Stem cells have long been an area of scientific intrigue and mystery. Neural stem cells in the brain are responsible for generating new cells for regular brain maintenance, as well as regeneration and healing after injury. These unique cells are a heterogeneous group, however. For example, stem cells can differentiate into different types of brain cells: some stem cells may produce neurons that migrate to different regions of the brain, while other stem cells may produce glial, or non-neuronal cells in the brain. Furthermore, it is thought that some stem cells may not become neurons or glia at all, but rather serve as a constant stem cell population. What makes a particular neural stem cell activate and drive regeneration, while another might remain dormant? Are there certain genes that play a role in determining the identity of a given stem cell? And ultimately, how can we use these different types of stem cells to promote regeneration and healing after brain injury?
A group in Martin-Villalba’s lab at the German Cancer Research Center sought to find out. In a paper recently published in the journal Cell Stem Cell, Llorens-Bobadilla, Zhao, and their co-authors characterized which genes were expressed by individual neural stem cells, and wanted to see whether they could use this knowledge to help promote brain repair after injury. To address these goals, they isolated single neural stem cells from the subventricular zone, a stem cell niche in the adult brain, and sequenced the RNA, or the transcripts of active genes, of each cell. In this way, they were able to measure which genes were active in each individual stem cell, and use statistical measures to organize cells with similar gene expression levels into separate groups.
By carefully analyzing the different genes expressed by the cells in the subventricular zone, the authors showed that neural stem cells clustered into two general populations: quiescent and active. Within the quiescent group, there were two subpopulations of neural stem cells: one that was dormant and one that was “primed-quiescent,” or at a waiting stage ready to be activated. Each of these groups had its own gene expression signature. Looking closely at the differences in gene expression between dormant and active stem cells, the authors found that active neural stem cells have a much higher rate of protein synthesis than dormant cells. Active stem cells also have a higher expression of genes that induce differentiation, or the generation of new brain cells.
Given these differences in the natural state of individual neural stem cells, the authors wanted to see whether they could stimulate dormant stem cells and drive them into the active state, which could have potential benefits in regeneration after injury. Because the subventricular zone has been found to produce cells that migrate to the striatum and cortex after injury, the authors reasoned that increasing the number of active neural stem cells would increase the number of cells that would arrive at the site of injury and help rebuild neural circuits. In order to try to activate dormant neural stem cells, the authors temporarily reduced the blood supply to the brains of mice, which decreased oxygen levels in the brain. This decreased brain oxygenation activated some subsets of dormant neural stem cells. The authors wanted to hone in on which genes were orchestrating the transition of these cells from their dormant state into becoming active stem cells. They found that these cells expressed high levels of genes whose products interact with a protein called interferon gamma. They went on to show that these proteins involved with interferon gamma were key driving factors for activating these dormant stem cells.
These results are novel and exciting, as they define the differences between individual neural stem cells at a depth and resolution that hasn’t been achieved before, as well as present a potential method of activating neural stem cells. They also raise several new questions: How do these different groups of neural stem cells contribute to normal brain maintenance and injury repair? How can we use this knowledge to promote regeneration and healing after injury or in neurological diseases? This study provides excellent building blocks and an extensive gene expression database for the next steps in answering these questions.