Donor Age Shows Up In Induced Stem Cells

 IPSCs. Credit: National Institute of Arthritis

When adult cells are reprogrammed into induced pluripotent stem cells (IPSCs), they appear to carry marks of their age

IPSCs are a massive scientific breakthrough, but they aren't perfect yet. Many scientists have raised concerns that these converted cells may not be entirely 'refreshed' in a manner equal to embryonic stem cells, and may carry harmful mutations of age-related problems that reduce their effectiveness. 

Raising concerns 

Scientists at the Scripps Institute have now confirmed some of these concerns; demonstrating that IPSC cells formed from adult cells have both age reflective methylation patterns (epigenetic regulation known to change with age) and an increased mutation load too. The process of reprogramming doesn't appear to erase many of these epigenetic marks. 

While allogeneic cell therapies involve using someone else's cells that are matched to the recipient to a degree, autologous therapies use a patient's own cells. These are preferable because they avoid immune complications, but this research suggests that in older patients these cells may be tarnished by age. 

"If you’re getting cells from these older donors, these seed cells that you use for reprogramming already have some accumulation of mutation load, and so that is actually  very important evidence, especially when they are looking at the potential functions of these mutations. Every cell line the researchers examined had at least one mutation in its exomic DNA and some of those mutations were potentially deleterious, even oncogenic. These damaging mutations might have some unexpected functional consequence when we’re looking at the clinical applications”

Testing the theory

To test whether IPSC cells carried traces of their real age, researchers examined methylation patterns in IPSCs formed from peripheral blood cells of 16 people, aged between 21 and 100. Perhaps predictably, they found that specific sites of the genome known to be methylated with age were indeed methylated more frequently, and sites that lose methylation showed a similar pattern. Curiously, while the conversion process is known to demethylate some of these CpG sites that gain methylation with age, in older patients their cells were resistant to this alteration. 

More positively, passaging and culturing the cells for a longer period proved able to erase many of these epigenetic differences. Mutations however did rise with donor age, until around 90 when they tailed off. This may be due to a loss of replicative cells, leaving only slow dividing cells behind. 

"Especially in older individuals, but probably in all individuals, a good practice would be to . . . screen your iPSCs beforehand using a genomic or genetic approach so that you can screen out lines that might have a pathogenic variant"

Read more at The Scientist