In 2011, Dr. Andras Nagy’s research team at Mount Sinai’s Samuel Lunenfeld Research Institute discovered that genetic abnormalities were associated with the processes involved in generation of induced Pluripotent Stem (iPS) cells. These are adult cells that have been converted into stem cells and gain the potential to become any type of cell in the body.
The team used a technique, called single nucleotide polymorphism (SNP) analysis, to identify variations on the chromosomes of iPS cells. Intriguingly they found that freshly established iPS cells had more chromosome damage than the same cells, which were allowed to keep dividing in culture dishes for two more months. In other words, over time, the highly damaged cells were lost.
This phenomenon supported the team’s conclusion that the early phase of the reprogramming process for iPS cells is the root cause of the acquired mutations. The majority of “freshly produced” cells are badly damaged. A minority of the cells, however, remains practically normal. During a period of growth over two months, these “good” cells out grow the damaged ones. However, with respect to future clinical use of these stem cells, the existence of mutant cells still introduces a significant risk of unexpected behaviour after cell transplantation, including the possibility of cancer formation.
In a recently published paper, Dr. Andras Nagy and two researchers in his lab, Drs. Samer Hussein and Judith Elbaz, reviewed a broad range of current studies focusing on the integrity of the genomic DNA of iPS cells during the reprogramming process.
“There is a dark side to stem cell therapy, and safety is a huge concern,” says Dr. Nagy, who is a Canada Research Chair in Stem Cells and Regeneration. He points out the following issues which need to be addressed to ensure the safety of stem-cell-based therapies before they can be brought to clinical therapies and treatments.
The risk of generating mutations and the likely solution for safety
“We make and grow stem cells, generating billions of them, and to achieve this, they must divide so many times. Cell division is the replication of the mother cell into two daughter cells, so as with any “copying,” this process is prone to errors,” says Dr. Nagy. “Can we spot a few potentially hazardous cells among the billions that might be needed to treat disease? It’s certainly not an easy task. We are currently working on a “safety system” that recognizes and eliminates cells that start behaving in an undesirable manner.”
The risk of trace contamination from stem cells in cell therapy
“There is a valid concern that if undifferentiated iPS cells (cells that can still become any type of cell in the body and have not been specialized for a certain use) are unknowingly transplanted into a patient during the process, these cells could also potentially form a type of “embryonic tissue” tumours, called teratomas,” says Dr. Nagy. “Before transplanting, we have to make sure that no undifferentiated iPS cells remain among the many cells which are transplanted into the patient.”
Dr. Judith Elbaz adds, “We are working on a fail-safe mechanism which would recognize and inactivate the undifferentiated cells that may form teratomas.” Such switches should increase confidence in therapies and ensure safe and effective use of stems cells in medical applications.”
Genome damage in induced pluripotent stem cells: assessing the mechanisms and their consequences.
Hussein SM, Elbaz J, Nagy AA.
Bioessays. 2013 Mar;35(3):152-62.