Finding the Sweet Spot: shifting metabolism keeps stem cells in suspended animation

The future is bright for a stem cell: it has the potential to become almost anything. This potential is one of its two defining characteristics. The second is that it can create copies of itself over and over again.

Researchers are announcing a new breakthrough on how best to keep embryonic stem cells (above) in a state of suspended animation.

Researchers are announcing a new breakthrough on how best to keep embryonic stem cells (above) in a state of suspended animation.

This second characteristic, known as the ability to self-renew, is of particular importance to researchers. After all, if they are to use stem cell technology to heal injury and treat disease, they must figure out how to keep them suspended in this embryonic state, so that large quantities can be grown in order to manufacture enough treatments for all who need them.

Unfortunately, that is easier said than done. But scientists have made extraordinary progress, developing a specific, nutrient-rich environment—a ‘medium’ called 2i—that can keep cells in a suspended, animation-like state.

The only problem was that they didn’t know why it worked.

Enter a joint team of scientists from The Rockefeller University and Memorial Sloan Kettering Cancer Center in New York, who today announce in the journal Nature that they may have cracked the case. According to team leader C. David Allis, it all comes down to the cell’s metabolism.

A cell’s metabolism is not unlike our body’s metabolism, though on a much smaller scale. Cellular metabolism refers to the process by which chemical reactions transform food into energy and other cellular products through something called the Citric Acid Cycle. The faster the cells’ metabolism, the faster the cycle produces energy, and vice versa.

Previously, scientists had observed a connection between the Citric Acid Cycle and the way in which a cell’s DNA was bundled into what is known as chromatin.

Embryonic stem cells (ES cells) have a different chromatin structure than mature, differentiated cells. This allows for heightened gene expression. [Credit: stembook.org]

Embryonic stem cells (ES cells) have a different chromatin structure than mature, differentiated cells. This allows for heightened gene expression. [Credit: stembook.org]

Chromatin is made by winding DNA strands around proteins called histones, much like winding strands of yarn around a tennis ball. The pattern in which DNA is organized into the chromatin structure is crucial: it affects which genes are switched on and off, and when.

For genes to become activated, or ‘expressed,’ they must be physically accessible within the chromatin structure. Postdoctoral researcher and co-first author Bryce Carey hypothesized that speeding up or slowing down a cell’s metabolism was responsible for which genes were accessible, and could therefore become activated. As he explained in a news release:

“What if, in stem cells, the changes to chromatin reflect a unique metabolism that helps to drive reactions that help to keep chromatin accessible? This connection would explain how embryonic stem cells are uniquely poised to activate so much of their genomes.”

To pinpoint the exact connection between metabolism and gene expression, Carey and co-first author Lydia Finley compared the metabolic functions of embryonic stem cells grown in the 2i medium and compared them to cells grown in a traditional medium made from bovine serum.

When study authors Bryce Carey (left) and Lydia Finley (right) exposed mouse embryonic stem cells to the metabolite alpha-ketoglutarate, those cells became more likely to renew themselves, appearing as pink colonies on the screen. This is one of the first demonstrations that a metabolite can influence the fate of stem cells. [Credit: Zach Veilleux / The Rockefeller University]

When study authors Bryce Carey (left) and Lydia Finley (right) exposed mouse embryonic stem cells to the metabolite alpha-ketoglutarate, those cells became more likely to renew themselves, appearing as pink colonies on the screen. This is one of the first demonstrations that a metabolite can influence the fate of stem cells. [Credit: Zach Veilleux / The Rockefeller University]

Surprisingly, the team found that the 2i cells were producing energy at staggering levels—through a molecular shortcut that cut out an entire step of the Citric Acid Cycle. This shortcut boosted the production of a protein called alpha-ketoglutarate, which in turn spurred more efficient energy production. It was as if the 2i medium instilled these embryonic stem cells with super powers.

Alpha-ketoglutarate appeared to be the key to shifting cells’ metabolism so that the right genes are expressed—thus keeping the cell in an embryonic state. Even cells growing in the traditional, bovine serum medium became supercharged when given a healthy dose of alpha-ketoglutarate.

These results not only solve a long-standing mystery of why the 2i medium was so superior for growing stem cells, they also pinpoint the particular protein—alpha-ketoglutarate—that is at the heart of this difference. This discovery, according to Allis, moves us closer to developing stem cell-based treatments in the clinic:

“This newly established link between metabolism and stem cell fate improves our understanding of development and regeneration, which may, in turn, bring us a little closer to harnessing stem cells’ ability to generate new tissue as a way to, for example, heal spinal cord injuries or cure Type 1 diabetes. It may also add a new dimension to our understanding of cancer, in which differentiated cells erroneously take on stem-cell like properties.”

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