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An alarm clock for dormant brain stem cells

No. 37 | 31/07/2015 | by Koh

Scientists from the German Cancer Research Center (DKFZ) generated a molecular profile of neural stem cells from the brains of mice. They discovered that a chemical messenger called interferon-gamma awakens certain neural stem cells from dormancy and induces their activation. The messenger substance, which is released in response to oxygen deficiency or damage incurred, may possibly be used to specifically activate brain stem cells in the wake of injuries or during degenerative diseases.

Olfactory bulb interneurons generated out of neural stem cells transplanted in the walls of the lateral ventricles.
© Ana Martin-Villalba, DKFZ

For decades, researchers were convinced that they do not exist: neural stem cells that take care of regeneration in the brain. By now, these cells have been detected in all mammals. They occur primarily in two defined areas of the brain: the hippocampus, where they play a key role in memory building, and in the subventricular zone, which is the largest reservoir of neural stem cells in adult animals.

The stem cells in the subventricular zone are considered to be the source of brain regeneration. They are not a uniform cell population. Scientists have found evidence suggesting that they are pre-determined to take varying developmental paths and can differentiate into various types of neurons.

“We are particularly interested in finding out how we can stimulate stem cells to regenerate damaged tissue after brain injury,” said Ana Martin-Villalba from the DKFZ. “We wanted to find out whether there are molecular characteristics to identify stem cells with regenerative potential.”

Enric Llorens-Bobadilla and Sheng Zhao from Martin-Villalba’s research division have now generated a molecular profile of neural stem cells from the brains of mice. For this purpose, they sequenced the complete RNA of individual stem cells, i.e., the transcripts of all genes that are active in these cells.

The scientists discovered that the neural stem cells occurred in different activation stages. Besides dormant and active dividing stem cells, they also found transition forms that had already been awakened from dormancy but had not yet started dividing actively.

The characteristic feature of dormant neural stem cells is their extremely reduced protein synthesis. The more active the cells are, the more they synthesize proteins and the more they reduce their glucose metabolism. At the same time, these cells increase the production of transcription factors that are essential for differentiation into specific cell types.

In order to find out how neural stem cells respond to brain injury, the researchers experimentally provoked a state of reduced blood supply in the brain s of mice before isolating the stem cells. The subsequent single-cell analysis showed that not all neural stem cells respond to the oxygen deficiency. Only a specific subpopulation of dormant stem cells assumed an “awakened resting state”. This was associated with the activation of protein synthesis and cell cycle control genes.

The researchers then searched for the mediator that transmits the activation signal in response to the oxygen deficiency to the stem cells. It turned out to be interferon-gamma that signalizes the emergency. This signaling molecule acts like an alarm clock that puts specific neural stem cells from their deep dormancy into a pre-active state.

Interestingly, a couple of years ago, Marieke Essers, who pursues research at the HI-STEM stem cell institute (financed by DKFZ and the Dietam Hopp-Foundation), was able to show that dormant blood stem cells are also awakened by interferon-alpha, a related immune mediator. 

“After injuries or during degenerative diseases such as Alzheimer’s or Parkinson’s, it is essential to replace damaged brain tissue by new, functioning neurons,” says Martin-Villalba. New neurons also continuously form in the healthy brain. However, this is a very restricted spectrum of neurons, which are mainly responsible for smell or creating new connections in the hippocampus. By contrast, interferon-gamma induces a specific group of stem cells to differentiate into a large variety of neurons that can assume various tasks. “We might use the interferon-gamma alarm clock to stimulate specific regeneration processes in the brain that may restore the capabilities of affected persons,” neuroscientist Martin-Villalba speculates. “Our working group now investigates how this can be done.”

Enric Llorens-Bobadilla, Sheng Zhao, Avni Baser, Gonzalo Saiz-Castro, Klara Zwadlo & Ana Martin-Villalba: Single cell transcriptomics reveals a population of dormant neural stem cells that become activated upon brain injury. Cell Stem Cell 2015, DOI: 10.1016/j.stem.2015.07.002

A picture is available at the Internet: http://www.dkfz.de/de/presse/pressemitteilungen/2015/bilder/MAX_aNSC.jpg

Caption: Olfactory bulb interneurons generated out of neural stem cells transplanted in the walls of the lateral ventricles.
Picture: Ana Martin-Villalba, DKFZ

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institution in Germany. More than 1,300 scientists at the DKFZ investigate how cancer develops, identify cancer risk factors and search for new strategies to prevent people from developing cancer. They are developing new methods to diagnose tumors more precisely and treat cancer patients more successfully. The DKFZ's Cancer Information Service (KID) provides patients, interested citizens and experts with individual answers to all questions on cancer.

Jointly with partners from the university hospitals, the DKFZ operates the National Center for Tumor Diseases (NCT) in Heidelberg and Dresden, and the Hopp Children's Tumour Center KiTZ in Heidelberg. In the German Consortium for Translational Cancer Research (DKTK), one of the six German Centers for Health Research, the DKFZ maintains translational centers at seven university partner locations. NCT and DKTK sites combine excellent university medicine with the high-profile research of the DKFZ. They contribute to the endeavor of transferring promising approaches from cancer research to the clinic and thus improving the chances of cancer patients.

The DKFZ is 90 percent financed by the Federal Ministry of Education and Research and 10 percent by the state of Baden-Württemberg. The DKFZ is a member of the Helmholtz Association of German Research Centers.

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