UCLA researchers led by Carla Koehler, professor of chemistry and biochemistry and Dr. Michael Teitell, professor of pathology and pediatrics, both members of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research and the Jonsson Comprehensive Cancer Center, have discovered a new agent that may be useful in strategies to remove pluripotent stem cells that fail-to-differentiate from their progeny, tissue-specific cells, potentially resulting in safer therapies for patients.
The study was published online ahead of press April 15, 2013 in Developmental Cell.
Pluripotent stem cells can become any cell in the body. When stem cells are differentiated into specific daughter cells such as nerve, muscle, or bone cells, not all of the stem cells differentiate, leaving some pluripotent stem cells mixed in with the differentiated cells. Because of the pluripotent stem cell's ability to become any cell type in the body, these cells can also become unintended cells such as bone in blood, or form tumors called teratomas. Therefore, identifying and removing pluripotent stem cells from the differentiated cells before using daughter cells is of utmost importance in stem cell-based therapeutics. Current methods for removing pluripotent stem cells are limited.
Studies in the model system Saccharomyces cerevisiae, simple baker's yeast, by Koehler, Teitell, and colleagues discovered a molecule called MitoBloCK-6 that inhibits assembly of the mitochondria, which are the power plants of cells. As the group moved to more complex systems, they showed that MitoBloCK-6 blocked cardiac development in the model organism, zebrafish. However, MitoBloCK-6 had no effect on differentiated cell lines that are typically cultured in the lab. "I was puzzled by this result, because we thought this pathway was essential for all cells regardless of differentiation state," said Koehler.
Post-doctoral fellow Deepa Dabir meticulously tested the compound on many differentiated cell lines, but the results were still the same: The cells remained healthy. Then the team decided to test MitoBloCK-6 on human pluripotent stem cells. Post-doctoral fellow Kiyoko Setoguchi showed that the pluripotent stem cells died in the presence of MitoBloCK-6, but shortly after differentiation, the daughter cells were resistant to death.
MitoBloCK-6 caused the pluripotent stem cells to die by triggering apoptosis, a process of cell suicide. The death of pluripotent stem cells left a population of differentiated cells, thus potentially reducing the risks of teratoma and other problems that would limit their use as a regenerative medicine treatment strategy.
"We discovered that pluripotent stem cell mitochondria undergo a change during differentiation into tissue-specific daughter cells," said Teitell, "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."
The above story is based on materials provided by University of California, Los Angeles (UCLA), Health Sciences. Note: Materials may be edited for content and length.
- Deepa V. Dabir, Samuel A. Hasson, Kiyoko Setoguchi, Meghan E. Johnson, Piriya Wongkongkathep, Colin J. Douglas, Johannes Zimmerman, Robert Damoiseaux, Michael A. Teitell, Carla M. Koehler. A Small Molecule Inhibitor of Redox-Regulated Protein Translocation into Mitochondria. Developmental Cell, 2013; 25 (1): 81 DOI: 10.1016/j.devcel.2013.03.006
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