Over a period of five years, scientists at the Johannes Gutenberg University Mainz have managed to create a genetically modified mouse in which the activity of the blood stem cells can be tracked. "This mouse was created from a single embryonic stem cell.
We are able to observe its blood stem cells in detail and see when they divide, i.e., become active, and when they are dormant," said Dr Ernesto Bockamp of the Institute for Toxicology. Observations made by the work groups of Professor Andreas Trumpp and Dr Anne Wilson in Lausanne and Heidelberg have shown that the dormancy of certain blood stem cells can be reversed by, for example, toxic stress; they become active but return to their dormant status once their work has been completed. These findings are not only of importance for basic research, but also for applied cancer research.
The important task of blood stem cells is to create millions of new daughter cells in our bodies. There is also a special group of blood stem cells, however, which remains practically dormant in so-called bone marrow 'niches' in low oxygen environments. "These dormant blood stem cells divide only very rarely, which actually makes a lot of sense," explains Bockamp. "In their state of dormancy, these cells are extremely well protected against external influences such as toxic damage, but also against undesirable changes such as mutations."
If the bone marrow is damaged or there is a sudden loss of many blood cells, the dormant blood stem cells are activated and turn into activated blood stem cells with the capacity for self-renewal and the production of millions of mature blood cells. Once the danger has passed and system equilibrium has been restored, these activated stem cells return to their niches and to a dormant state.
It was by creating the new mouse model that toxicologists from Mainz University established the prerequisites for obtaining these new insights. The mouse model created by Dr Leonid Eshkind made it possible to package the mouse's DNA in a luminescent green sheath. The green, fluorescent protein of a jellyfish was used to color the histones to which the DNA is attached, i.e., the normally non-luminescent packaging of the genes. "By adding a certain substance to the drinking water of the mouse, we are able to interrupt this highly specific labeling process and thus to stop the incorporation of green fluorescence into the blood stem cells," Eshkind reported. During the early 1980s, Dr Eshkind had been one of the first scientists worldwide to create genetically modified mice.
In the work now published in Cell, the Bockamp/Eshkind work group reported on the construction of a type of gene switch with which a specific characteristic - in this case fluorescence - can be switched on or off in a living mouse. "We can therefore externally control gene expression in stem cells," Bockamp added. "In the field of switchable, genetically-modified mouse models, we are among the leaders in Germany and want to use this extremely effective technology increasingly in future."
Control over the labeling process is indispensable - after all, the aim is to observe the behavior of the stem cells. Should the cells divide because they have been activated - perhaps by an injury - the fluorescence in the two daughter cells is reduced to 50 percent, then to 25 percent if they divide again, and so on. "In this way we can accurately determine how often the labeled stem cell has divided once the labeling process has been stopped," said Bockamp. His colleagues in Lausanne and Heidelberg found out that there is a small group of special blood stem cells that divide extremely rarely, i.e. only once every 145 days or five times during the life span of a mouse, and which can switch between dormancy and self-renewal in an emergency. Bockamp pointed out that the actual analysis of the cell division processes is not possible in Mainz, due to a lack of technical infrastructure. The group plans to focus increasingly on cancer research in its future work.
- Anne Wilson, Elisa Laurenti, Gabriela Oser, Richard C. van der Wath, William Blanco-Bose, Maike Jaworski, Sandra Offner, Cyrille F. Dunant, Leonid Eshkind, Ernesto Bockamp, Pietro Liσ, H. Robson MacDonald and Andreas Trumpp. Hematopoietic Stem Cells Reversibly Switch from Dormancy to Self-Renewal during Homeostasis and Repair. Cell, 4 December 2008 DOI: 10.1016/j.cell.2008.10.048
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