Adult stem cells are flexible and can transform themselves into a wide variety of special cell types. Because they are harvested from adult organisms, there are no ethical objections to their use, and they therefore open up major possibilities in biomedicine. For instance, adult stem cells enable the stabilization or even regeneration of damaged tissue. Neural stem cells form a reservoir for nerve cells. Researchers hope to use them to treat neurodegenerative disorders such as Parkinson's and Alzheimer's disease. Tbingen researchers led by Professor Olga Garaschuk of the University of Tbingen's Institute for Physiology, working with colleagues from Yale University, the Max Planck Institute of Neurobiology in Martinsried and the Helmholtz Center in Munich, studied the integration of these cells into the pre-existing neural network in the living organism. The results of their study have been published in the latest edition of Nature Communications.

There are only two places in the brains of adult mammals where stem cells can be found -- the lateral ventricles and the hippocampus. These stem cells are generating neurons throughout life. The researchers focused on a stem cell zone in the lateral ventricle, from where progenitors of the nerve cells migrate towards the olfactory bulb. The olfactory nerves which start in the nasal tissue run down to this structure, which in mice is located at the frontal base of the brain. It is there that the former stem cells specialized in the task of processing information on smells detected by the nose. "Using the latest methods in microscopy, we were for the first time able to directly monitor functional properties of migrating neural progenitor cells inside the olfactory bulb in mice," says Olga Garaschuk. The researchers were able to track the cells using special fluorescent markers whose intensity changes according to the cell's activity.

The study showed that as little as 48 hours after the cells had arrived in the olfactory bulb, around half of them were capable of responding to olfactory stimuli. Even though the neural progenitor cells were still migrating, their sensitivity to odorants and their electrical activity were similar to those of the surrounding, mature neurons. The mature pattern of odor-evoked responses of these cells strongly contrasted with their molecular phenotype which was typical of immature, migrating neuroblasts. "Our data reveal a remarkably rapid functional integration of adult-born cells into the pre-existing neural network," says Garaschuk, "and they show that sensory-driven activity is in a position to orchestrate their migration and differentiation as well as their decision of when and where to integrate."

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Stem cell specialization observed in the brain

Under normal conditions, many of the different types of tissue-specific adult stem cells, including hematopoietic stem cells, exist in a state or dormancy where they rarely divide and have very low energy demands. "Our theory was that this state of dormancy protected hematopoietic stem cells from DNA damage and therefore protects them from premature aging," says Dr. Michael Milsom, leader of the study.

However, under conditions of stress, such as during chronic blood loss or infection, hematopoietic stem cells are driven into a state of rapid cell division in order to produce new blood cells and repair the damaged tissue. "It's like forcing you out of your bed in the middle of the night and then putting you into a sports car and asking you to drive as fast as you can around a race circuit while you are still half asleep," explains Milsom. "The stem cells go from a state of rest to very high activity within a short space of time, requiring them to rapidly increase their metabolic rate, synthesize new DNA and coordinate cell division. Suddenly having to simultaneously execute these complicated functions dramatically increases the likelihood that something will go wrong."

Indeed, experiments described in the study show that the increased energy demands of the stem cells during stress result in elevated production of reactive metabolites that can directly damage DNA. If this happens at the same time that the cell is trying to replicate its DNA, then this can cause either the death of the stem cell, or potentially the acquisition of mutations that may cause cancer.

Normal stem cells can repair the majority of this stress-induced DNA damage, but the more times you are exposed to stress, the more likely it is that a given stem cell will inefficiently repair the damage and then die or become mutated and act as a seed in the development of leukemia. "We believe that this model perfectly explains the gradual accumulation of DNA damage in stem cells with age and the associated reduction in the ability of a tissue to maintain and repair itself as you get older," Milsom adds.

In addition, the study goes on to examine how this stress response impacts on a mouse model of a rare inherited premature aging disorder that is caused by a defect in DNA repair. Patients with Fanconi anemia suffer a collapse of their blood system and have an extremely high risk of developing cancer. Mouse models of Fanconi anemia have exactly the same DNA repair defect as found in human patients but the mice never spontaneously develop the bone marrow failure observed in nearly all patients.

