Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

UCLA Stem Cell Scientists Uncover Mechanism that Regulates Human Pluripotent Stem Cell Metabolism

16.11.2011
Human pluripotent stem cells, which can develop into any cell type in the body, rely heavily on glycolysis, or sugar fermentation, to drive their metabolic activities.

In contrast, mature cells in children and adults depend more on cell mitochondria to convert sugar and oxygen into carbon dioxide and water during a high energy-producing process called oxidative phosphorylation for their metabolic needs.

How cells progress from one form of energy production to another during development is unknown, although a finding by UCLA stem cell researchers provides new insight for this transition that may have implications for using these cells for therapies in the clinic.

Based mostly on visual appearance, it had been assumed that pluripotent stem cells contained undeveloped and inactive mitochondria, which are the energy-producing power plants that drive most cell functions. It was thought that stem cell mitochondria could not respire, or convert sugar and oxygen into carbon dioxide and water with the production of energy. This led most scientists to expect that mitochondria matured and gained the ability to respire during the transition from pluripotent stem cells into differentiated body cells over time.

Surprisingly, UCLA stem cell researchers discovered that pluripotent stem cell mitochondria respire at roughly the same level as differentiated body cells, although they produced very little energy, thereby uncoupling the consumption of sugar and oxygen from energy generation. Rather than finding that mitochondria matured with cell differentiation, as was anticipated, the researchers uncovered a mechanism by which the stem cells converted from glucose fermentation to oxygen-dependent respiration to achieve full differentiation potential.

The four-year study appears in the Nov. 15, 2011 issue of The EMBO Journal, a peer-reviewed journal of the European Molecular Biology Organization. Teitell collaborated with Carla Koehler, a UCLA professor of chemistry and biochemistry, for the study.

“A lot of attention is being paid to the role of metabolism in pluripotent stem cells for making properly differentiated cell lineages for research and potential clinical uses,” said study senior author Dr. Michael Teitell, a researcher with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and a professor of pediatrics, pathology and laboratory medicine, and bioengineering.

The initial question prompting our study was whether metabolism in pluripotent stem cells and cancer cells, which also rely heavily on glycolysis, were molecularly similar,” he said. “This question led us to study the details of energy-generation by mitochondria in pluripotent stem cells.”

Cells make energy in the form of ATP mainly in two ways, by glucose uptake and fermentation in the cytoplasm or by using respiration, in which glucose and oxygen are consumed to make carbon dioxide and water to fuel cell functions. Teitell and his team expected that pluripotent stem cells could not respire because of prior reports on the immature appearance and paucity of mitochondria.

Teitell’s team found that the molecular complexes responsible for respiration, called the electron transport chain, in the mitochondria of pluripotent stem cells were functional, and yet the cells instead relied on glycolysis for energy production. The researchers speculated that there were one or more unknown regulators that kept the stem cells from respiring, since the electron transport chain was functional.

Jin Zhang, a graduate student and first author of the study, discovered that a protein called uncoupling protein 2 (UCP2), was highly expressed in the stem cells. He also found that UCP2 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, inhibiting the stem cell’s ability to respire as a method for generating energy.

As pluripotent stem cells were driven to develop into mature cell types, UCP2 expression was shut off, allowing respiration substrates to enter the mitochondria for energy generation, switching the cells from glycolysis to oxidative phosphorylation. Manipulating UCP2 expression, by keeping it switched on in differentiating cells, disturbed their maturation, a finding that could make them unsuitable for clinical use and also pointing to the importance of properly functioning metabolism for generating safe, high quality cells.

Teitell and his team confirmed these findings in both human embryonic stem cells and in induced pluripotent stem cells, which are mature body cells that are genetically reprogrammed to have similar abilities and attributes as the pluripotent embryonic stem cells.

“A main question that evolved during the study was whether it was the process of pluripotent stem cell differentiation that was altering the pattern of metabolism, or was it the change in the pattern of metabolism that altered the process of differentiation, a typical chicken-or-the-egg question,” Teitell said. “We over-expressed UCP2 in the stem cells and showed that metabolism patterns changed before markers of pluripotency or cell maturation changed, indicating that changes in metabolism affect changes in differentiation and not the other way around, at least for UCP2. This was important, to show causation for metabolic changes in driving the process of cell differentiation. However, it still leaves open the key question of exactly how manipulating cell metabolism controls cell differentiation, a question we are working hard to address.”

Since metabolism in pluripotent stem cells and cancer cells appear quite similar, Teitell said the finding could potentially be used to target UCP2 in malignant tumors that express it, of which there are many. Silencing UCP2 could force cancer cells to respire, which might impair their ability to grow quickly.

The study was supported in part by the California Institute for Regenerative Medicine, an Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research training grant, the National Institutes of Health and the National Center for Research Resources.

The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA’s Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. To learn more about the center, visit our web site at http://www.stemcell.ucla.edu. To learn more about the center, visit our web site at http://www.stemcell.ucla.edu.

Kim Irwin | Newswise Science News
Further information:
http://www.ucla.edu
http://www.stemcell.ucla.edu

More articles from Life Sciences:

nachricht New application for acoustics helps estimate marine life populations
16.01.2018 | University of California - San Diego

nachricht Unexpected environmental source of methane discovered
16.01.2018 | University of Washington Health Sciences/UW Medicine

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

Im Focus: A thermometer for the oceans

Measurement of noble gases in Antarctic ice cores

The oceans are the largest global heat reservoir. As a result of man-made global warming, the temperature in the global climate system increases; around 90% of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Gran Chaco: Biodiversity at High Risk

17.01.2018 | Ecology, The Environment and Conservation

Only an atom thick: Physicists succeed in measuring mechanical properties of 2D monolayer materials

17.01.2018 | Physics and Astronomy

Fraunhofer HHI receives AIS Technology Innovation Award 2018 for 3D Human Body Reconstruction

17.01.2018 | Awards Funding

VideoLinks
B2B-VideoLinks
More VideoLinks >>>