A young man’s game

Stem cells from older donor patients may be less effective than their younger counterparts, according to Tulane University study

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DURHAM, N.C.—Everyone is aware of the pitfalls of aging, but research out of Tulane University suggests even more consequences to getting older: Our stem cells may become less effective than cells from younger donors over time.
Publishing a study in a recent issue of STEM CELLS Translational Medicine, Tulane University's Center for Stem Cell Research and Regenerative Medicine, which has for more than a decade been engaged in stem cell clinical trials for multiple sclerosis (MS)—has demonstrated for the first time that adipose-derived stem cells donated by older people are less effective than cells from their younger counterparts.
"This study in an animal model of MS is the first to demonstrate that fat-derived stem cells from older human donors have less therapeutic effectiveness than cells from young donors," says Dr. Anthony Atala, editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. "The results point to a potential need to evaluate cell therapy protocols for late-onset multiple sclerosis patients."  
There is no cure and no treatment eases the severe forms of MS, a neurodegenerative disease characterized by inflammation and scar-like lesions throughout the central nervous system (CNS). However, studies on animals have shown that transplantation of mesenchymal stem cells (MSCs) holds promise as a therapy for all forms of MS. The MSCs migrate to areas of damage, release trophic (cell growth) factors and exert neuroprotective and immunomodulatory effects to inhibit T cell proliferation.  
But it's unclear if MSCs derived from older donors have the same therapeutic potential as those from younger ones, notes Dr. Bruce Bunnell, a lead author on the Tulane study.  
"My lab has been interested in MSC cells for the last 12 years, and we are interested in applying them for disease treatment," Bunnell tells DDNews. "While MSCs don't differentiate and graft like we hoped they would 10 years ago, they have such an interesting biology spin in that they quiet inflammatory response, making them potentially potent applications for disease treatment. But as a consequence of looking at things like age, one of our graduate students noticed that as donors age, the microRNA patterns in their cells changed pretty dramatically, but had nothing to do with the site or disease."  
In fact, aging is known to have a negative impact on the regenerative capacity of most tissues, and human MSCs are every bit as 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, Bunnell says.  
To probe these issues, Bunnell's lab induced mice with chronic experimental autoimmune encephalomyelitis (EAE) and treated them before disease onset with human adipose-derived MSCs derived from younger (less than 35 years) or older (over age 60) donors. The results corroborated previous studies suggesting that older donors are less effective than their younger counterparts.  
"We found that, in vitro, the stem cells from the older donors failed to ameliorate the neurodegeneration associated with EAE," Bunnell explains. "Mice treated with older donor cells had increased inflammation of the central nervous system, demyelination leading to an impairment in movement, cognition and other functions dependent on nerves and a proliferation of splenocytes, compared to the mice receiving cells from younger donors."  
The T cell proliferation assay results in the study indicate that older MSCs might actually stimulate the proliferation of the T cells, while younger stem cells are capable of inhibiting the proliferation of T cells.
"A decrease in T cell proliferation would result in a decreased number of T cells available to attack the CNS in the mice, which directly supports the results showing that the CNS damage and inflammation is less severe in the young MSC-treated mice than in the old MSC-treated mice," Bunnell says.
So exactly how "old" is old?
"We had two groups of donors, and the mean age of the older donors was over 60," Bunnell says. "In younger donors, the mean age was around 20 to 25 years old. My hypothesis is that these cells change gradually over time, but this has not been proven yet."  
As stem cell clinical trials for MS patients become more common, it is crucial for researchers to understand the biologic changes and therapeutic effects of older donor stem cells, Bunnell says. Next, his lab will study key changes in microRNA that occur as a donor ages, such as changes in expression patterns, growth regulation and transcription factors.  
"We are in the infancy of understanding the impact of changing microRNA," he says. "Secondly, the most interesting question to me that came out of this is what is aging doing that is changing these cells? What is going on in the biological environment in the human body that is changing these cells? If you can figure that out, you may be able to improve the quality of these cells."  
The full article, "Age of the donor reduces the ability of human adipose-derived stem cells to alleviate symptoms in the experimental autoimmune encephalomyelitis mouse model," can be accessed at http://www.stemcellstm.com.

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