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There is a way back, at least for B-cells

05 Jul 2002

IMP-scientists were able to transform specialised blood cells back into progenitor cells with stem cell-like qualities. This not only proves the enormous plasticity of this system, it may also be of medical significance for future therapies.

At the IMP, stem cells have been a hot topic for quite a while. Only last year, Prof. Meinrad Busslinger, a Swiss biologist and Senior Scientist at the IMP, was awarded the prestigious Wittgenstein-prize by the Austrian government for his achievements in stem cell research. Busslinger’s work focusses mainly on the hematopoetic system.

Hematopoetic stem cells are found in the bone marrow of mammals. After having undergone several steps of differentiation, they give rise to specialised blood cells. Among them are macrophages, antibody-producing B-cells and T-cells, which are responsible for the cellular immune response. Meinrad Bussslinger’s work focuses on the factors that commit a cell to a certain developmental pathway. Such factors are already well known for B-cells: entry of progenitor cells into the B-cell pathway depends on the activation of the gene Pax5. Under the influence of Pax5, a pro-B-cell develops into a mature B-cell. Until recently, however, it was not clear whether the process of differentiation is irreversible (that would be the case if the ‘packaging’ of the genome were chemically altered = epigenetic fixation), or whether there is a way back.

The answer comes from Meinrad Busslinger and his IMP-colleagues Ingvild Mikkola, Barry Heavey and Markus Horcher and has been published recently in the journal Science (5.7.2002). The team gathered pro-B-cells from mice, cultivated them in vitro and forced them into the B-cell pathway by submitting them to the influence of Pax5. When the scientists removed the gene Pax5, using a highly sophisticated technique, the cells transformed back to an early developmental stage with broad multilineage potential. In other words, they acquired stem cell-like qualities. Under carefully chosen conditions, these progenitor cells could then be persuaded to differentiate, for example, into macrophages. Injected back into mice, they would preferentially develop into fully functional T-cells. 

These experiments prove that the development of immune cells is not a “one-way street”. That discovery could even lead to new therapeutic concepts in human medicine. As Meinrad Busslinger describes, patients with severly impaired T-cell function (such as in AIDS or hereditary forms of immuno deficiency) might one day benefit from his work. One could imagine to treat such patients with human Pax5-deficient B-cells in order to regenerate the entire T-cell system from them. However, for this idea to become more than just speculation, the mouse experiment - which Meinrad Busslinger calls a “proof of principle” experiment - has to be successfully repeated in humans. The next challenge for the scientists is already waiting.

Original Publication

Ingvild Mikkola, Barry Heavey, Markus Horcher, Meinrad Busslinger: Reversion of B Cell Commitment upon Loss of Pax5 Expression. Science 297 (5578): 110-113, 5 July 2002.