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Coaxing Stem Cells: Where is that manual…

VCR Diagram

Breaking news: Stem cells don’t come with user manuals. That may be a little daunting for those of us who remember the VCR with its blinking 12:00 that you could never seem to get rid of. But thanks to some persistent scientists, the secrets of stem cells are finally coming out and a new discovery just helped solve a huge piece of the puzzle. All this thanks to a new technique that coaxes stem cells [which can become any cell in the body] to take the first step to specialization.

“Everybody knows that for an embryo to form, somehow a single cell has a way to self-organize into multiple cells, but the in vivo microenvironment is not well understood,” said study leader Ning Wang, a professor of mechanical science and engineering. “We want to know how they develop into organized structures and organs. It doesn’t happen by random chance. There are biological rules that we don’t yet understand.”

During fetal development, any tissue in the human body, from organs to eyeballs are formed out of a small ball of stem cells. First, that ball will separate into three different cell lines [called germ layers] which end up being different things in the body.

This crucial first step has eluded researchers in the lab. No one has been able to crack the code to get the cells to form the three distinct germ layers, in the correct order [for those interested it’s endoderm on the inside, mesoderm in the middle and ectoderm on the outside]. This posed a major hurdle in the application of stem cells for regenerative medicine, particularly because researchers need to understand how tissues develop before they can reliably recreate the process.

“It’s very hard to generate tissues or organs, and the reason is that we don’t know how they form in vivo,” Wang said. “The problem, fundamentally, is that the biological process is not clear. What is the biological environment that controls this, so they can become more organized and specialized?”


The research team demonstrated that not only is it possible for mouse embryonic stem cells to form three distinct germ layers in the lab, but also that achieving the separation requires a careful and complex combination of correct timing, chemical factors and mechanical environment. They ended up using a particular trick to do this, cell lines that fluoresce in different colors when they become part of a germ layer, which allowed the researchers to monitor the process dynamically.

The researchers deposited the stem cells in a very soft gel matrix, attempting to recreate the properties of the womb. They found that several mechanical forces played a role in how the cells organized and differentiated – the stiffness of the gel, the forces each cell exerts on its neighbors, and the matrix of proteins that the cells themselves deposit as a scaffolding to give the developing embryo structure. If you remember the silly putty post I made then you already are aware of part of the discovery.

The researchers found that by adjusting the mechanical environment, they were able to observe how the forces affected the developing cells. They found the particular combination that yielded the three germ layers. But that isn’t all, they also figured out that they could direct layer development by changing the mechanics, even creating an environment that caused the layers to form in reverse order! How cool is that?!

For now the group is working to improve their technique for greater efficiency. The hope is that other researchers will be able to use this to bridge the gap between stem cells and tissue engineering, which could end the need for organ donor lists.

Already know how to program stem cells like your VCR? Where were you when I needed you? I mean, you probably want the full study — here!

Poh Y.C., Chen J., Hong Y., Yi H., Zhang S., Chen J., Wu D.C., Wang L., Jia Q. & Singh R. & (2014). Generation of organized germ layers from a single mouse embryonic stem cell., Nature, PMID:


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