Deciphering Embryonic Stem Cell Differentiation

The mechanisms governing stem cell differentiation are complex indeed, but deciphering this biochemistry is the key to controlling cells for tissue engineering and regenerative medicine - producing replacement tissue on demand, and eventually creating totipotent stem cells on demand. Here is a selection of recent articles on step by step progress in this area:

Scientists announce stem-cell discovery

The scientists say the imprints, or "signatures," appear near the master genes that control embryonic development and probably coordinate their in the early stages of cell differentiation. Not only do the findings help to unlock the basis for embryonic stem cells' seemingly unlimited potential but the researchers say they also suggest ways to understand why ordinary cells are so limited in their abilities to repair or replace damaged cells.

"This is an entirely new and unexpected discovery," said Brad Bernstein, lead author of the study, an assistant professor at Harvard and a researcher in the Chemical Biology program at the Broad Institute. "It has allowed us to glimpse the molecular strategies that cells use to maintain an almost infinite potential, which will have important applications to our understanding of normal biology and disease."

How embryonic stem cells maintain their identity

The results also add to the team's earlier finding, reported in Cell last year, that a trio of transcription factors--Oct4, Sox2, and nanog--are key regulators of embryonic stem cells' pluripotency and self-renewal," he said. Pluripotency refers to the cell's ability to develop into multiple cell types. The three factors apparently work together to activate pathways critical for stem cell identity, while repressing those leading to differentiation.

Notch Promotes Neural Lineage Entry by Pluripotent Embryonic Stem Cells

Pluripotent [embryonic stem (ES)] cells should be a valuable source of neural cell types for cell biological investigation, neurodegenerative disease modelling, pharmaceutical screening, and possibly even regenerative therapies. If ES cells are to be harnessed effectively for these goals, it will be necessary to develop robust methods for directing neural commitment and suppressing differentiation into other lineages. In this study we have presented evidence for an unsuspected role of the Notch signalling pathway in promoting and directing primary fate choice in ES cell differentiation. Activation of Notch thus emerges as a key tool for steering ES cells toward the neural fate and away from nonneural fates.

If you're up for light scientific literature, the Notch paper above illustrates the real complexity in the study of cellular biochemistry: cells talk to and influence one other. Put a bunch of cells together, and they'll respond in all sorts of interesting, emergent ways to the introduction of biochemical signals of differentiation, signalling between one another all the while.

Furthermore, even at standard cell densities, 5% to 10% of cells still resist differentiation. This is approximately half the number observed for control cultures but nonetheless raises the question why do some ES cells elude neural commitment?


In the developing embryo, neighbouring cells must continually communicate with each other to coordinate patterning of tissues. Notch signalling patterns tissues by at least two types of mechanism. Lateral inhibition mechanisms ensure that neighbouring cells follow different fates, so that one single cell type does not dominate within a particular region. Lateral induction, a form of community effect, acts in the opposite way to ensure that cells within a particular region adopt the same fate choice. In the context of neural induction from ES cells, our findings indicate that Notch signalling acts to amplify and consolidate neural specification.

The complexity is enormous; researchers must develop better methodologies to work with very complex situations in order to keep up the rate of progress in biotechnology and medical science.

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