Embryonic Stem Cells: Understanding Their Secrets

Embryonic Stem Cells (ESCs) intrigue us because at a certain stage they are totipotent--they can become any cell type in the body, given the proper inducements. The two reports discussed here come from a Eurekalert newsrelease.

Two studies in the April 21, 2006 Cell report new details of the "genetic program" that affords embryonic stem cells the flexibility to give rise to any cell type in the body. Both groups identified mechanisms by which the embryonic stem cells of mice or humans keep from going down any one particular developmental path--that of muscle or nervous tissue, for example--while remaining "poised for activation."

Human embryonic stem cells can be kept in an undifferentiated state and selectively induced to form many specialized cell types, which could potentially replace cells lost or damaged by disease. The new findings may therefore aid in the realization of embryonic stem cells' therapeutic potential for regenerative medicine, according to the researchers, while furthering scientists' understanding of early development.

In one of the studies, Richard Young of the Whitehead Institute, and his colleagues, found that a member of the so-called Polycomb-group proteins is distributed across a special set of more than 200 developmental genes in human embryonic stem cells. Polycomb proteins are known to silence gene activity through chemical, or "epigenetic," modifications that alter the way that DNA is packaged into chromatin.

"We saw that the Polycomb protein preferred to occupy genes for most of the human developmental regulators to repress their activity," Young said. "These genes encode transcription factors that control development downstream of the embryo."

....Developmental genes found in association with the Polycomb protein were also occupied by histone proteins chemically modified at sites known to repress gene activity, they found. Histones--the chief proteins of chromatin--act as spools around which DNA winds and play a role in gene regulation.

Furthermore, they found, the silenced developmental genes became preferentially activated in human embryonic stem cells undergoing differentiation.

The findings help to explain earlier results in mice deficient for Polycomb proteins, Young said. The embryonic stem cells of those mice were "extremely unstable" and tended to specialize or die in culture, he said.

....In the second paper, Bradley Bernstein of Massachusetts General Hospital and Harvard Medical School, and his colleagues, report the discovery of a unique chromatin structure that marks key developmental genes in embryonic stem cells. The structure, which they call "bivalent domains," includes a pattern of chemical modification with both repressive and activating characteristics.

"In differentiated cells, chromatin is either 'on' or 'off' in accordance with the identity of that particular cell--rarely or never in between," Bernstein said.

"In embryonic stem cells, we found a totally different structure. The developmental genes of stem cells bear evidence of both active and repressive states. It's the first time this has been seen."

The genes appeared to be in a silent state, he explained, but with an activating influence that could allow them to turn on rapidly as needed. He suggested that by preserving the potential of key developmental genes, the bivalent domains may contribute to the unique ability of embryonic stem cells to form the many different tissues in the body.

When the researchers examined the state of the same genes in a collection of differentiated cell types, they found that the bivalent domains had been replaced by either repressive or activating modifications, in accordance with the cell's identity. Muscle cells, for example, must express the master genes for muscle, while silencing those specifically required for other cell types, Bernstein explained.

The team suggests that a comprehensive inventory of the presence or absence of bivalent domains over key developmental genes may provide valuable markers of cell identity and differentiation potential, in both health and disease. Bernstein said the findings also suggest that therapies that modify cells' epigenetic state might prove useful in the field of regenerative medicine. Source.

These studies contain fascinating information, marking important milestones in the understanding of ESCs and their totipotentiality. If the information learned here can be transferred to better understanding pluripotent stem cells of various sources, and can help to develop ways of de-differentiating cells then re-differentiating them as different cell types, the current bottleneck at the ESC-line level will eventually be bypassed. In other words, better understanding ESCs may bring us to a point where ESCs are not as important in the field of regenerative medicine as they are currently.