Stem Cell Age May Explain Trial Failures

  Older stem cells may not work on multiple sclerosis (MS)—and possibly many other disorders—says new Tulane University research, supporting other recent studies. “Our manuscript is one of the first reports to show that the biological age of stem cells…


Older stem cells may not work on multiple sclerosis (MS)—and possibly many other disorders—says new Tulane University research, supporting other recent studies.

“Our manuscript is one of the first reports to show that the biological age of stem cells can impact their efficacy for disease treatment,” says Bruce Bunnell, Director of the Tulane University Center for Stem Cell Research and Regenerative Medicine.

An increasing number of clinical trials involve the removal of mesenchymal stem cells (MSCs) from MS patients. After the cells are expanded (replicated) they are strategically transplanted back into the patients.

The purpose is to alleviate symptoms of MS, an autoimmune disease that attacks the brain and spinal cord. MSCs can home to areas of damage, release healing trophic factors, and exhibit immunomodulatory effects.

But results have been “markedly mixed,” the Stem Cells Translational Medicine report states, “with some patients improving, others remaining unchanged, and several progressing in severity.”  Bunnell’s group guessed one reason for that could be donor age.

Their study compared, says Bunnell, MSCs from the fat of young patients who were a mean age of 26, and older patients who were a mean age of 63, in mouse models of MS (mice given experimental autoimmune encephalomyelitis [EAE]).

The result was clear, the authors report. Disease symptoms were staved off in mice receiving young cells. Not so, in mice receiving older cells.
“Although the stem cells from older donors do not seem to exacerbate EAE in the mouse, our results indicate that older donor MSCs have lost the ability to alleviate EAE-associated symptoms. The striking differences in clinical presentation between younger and older (stem cell) treated EAE mice emphasize the need to determine the therapeutic effectiveness of autologous cell transplantation in older patients, especially those with demyelinating or inflammatory diseases like MS,” the group wrote.
Motor function, spinal cord pathology, T-cell proliferation rates, and levels of healing hepatocyte growth factor were all significantly better in mice treated with stem cells from younger donors.
Other recent papers have come to similar conclusions about the limited nature of older stem cells.
In May 2012, Washington University oncologist Timothy Ley published a Nature paper finding most mutations in induced pluripotent stem (iPS) cells, made from skin cells, occurred before becoming iPS cells. (IPS cells are embryonic-like cells created by turning back the clock on, or dedifferentiating, adult cells.) The process of dedifferentiating adult skin cells was not the main cause of mutations.
Normal adult skin cells are plenty mutated on their own, the team reported.
In July 2012, Ley and his Washington University colleague Richard Wilson found a similar phenomenon occurs in healthy hematopoietic (blood) stem cells before they take a cancerous turn. “Our data suggest that most of the somatic events in Acute Myeloid Leukemia (AML) genomes appear to be random, preexisting, background mutations in the hematopoietic cell that acquired the key initiating mutation. This event ‘‘captures’’ the mutational history of this cell as it evolves to become the founding clone at presentation,” the team wrote in Cell.
To determine this, the team looked at mutations in blood stem cells across donor age. They found blood stem cells accumulate ten mutations per year. By the time people hit 50, they have accumulated 500 mutations per blood stem cell. They tend to need only three additional mutations to acquire AML.
Finally, this February, the team of Johns Hopkins cancer genetics pioneer Burt Vogelstein reported on a mathematical model predicting that half of all mutations in tumors in self-renewing tissues—including blood, skin, and gastrointestinal organs—exist prior to tumor formation. The model held up even though the different tissues self-renew at different rates: the colon, a week; the blood, a month. “Bert Vogelstein applied the idea (of the above papers ) to solid tumors as well, and it holds up,” says Ley.
Stem cell age matters, say these researchers. This may affect both adult stem cell transplants, and planned iPS cell treatments.
If this continues to prove true, there are ways around it, many have noted. In the future, people may bank their stem cells when they are young. Already, many parents bank infants’ cord-blood stem cells. Cord blood stem cell expansion techniques are improving. And cord-blood stem cells more efficiently dedifferentiate into iPS cells than adult cells, say cord blood experts.
Then there are embryonic and fetal stem cells, and the IVF-clinic technique involving pre-implantation genetic diagnosis (PGD) of cells removed from eight-cell embryos. Those removed PGD cells are embryonic stem cells. Why not give IVF babies a lifelong supply of their own embryonic stem cells, some researchers ask? The company ACT has published preliminary work finding this option feasible.
Still others note the jury is out—on most cells.
“That stem cells from older people change in function now seems a fact of life. How this affects stem cell therapies, however, is hardly studied,” says the University of Ulm’s Hartmut Geiger, who recently wrote about rejuvenating aged blood stem cells for Nature Reviews Immunology. “The authors of the interesting Tulane study have started to tackle the question of whether adipose-derived MSCs (ASCs) show a distinct modulatory influence in an experimental murine model of MS. Their findings support the idea that ASC from patients over 60 years might have reduced modulatory function. But the number of ASC samples from elderly donors was small, and tested in a combined fashion (cells from all donors together).”
As the Tulane team writes, larger sample sizes are needed, Geiger says. “This work shows aged MSCs as a therapeutic vehicle might result in reduced effectiveness. Most clinical trials with MSCs currently present with mixed outcomes. Age of MSCs might play a role. But a lot of other parameters might play into outcomes. The field of MSC generation and derivation is very diverse and not well standardized. A starting point might be to focus on age-specific influences and compare them among laboratories.”


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