Embryonic stem cells differ from other cells in the body. They can divide seemingly endlessly; they do not perform a specialized function; and, ultimately, they can become any other type of cell. How they do this remains a mystery, but new research has uncovered some of the genes that allow these cells to renew themselves.

Molecular biologist Ihor Lemischka of Princeton University and his colleagues used a bent sequence of RNA--so-called short hairpin RNA (shRNA)--to sequentially turn on and off various genes within embryonic stem cells from a mouse. The shRNA, delivered by a virus, allowed the researchers to determine whether a given gene helped control stem cell differentiation. Focusing on 70 genes that make transcription factors--proteins that control a suite of other genes--the scientists found 10 likely candidates.

The team then engineered versions of these genes that could be turned on and off by the presence of the drug doxycycline to uncover their specific effects. Seven of the identified genes proved to be potent regulators of a stem cell's ability to split and then renew itself. Without them, the cell rapidly became specialized, losing its unique pluripotent status.

The research offers hope of one day being able to control the renewal and development of stem cells into specific specialized cells. "This is the beginning of developing ways of manipulating these cells toward desired ends," Lemischka offers. "In some ways, it's just the tip of the iceberg. We haven't looked at all the genes."

Lemischka and his colleagues plan to continue research into mouse stem cells as well as human colonies. "One of the clear goals is to perform similar studies in the human embryonic stem cell system," he notes. The research was published online yesterday in Nature.

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