The fresher the better

DURHAM, N.C.—Stem cells are being lauded and explored inmultiple indications, one of them being multiple sclerosis (MS). Transplants ofmesenchymal 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 isknown, and has been reported in a recent study in STEM CELLS Translational Medicine, is that adipose-derived stemcells from older donors are proving less effective than cells from youngerdonors.

MSCs are a promising therapy for MS because they travel toareas of damage caused by the disease and release trophic (cell growth)factors, in addition to exerting neuroprotective and immunomodulatory effectsto inhibit T cell proliferation. MS-related clinical trials have confirmed thesafety of this kind of therapy, but Bruce Bunnell, Ph.D., of TulaneUniversity's Center for Stem Cell Research and Regenerative Medicine, saysquestions still remain as to the exact mechanism by which MSCs provide thisbenefit to MS patients.

"All of our data would indicate that the [MSC] cells arevery good and very efficient at quieting the inflammatory component of thedisease," says Bunnell. "When we look at a molecular, pathologic level, we seethat the myelin destruction caused by the disease is nowhere near what it wasprior to treatment [with the MSCs], or if we treat with other cell types, or doa mock treatment. So whatever is going on seems to be able to help preservemyelin, 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 immunecell infiltration into the spinal cord that causes this immune-mediateddisruption of myelin. What we think is happening is by quieting theinflammatory component, you're reducing the amount of inflammatory cellinflammation into the spinal cord, and that results in a decrease in the amountof myelin destruction."

Bunnell served as lead author for this study, workingalongside a team of his colleagues in Tulane as they tested MSCs transplants inmice. The team induced chronic experimental autoimmune encephalomyelitis inmouse models, a disease similar to MS, and treated them before the onset of thedisease with human adipose-derived MSCs derived from donors who were eitheryounger than 35 years of age or older than 60 years of age. Their results showedthat the transplants provided by older donors are less effective and that theolder MSCs might actually increase the proliferation of T cells and associatedattacks on the central nervous system. Invitro, mice that received stem cells from older donors faced increasedcentral nervous system inflammation, demyelination resulting in impairedmovement and cognition, and an increase in splenocytes compared to mice thatreceive cells from younger donors.

"Aging is known to have a negative impact on the regenerativecapacity of most tissues, and human MSCs are susceptible to biologic agingincluding changes in differentiation potential, proliferation ability and geneexpression. These age-related differences may affect the ability of older donorcells to migrate extensively, provide trophic support, persist long-term andpromote repair mechanisms," said Bunnell.

Bunnell notes that it's too early for these tests in mice toprovide much data about the possible results in humans, though early data ispromising. The mice that received the MSC treatments were "pretty wellprotected from disease onset," he notes, adding that while some demonstratedsigns of disease, it was never as bad as in the mice who received mocktreatments or other stem cells. While they haven't ascertained yet whether suchtransplants could provide long-term benefit to patients, tests in mouse modelsindicate that a single dose can offer improvements for long periods of time, headds.

As they continue to pursue this research, Bunnell says he'dlike to move this into human trials, as only small studies in human have beendone so far in the United States. Additionally, he hopes to study the ageprocess more closely to figure out how age reduces the quality of the MSCs, andif it is possible to alter those processes.

Bunnell says that while these transplants probably don'trepresent a cure—noting that one is impossible "until we understand themolecular pathology" of the disease—he does believe they will help to preservemyelin and "tremendously slow down the immune-mediated destruction associatedwith the disease."

"While that may not be viewed as a true cure for thedisease, I think we're going to allow people to have a much better life forlonger periods of time; they'd still have MS, but it's not going to ravage themthe way it potentially would if we didn't give them stem cells," Bunnellexplains.