R&D News: UCLA researchers identify mechanism that regulates human pluripotent stem cell metabolism
The study findings may have implications for using these cells for therapies in the clinic and could potentially be used to target uncoupling protein 2 (UCP2) in malignant tumors that express it, since metabolism in pluripotent stem cells and cancer cells appears quite similar. Silencing UCP2 could force cancer cells to respire, which might impair their ability to grow quickly, the researchers point.
The researchers have uncovered a mechanism by which the stem cells switch from glucose fermentation to oxygen-dependent respiration to achieve full differentiation potential.
Michael Teitell, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA collaborated with Carla Koehler, a UCLA professor of chemistry and biochemistry, on the study.
The team which began its study on energy-generation by mitochondria in pluripotent stem cells, found that the molecular complexes responsible for respiration in the mitochondria of pluripotent stem cells were functional though the cells still relied on glycolysis for energy production.
Jin Zhang, a UCLA graduate student and first author of the study, discovered that UCP2 which is highly expressed in the stem cells, blocked respiration substrates derived from sugar from gaining access to the mitochondria, instead shunting them to the glycolytic and biosynthesis pathways located in the cytoplasm, thus inhibiting the stem cells' ability to respire as a method of generating energy.
The team finds manipulation of UCP2 expression by keeping it switched on in differentiating cells could make them unsuitable for clinical use signifying the importance of effective functioning metabolism to generate safe and high-quality cells.
The findings had been confirmed in both human embryonic stem cells and in induced pluripotent stem cells that are mature body cells genetically reprogrammed similar to pluripotent embryonic stem cells.
Over-expression of UCP2 indicated that changes in metabolism affect changes in differentiation and not the other way around.
The study was conducted in collaboration with the California Institute for Regenerative Medicine, the National Institutes of Health and the National Center for Research Resources and with the help of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research training grant.
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