Stem Cell Circuitry

Stem Cell Circuitry

A fairly detailed press release from the Howard Hughes Medical Institute reports that researchers there have created a mathematical model of hematopoietic stem cells which helps explain how they become white blood cells. The researchers studied stem cells called myeloid progenitors, which can turn into either macrophages or neutrophil cells (vividly described as garbage disposals and vultures, respectively), and express genes for both. By looking at this “circuitry” and how the myeloid cells developed, the scientists found that increased concentration of one transcription factor normally found in macrophages turned off the signals which would direct the cell to develop into a neutrophil. Both macrophages and nuetrophils expressed low levels of this protein (PU.1); it was increasing the concentration that made a difference. They also identified a repressor gene in the neutrophil cells which shuts off the regulatory genes needed to become a macrophage.

The researchers then used the presence of the PU.1 and of the repressor gene to develop a mathematical model of the regulatory network of the stem cells. The amount of one of the two genes countering each other decreases as the other genes is increased. Theoretically this could be used to predict what a cell would become. I don’t entirely understand why having a mathematical model is more useful than looking at the genes in the standard biological ways, unless it enables more precise predictions or allows work to be done extensively on the computer before trying to duplicate the results in the lab. I would expect that there have to be certain constants for some genes and not for others, and I don’t have any guess as to whether proportionality is sustained. One of the keys seems to be that the transcription factors are operating in a binary fashion: if A is on, B must be off; if B is on, A must be off. It may be that this model provides a paradigm that can be manipulated with more control than other kinds of experiments. At any rate, it’s interesting.

Wnt Crucial to Pancreas and Liver Development

Wnt Crucial to Pancreas and Liver Development

I reported a while ago (Ribbit! 5/11/06) on research being done at the University of Edinburgh on the African clawed frog. Now, according to a story on Scientist Live, the researchers have shown that in frogs the anterior endoderm, from which the liver, pancreas, intestinal lining, and other organs develop, is formed by a cascade action leading to production of the Wnt protein. Research on mouse embryonic stem cells suggests that the same action may exist in mammals and that Wnt may be useful in directing embryonic stem cells to differentiate into anterior endoderm cells. Another related finding is that turning off the Nodal protein is also important to the development of the anterior endoderm, and the researchers are trying to use Wnt to turn off the Nodal protein in mouse ESCs.

New Research on Mesenchymal Stem Cells’ Plasticity

New Research on Mesenchymal Stem Cells’ Plasticity

Researchers at the University of Pennsylvania have found out that the environment surrounding mesenchymal stem cells is highly determinative of how the cells will differentiate. The press release says, “According to the researchers, soft microenvironments that mimic the brain guide the cells toward becoming neurons, stiffer microenvironments that mimic muscle guide the cells toward becoming muscle cells and comparatively rigid microenvironments guide the cells toward becoming bone.” Cells have structures called the skeleton and use chemical signals as we use muscles to move; the stem cells can therefore “feel” how hard they are pressing against their surrounding environment. This triggers particular chemical signals telling them how to differentiate.

Because the cells are in part triggered to differentiate through their physical environment, changes to the environment might cause the cells to fail to differentiate even if the chemical conditions are right. The example given in the press release is that of heart damage, where scar tissue prevents the cells from differentiating into heart muscle tissue.

The researchers hope that this work can be used to create stem-cell specific environments in the lab so that appropriate cells could be transplanted. Possibilities of this were shown by the fact that the cells reacted differently to different firmness in the gel culture medium.

I wonder if there are similar conditions for the growth of embryonic stem cells. On the face of it it seems like their earliest signals would have to be entirely chemical, since there is no variance in the environment, but perhaps as the embryo develops physical environments become significant to the fetal stem cells.