Ever since 2006 when Japanese researcher Shinya Yamanaka showed that you could take an adult cell, such as those in your skin, and reprogram it to act like an embryonic stem cell, the scientific world has looked at these induced pluripotent stem (iPS) cells as a potential game changer. They had the ability to convert a person’s own cells into any other kind of cell in the body, potentially offering a way of creating personalized treatments for a wide variety of diseases.
Fears that this reprogramming method might create some cancer-causing genetic mutations seemed to have been eased when two recent studies suggested this approach is relatively safe and unlikely to lead to any tumors in patients. We funded one of those studies and blogged about it.
Reason for caution
But now a new study in the journal Cell Stem Cell says “not so fast”. The study says the older the person is, the greater the chance that any iPS cells derived from their tissue could contain potentially harmful mutations, but not in the places you would normally think.
A team at Oregon Health and Science University, led by renowned scientist Shoukhrat Mitalipov, took skin and blood samples from a 72-year-old man. The scientists examined the DNA from those samples, then reprogrammed those cells into iPS cells, and examined the DNA from the new stem cells.
When they looked at the cells collectively the levels of mutations in the new iPS cells appeared to be quite low. But when they looked at individual cells, they noticed a wide variety of mutations in the mitochondria in those cells.
Now, mitochondria play an important role in the life of a cell. They act as a kind of battery, providing the power a cell needs to perform a variety of functions such as signaling and cell growth. But while they are part of the cell, mitochondria have their own genomes. It was here that the researchers found the mutations that raised questions.
Older cells have more problems
Next they repeated the experiment but this time took skin and blood samples from 14 people between the ages of 24 and 72. They found that older people had more genetic mutations in their mitochondrial DNA that were then transferred to the iPS cells derived from those people. In some cases up to 80 percent of the iPS cell lines generated showed mitochondrial mutations. That’s really important because the greater the amount of mutated mitochondrial DNA in a cell, the more its ability to function is compromised.
In a news release, Mitalipov says this should cause people to pause before using iPS cells derived from an older person for therapeutic purposes:
“Pathogenic mutations in our mitochondrial DNA have long been thought to be a driving force in aging and age-related diseases, though clear evidence was missing. Now with that evidence at hand, we know that we must screen stem cells for mutations or collect them at younger age to ensure their mitochondrial genes are healthy. This foundational knowledge of how cells are damaged in the natural process of aging may help to illuminate the role of mutated mitochondria in degenerative disease.”
To be clear, the researchers are not saying these iPS cells from older people should never be used, only that they need to be carefully screened to ensure they are not seriously damaged before being transplanted into a patient.
A possible solution
Mitalipov suggests a simple way around the problem would be to identify the iPS cell with the best mitochondria, and then use that as the basis for a new cell line that could then be used to create a new therapy.
Taosheng Huang, a researcher at the Mitochondrial Disorders Program at Cincinnati Children’s Hospital Medical Center, is quoted in the news release saying the lesson is clear:
“If you want to use iPS cells in a human, you must check for mutations in the mitochondrial genome. Every single cell can be different. Two cells next to each other could have different mutations or different percentages of mutations.”