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The development of brain stem cells into new nerve cells and why this can lead to cancer

No. 06 | 31/01/2019

Stem cells are true "Jacks-of-all-trades" of our bodies, as they can turn into the many different cell types of all organs. This allows the tissues such as muscle or even brain to renew and to heal after injury. This amazing "multipotency" makes stem cells in the adult body key tools for the future of regenerative medicine. Scientists at the German Cancer Research Center (DKFZ) now publish in the journal "Nature" how brain stem cells make the decision to transform into new nerve cells.

TOR activity (red) in the brain of a mouse. The newly generated immature nerve cells (neuroblasts) are shown in green. The dotted line shows the "Bulbus Olfactorius", a part of the brain into which the immature nerve cells migrate.
© Ana Martin-Villalba/DKFZ

Ana Martin-Villalba and her research team at the German Cancer Research Center followed stem cells along the path to neurons. The scientists analyzed at every step which genes where switched on and which of them were actually turned into new proteins. They expected to find that stem cells would simply switch their stem cell genes entirely off in order to become a neuron. But things turned out to be much more complicated. Martin-Villalba and her co-workers found that stem cell genes were not switched off, but simply put on standby, by preventing them from making the protein product that keeps the cell multipotent.

"To go into this standby mode and thus start the journey to become a neuron, stem cells switch off their inner signal to proliferate (called TOR) and stop to divide," says Ana Martin-Villalba. Very surprisingly, the researchers also found that stem cells always buy a return ticket. Just as flights can travel back and forth between countries, switching on or off TOR allows cells to travel from stem cell to neuron or back. "Thus, the decisions of a stem cell to become a neuron, remains reversible for some time," says Avni Baser, the scientist leading this project.

Normally, the travel of stem cells is in one direction to make nerve cells, unless something goes wrong in between. But if stem cells cannot properly control their TOR signal, they keep going back to stem cells, which in the long run can cause brain cancer rather than healing the brain. Indeed, in many cancers the levels of the TOR signal is artificially high. For future developments of stem cell therapy, understanding and controlling TOR activity in stem cell will thus be very important.

Avni Baser, Maxim Skabkin, Susanne Kleber, Yonglong Dang, Gülce S. Gülcüler Balta,
Georgios Kalamakis, Manuel Göpferich, Damian Carvajal Ibañez, Roman Schefzik,
Alejandro Santos Lopez, Enric Llorens Bobadilla, Carsten Schultz, Bernd Fischer & Ana Martin-Villalba: Onset of differentiation is posttranscriptionally controlled in adult neural stem cells.
Nature 2019, DOI: https://doi.org/10.1038/s41586-019-0888-x

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. At DKFZ, more than 1,300 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. DKFZ’s Cancer Information Service (KID) provides individual answers to all questions about cancer for patients, the general public, and health care professionals. Jointly with partners from Heidelberg University Hospital, DKFZ runs the National Center for Tumor Diseases (NCT) located in Heidelberg and Dresden, and, also in Heidelberg, the Hopp Children’s Cancer Center (KiTZ). In the German Cancer Consortium (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center at the NCT and DKTK sites is an important contribution to the endeavor of translating promising approaches from cancer research into the clinic in order to improve the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

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