Friday, 19 April 2013

UCLA researchers identify molecule that reduces malignancy risk in stem cell therapies

One of the major problems researchers face when culturing stem cells for therapeutic purposes, is the possibility of malignant cells arising from stem cells that have failed to differentiate properly. However, researchers at the University of California, Los Angeles (UCLA), may have solved this problem, as they have discovered a new agent that can be used to remove any undifferentiated stem cells from the rest of the specialized cells.

When a scientist grows stem cells in the lab he can use many different ingredients to turn them into specific types of cells, like muscle heart cells (cardiomyocytes) or neurons. Hoverer, some cells "escape" and retain their undifferentiated nature. If left unintended, these stem cells may turn into undesired cells/tissues or even form tumours when transplanted to a patient. This is why it's so crucial to first remove any differentiated cells from the specialized ones. Unfortunately, the currently available methods for doing this are limited, say the UCLA researchers.

In previous studies on Saccharomyces cerevisiae (a species of yeast), Carla Koehler and Michael Teitell, leading authors of the new study, had shown that a protein called MitoBloCK-6 (mitochondrial protein import blocker) inhibits the assembly of new mitochondria, commonly known as our "cellular power plants".


Saccharomyces cerevisiae
Saccharomyces cerevisiae


Overtime, the researchers explored the effects of MitoBloCK-6 in other, more complex organisms and eventually found that in zebrafish the molecule blocks embryonic cardiac development. However, it was found to have no effect on differentiated cells.

“I was puzzled by this result, because we thought this pathway was essential for all cells regardless of differentiation state” said Koehler

Deepa Dabir, chief author of the study, tried MitoBloCK-6 in many other differentiated cell lines with the results always being the same. The protein had no negative impact on any type of specialized cell. Then, the research team tried the protein on human pluripotent stem cells. The protein quickly killed all pluripotent stem cells while differentiated human cells were found to be quire resistant.


A mitochondrion
Diagram of a mitochondrion



According to the study, MitoBloCK-6 causes cell death by triggering apoptosis, a process of programmed cell death or simply put "cell suicide".

“We discovered that pluripotent stem cell mitochondria undergo a change during differentiation into tissue-specific daughter cells,which could be the key to the survival of the differentiated cells when the samples are exposed to MitoBloCK-6. We are still investigating this process in mitochondria, but we
now know that mitochondria have an important role in controlling pluripotent stem cell survival.” said Teitell.

The researchers believe that MitoBloCK can be used to greatly improve any current method that removes pluripotent stem cells that fail to differentiate from specialized cells, potentially leading to safer stem cell-based therapies for patients.

“It is exciting that our research in the one-cell model Baker’s yeast yielded an agent for investigating and controlling mitochondrial function in human pluripotent stem cells. This illustrates that mitochondrial function is highly conserved across organisms and confirms that focused studies in model systems provides insight into human stem cell biology. When we started these experiments, we did not predict that we would be investigating and controlling mitochondrial function in pluripotent stem cells,” said Koehler.

Reference
Dabir, D., Hasson, S., Setoguchi, K., Johnson, M., Wongkongkathep, P., Douglas, C., Zimmerman, J., Damoiseaux, R., Teitell, M., & Koehler, C. (2013). A Small Molecule Inhibitor of Redox-Regulated Protein Translocation into Mitochondria Developmental Cell, 25 (1), 81-92 DOI: 10.1016/j.devcel.2013.03.006 

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