Induced pluripotent stem cells (iPSCs) are adult cells treated to regain the properties of stem cells, which have enormous therapeutic potential. However, the process by which cells are converted into iPSCs is known to introduce mutations, and mitochondria are especially susceptible.
'Under normal physiological conditions, mitochondrial DNA is 10 to 20 times more susceptible to mutation than nuclear DNA. Transforming adult cells into stem cells is a harsh process, so we expected mutation rates to be just as high or higher,' said co-lead author Professor Tobias Deuse at the University of California, San Francisco (UCSF).
Although mitochondria contain only 17 genes, they are very plentiful in some cells types, meaning that they can be disproportionately represented in the transcriptome.
'In cells that do a lot of work, like heart muscle cells, up to a third of the cell's protein-producing mRNA molecules are mitochondrial in origin. This means that the burden of a single mitochondrial mutation may be tremendous. You don't end up with just a few proteins that can potentially provoke an immune response – you end up with thousands,' said senior author Professor Sonja Schrepfer also at UCSF.
The researchers conducted experiments in mice, where stem cells were created that perfectly matched the recipient mouse's nuclear DNA but differed by a single base-pair in two mitochondrial genes. Immune cells were retrieved a few days after to cells were introduced to the mice, and tested against various mitochondria protein fragments. Only samples containing the proteins produced from the changed genes triggered a response.
To test the hypothesis in humans, the researchers looked at kidney and liver transplant recipients, where the mitochondrial genome differed between the donor and the recipient. They were able to isolate immune cells from the transplant recipients and see the same response to the mitochondrial proteins that matched the donor, but not the recipient DNA. Even a change of one base was sufficient.
'The bottom line is that we want to make people aware of this phenomenon. Just because iPSCs are derived from your own cells doesn't necessarily mean they won't induce an immune response. It's very easy to introduce mutations during iPSC production, so it's critical that iPSC and stem cell products used therapeutically are screened for mitochondrial mutations prior to transplant,' said the authors.
The international team published the study in Nature Biotechnology.