensively, provide trophic support, persist long-term and promote repair mechanisms," said Bunnell.
Bunnell notes that it's too early for these tests in mice to provide much data about the possible results in humans, though early data is promising. The mice that received the MSC treatments were "pretty well protected from disease onset," he notes, adding that while some demonstrated signs of disease, it was never as bad as in the mice who received mock treatments or other stem cells. While they haven't ascertained yet whether such transplants could provide long-term benefit to patients, tests in mouse models indicate that a single dose can offer improvements for long periods of time, he adds.
As they continue to pursue this research, Bunnell says he'd like to move this into human trials, as only small studies in human have been done so far in the United States. Additionally, he hopes to study the age process more closely to figure out how age reduces the quality of the MSCs, and if it is possible to alter those processes.
Bunnell says that while these transplants probably don't represent a cure— noting that one is impossible "until we understand the molecular pathology" of the disease—he does believe they will help to preserve myelin and "tremendously slow down the immune-mediated destruction associated with the disease."
"While that may not be viewed as a true cure for the disease, I think we're going to allow people to have a much better life for longer periods of time; they'd still have MS, but it's not going to ravage them the way it potentially would if we didn't give them stem cells," Bunnell explains.