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The darker side of regenerative medicine: working toward safer stem cell therapies

Stem cells have been widely touted as a source of great hope for their use in medicine, such as in the development of new drugs to prevent and treat illnesses like Parkinson’s disease, wound healing and spinal cord injury. But techniques for generating these highly malleable cells have also created concerns around safety in stem cell therapies.

 

 

 

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. 05512_nagy_andras_web photo.jpg

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.”

 

 



Hussein SM, Elbaz J, Nagy AA.
Bioessays. 2013 Mar;35(3):152-62.
 
 

 

 nagy_stem cell image.jpg

 

What are iPS cells?
Stem cells are present in most adult tissues, but in very small quantities, and they are not easily accessible. Typically, they can only become the type of cells in the tissue of the body where they are located. For example, a neural stem cell can only generate neurons or other cells of the brain and nervous system.
 
In 2006, Shinya Yamanaka and his student Kazutoshi Takahashi at Kyoto University showed that the expression of only four specific genes is sufficient to reprogram fully developed adult cells into stem cells. These cells, termed induced Pluripotent Stem (iPS) cells, have the ability to become any type of cell in the body that might be needed to treat disease.
 
Considering the huge promise these cells hold, it is not surprising that only six years later (in 2012) Yamanaka’s discovery was recognized by the highest scientific award, the Nobel Prize. Scientists, however, still do not fully understand the nature and properties of these cells. There is much to be learned before safe stem cell-based therapies can be broadly applied in the clinic.
 

 

 

 

 

 



 



 

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Ontario Health Study Faculty of Medicine, University of Toronto. mitacs honorary partner

 

 
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