"We felt that stress induced DNA damage was the missing ingredient that was required to cause hematopoietic stem cell depletion in these mice," says Milsom. When Fanconi anemia mice were exposed to stimulation mimicking a prolonged viral infection, they were unable to efficiently repair the resulting DNA damage and their stem cells failed. In the same space of time that normal mice showed a gradual decline in hematopoietic stem cell numbers, the stem cells in Fanconi anemia mice were almost completely depleted, resulting in bone marrow failure and an inadequate production of blood cells to sustain life.

"This perfectly recapitulates what happens to Fanconi anemia patients and now gives us an opportunity to understand how this disease works and how we might better treat it," commented Milsom.

Prof. Dr. Andreas Trumpp, director of HI-STEM and head of the Division of Stem Cells and Cancer at the DKFZ believes that this work is a big step towards understanding a range of age-related diseases. "The novel link between physiologic stress, mutations in stem cells and aging is very exciting," says Trumpp, a co-author of the study. "By understanding the mechanism via which stem cells age, we can start to think about strategies to prevent or at least reduce the risk of damaged stem cells which are the cause of aging and the seed of cancer."

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A good night's sleep keeps your stem cells young

19 hours ago Stem cells can be specifically distinguished from mature neural cells within a neurosphere using the novel fluorescent label CDy5 (red), with nuclei (blue) and cytosol (green). Credit: A*STAR Singapore Bioimaging Consortium

A labeling compound identified at A*STAR that specifically marks neuronal stem cells is not only a useful research tool, but could also assist clinical efforts to repair neurological damage in patients.

Even as adults, we retain reservoirs of neural stem cells that can develop into mature replacements for dead or damaged neurons. However, these reserves are relatively small, and insufficient for repairing severe injuries to the brain or spinal cord. Larger numbers of these stem cells could potentially be grown in culture dishes, but to do so researchers would need to be able to separate them from mature, fully developed neurons that are ineffective for tissue repair.

Young-Tae Chang's group at the A*STAR Singapore Bioimaging Consortium is looking for a way "to find and isolate neural stem cells using fluorescent dyes, to then grow them in larger numbers to treat neuronal damage or neurodegenerative diseases."

Chang and Sohail Ahmed of the A*STAR Institute of Medical Biology recently succeeded in identifying such a dye. One of the challenges in cultivating neural stem cells is that although some will divide 'symmetrically' to yield two new stem cells, others divide 'asymmetrically' to produce one stem cell and one mature neuron or glial cells.

Reliably identifying true stem cells with existing dyes has proved challenging to date. "These dyes just diffuse out into both cells," says Chang. He and Ahmed therefore screened a large library of fluorescent chemical compounds in search of a dye that consistently remains stem-cell-specific.

One molecule, which the researchers named CDy5, proved particularly promising. Cultured neural stem cells gradually form structures called neurospheres, composed of both stem cells and neural cells of various stages of maturity. After labeling neurospheres with CDy5, Chang and Ahmed separated out the brightly labeled cells from the dimly labeled ones. Strikingly, cells that were strongly labeled by CDy5 were ten times more likely to form neurospheres (see image). Experiments with single cells showed that this dye remained stem-cell-specific even during asymmetric division, and the researchers subsequently learned that CDy5 forms a strong chemical bond with a protein that is exclusively active in neural stem cells.

Chang intends to use CDy5 to identify culture conditions that either help stem cells maintain their identity or prompt their development into mature nervous tissue. He is also keen to make this tool available to other groups. "I will distribute CDy5 to whoever is interested in using the probe and am excited to see what kinds of new applications or discoveries result," he says.

Explore further: Unlocking the potential of stem cells to repair brain damage

More information: Yun, S.-W., Leong, C., Bi, X., Ha, H.-H., Yu, Y. H. et al. "A fluorescent probe for imaging symmetric and asymmetric cell division in neurosphere formation." Chemical Communications 50, 74927494 (2014). dx.doi.org/10.1039/c4cc02974g

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Scientists learn to monitor neural stem cells that might help repair neurological damage