Small RNAs May Play Big Role in Embryonic Stem Cells

By Eric Sauter

An international team led by scientists at The Scripps Research Institute has used a new method to discover an unusual molecular signature in human embryonic stem cells that may lead to development of new cell-based therapeutics.

The team reports that human embryonic stem cells, which are pluripotent and self-renewing, contain a unique group of small molecules, called microRNAs, that are known to control production of proteins in cells. By examining 14 different strains of human embryonic stem cells, and comparing them to a large group of other cell types, the scientists discovered that the embryonic stem cells all shared the same profile of microRNAs.

The study was published April 10, 2008, in an advance, online edition of the journal Stem Cells.

"This is a landmark study," said Jeanne Loring, a professor at Scripps Research and director of the Scripps Research Center for Regenerative Medicine, who led the study with Louise Laurent, a clinical fellow in her lab, and Jian-Bing Fan from Illumina, Inc. "We report the m ost comprehensive determination of microRNA expression in human embryonic stem cells to date and detail differences in microRNA expression that may be key to regulating stem cell pluripotence—the ability to change into other cell types."

This study also documents the first report of a new method for rapidly analyzing microRNAs—a microarray that enables scientists to rapidly conduct genetic testing on a mass scale. The microarray allowed the researchers to measure more than 700 different microRNAs in 26 different cell types.  

High-Level Regulators

First discovered in the roundworm C. elegans, microRNAs are small, naturally occurring bits of RNA, a part of the human genome known to control critical points in the development of plants and lower animals. However, the exact role of microRNAs in mammalian development is still not well understood.

Although microRNAs do not code for protein expression by the cell, they do control the activity of genes through their influence on messenger RNA. Once thought of as mere genetic helpers, it has now been shown that microRNAs can prevent proteins from being produced by messenger RNA.

"MicroRNAS are high-level regulators," Loring said. "They control whole suites of proteins and signaling processes. Our most important discovery is that microRNAs made specifically by human embryonic stem cells almost all share the same 'seed sequence.' (Seed sequences are the parts of microRNAs that interact with cellular machinery and regulate synthesis of proteins.) We're certain that the shared seed sequences aren't an accident. Embryonic stem cells are actively and robustly preventing the synthesis of certain proteins, and this may be key to maintaining their unique qualities of self-renewal and pluripotence."

In the new study, the researchers found that that a significant proportion of microRNAs in human embryonic stem cells occur in clusters in the genome, including two very large clusters not previously associated with stem cells. Because of its location in the genome, the study said, one of the clusters could play a role in chromosomal abnormalities that often lead to the development of cancer.

The study also found that oncogenic microRNAs, which are associated with human cancers, are overrepresented in human embryonic stem cells, while tumor suppressor microRNAs are unusually rare. This suggests that while human embryonic stem cells are not closely related to any one type of cancer cell, they may share some self-renewal mechanisms with cancer cells as a class, the study said.

"The point is," Loring said, "that while oncogenic microRNAs are highly expressed in some human embryonic stem cells, the cells themselves are not oncogenic. This might be a cautionary tale, though, with the moral that we pay particular attention to changes made in cellular microRNA so we don't trigger any abnormal events."

But the most important aspect of their work, Loring believes, is that some day in the future microRNAs may be used to reprogram any cell type to become as pluripotent as embryonic stem cells. "It should be possible to treat cells with a mixture of microRNAs," she said, "to reprogram them to become blood cells or cardiac cells or neurons."

In addition to Loring, Laurent, and Fan, authors of the study, Comprehensive MicroRNA Profiling Reveals A Unique Human Embryonic Stem Cell Signature Dominated By a Single Seed Sequence, include Christina Lu of The Scripps Research Institute; Jing Chen of Illumina, Inc; Igor Ulitsky and Ron Shamir of Tel Aviv University; and Franz-Josef Mueller of The Scripps Research Institute and Universitätsklinikum Schleswig-Holstein. To read the article, go to Stem Cells at http://stemcells.alphamedpress.org/cgi/content/abstract/2007-1081v1 .

The study was supported by the National Institutes of Health, the California Institute for Regenerative Medicine, the Edmond J. Safra Bioinformatics, the Christian-Abrechts Universität, and Hamburger Krebsgesellschaft.

Send comments to: mikaono[at]scripps.edu

"We report the most comprehensive determination of microRNA expression in human embryonic stem cells to date and detail differences in microRNA expression that may be key to regulating stem cell pluripotence—the ability to change into other cell types."

—Jeanne Loring