Mitochondrial mutations could hamper stem cell therapies

A study has found that stem cells from older people accumulate high numbers of mitochondrial DNA (mtDNA) mutations, which could limit their therapeutic value.

Most of a cell's DNA is contained in its nucleus, but a small proportion is located in its mitochondria, where the rate of mutation can be 10–20 times higher.

Professor Taosheng Huang, director of the Mitochondrial Medicine Program at Cincinatti Children's Hospital and one of the lead authors of the study, said: 'People tend to look just at the nuclear genome. But if you want to use induced pluripotent stem (iPS) cells in a human, you must check for mutations in the mitochondrial genome.'

Professor Huang's team originally sequenced the mtDNA of skin cells taken from a 72-year-old and found the overall level of mutations was low. But when they re-examined the cells individually, they discovered that the mtDNA mutation rate was highly variable between different cells, and in some cases it was so high that the mitochondria were unable to function properly.

As stem cell lines are created from individual cells, it is important that the originating cell is healthy, otherwise these defects could negate the benefits of stem cell treatments.

The team then created iPS cell lines from blood and skin cells of adults aged 24–72 and investigated the effects of age on mtDNA mutations. As they report in Cell Stem Cell, they found the stem cells of older people had much higher rates of mtDNA mutations than those from younger people.

Professor Huang suggested that it is therefore critical to create multiple iPS cell lines and sequence them individually for mtDNA mutations. Alternatively, it might be simpler just to use stem cells from younger adults, he wrote.

Dr Dieter Egli of the New York Stem Cell Foundation told Nature News that 'this is definitely going to have an impact' on clinical trials using iPSC cells, and that more screening of mtDNA would be needed for therapy. 'You can't just assume it does or doesn't work,' he said.

Mitochondrial defects are implicated in normal ageing, as well as in many age-related diseases, but Dr Egli added that it would be difficult to determine which mutations are meaningful. 'It's going to be very hard to find a cell line that's perfect,' he concluded.