A gap in the fence
Brain stem cells have deceived the blood-brain barrier
Polina Loseva, N+1
A group of Israeli biologists has discovered that the barrier between blood and brain tissues is not as strong and impervious to large substances as previously thought. They noticed that neuronal stem cells with their processes directly contact the cells of the vascular wall. Moreover, stem cells, apparently, cause the vascular wall to capture and transfer substances from the blood to them. Such transportation also turned out to be indiscriminate: not only dyes and harmless carbohydrates, but also a drug for chemotherapy got into the nervous tissue in the experiment. The work was published in the journal eLife (Licht et al., Hippocampal neural stem cells facilitate access from circulation via apical cytoplasmic processes).
In the brain of an adult mammal, there are two zones in which the precursors of nerve cells are concentrated: the olfactory bulb and the dentate gyrus of the hippocampus. It is not easy to understand how actively they divide during the life of the organism, but, apparently, they spend most of their time at rest, although in some experiments scientists have found that neurogenesis in the hippocampus can increase or, conversely, slow down – for example, after transfusion of blood to mice from young or old counterparts, respectively.
It is unclear exactly how neuronal stem cells in the hippocampus react to blood composition. Theoretically, they should be separated from the blood by a blood–brain barrier - a barrier that consists of a vessel wall and intercellular substance. Therefore, there are only two possible ways in which blood can act on stem cells. Either they break the barrier by reaching the vessel directly, or the blood acts on the cells of the vessel wall, and they already secrete their signaling substances into the brain tissue.
Tamar Licht, together with colleagues from the Hebrew University in Jerusalem, used a line of genetically modified mice in which only neuronal stem cells produce red fluorescent protein. These cells resemble a tree in shape: their body lies in one cellular layer ("crown"), and a long process ("trunk") goes into another layer, where it gives many small processes, the functions of which remain unclear. The researchers examined sections of the mouse hippocampus in an electron microscope and found that these small processes surround blood vessels.
Histological section of the hippocampus (right) and the simulation result (left). Dark cells are neural stem cells of the hippocampus (colored green in the model). The vessels are colored red. Figures from the article by Licht et al.
As a rule, there are at least two layers between the neuron and the lumen of the capillary – the endothelial cell (vessel walls) and the basement membrane (layer of intercellular substance), sometimes other cells surrounding the vessel are added. But after carefully examining the sections of the hippocampus, the authors of the work noticed that the basement membrane continuously covers only 30 percent of the surface of the vessels, in the remaining places "holes" are formed where stem cell processes can penetrate.
Thus, it turned out that the blood-brain barrier in the hippocampus is thinner than it should be, and in some places consists of only one endothelial cell. The researchers injected a dye into the blood of mice, and then again examined sections of the hippocampus and noticed that active transport was going through the endothelial cells – there were many membrane bubbles with dye in their cytoplasm. Moreover, there were especially many of them in those cells that were in direct contact with neuronal stem cells.
The authors of the work tried to "feed" other substances to neuronal stem cells. First, they injected high–molecular dextran, a carbohydrate that usually does not pass through the blood-brain barrier, into the blood of mice. And indeed, in other areas of the brain, it was found only in the lumen of blood vessels, but in the hippocampus it was found both inside endothelial cells and inside stem cell processes. Then other mice were injected with doxorubicin, a common chemotherapy drug that usually causes cognitive impairment as a side effect. It turned out that doxorubicin also gets inside neural stem cells.
Penetration of high-molecular carbohydrate (colored red) into the hippocampus. Neural stem cells are marked in green, and endothelial cells are marked in white.
Thus, the researchers found that the blood-brain barrier is not as strong in all places as previously thought. Moreover, it turns out to be permeable in the most "tender" place of the brain – where the processes of stem cells are directly adjacent to it. Moreover, it seems that neuronal stem cells somehow force endothelial cells to transfer substances from the blood to them. But this transport turns out to be not selective – substances of different sizes, both useful for cells and harmful, get into the brain. This fact explains why some drugs can inhibit neurogenesis as a side effect, but at the same time gives hope that it is possible to find a way to stimulate neurogenesis artificially.
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