Atlas of brain blood vessels provides fresh clues to brain diseases

As in other parts of the body, the vasculature in the brain consists of arteries, veins and thin connecting vessels, capillaries, through which oxygen, nutrients and waste products are exchanged. However, brain blood vessels differ from other vessels in an important aspect ¬ the blood-brain barrier – that strictly controls which substances can pass through the blood vessel wall. The blood-brain barrier protects the brain from potentially toxic substances that have reached the blood from the food, gut microbiome or infections, while at the same time allowing selective passage of what the brain needs to form and function.

“It has become increasingly clear that a healthy blood-brain barrier is a pre-requisite for a functioning brain, and that dysfunction of the blood brain barrier is part of most, perhaps all, diseases in the brain. Exactly how the blood-brain barrier is composed has not been clarified and therefore detailed characterisation of the brain blood vessels and their barrier function was needed,” says Christer Betsholtz, professor at Uppsala University and Karolinska Institutet, who has led the present study.

The cellular and molecular map produced by the research group at IGP, in collaboration with researchers at Karolinska Institutet, has been done with a relatively new technique called single cell RNA sequencing. In short, with this technique brain blood vessels were disrupted into individual cells that subsequently, one by one, were characterised regarding their gene activity, and compared to each other. Then both the basic cell type of each cell was determined and any potential, gradual specialisations.

“Not only did we find the cell types that are known to make up all blood vessels but we also found gradual differences in the cells along the direction of the blood flow, from artery via capillary to vein. For the first time we could see in detail how the blood-brain barrier differs between the different cell types in brain blood vessels,” says Michael Vanlandewijck, researcher at Uppsala University and first author of the article.

The blood-brain barrier has so far been considered as a specialisation of endothelial cells i.e. the cells that line the inside of the vessels. However, the new study shows that several other cells types are involved. One of these is pericytes, a so far anonymous cell type located in the capillary wall. These cells have now for the first time been molecularly characterised and the researchers found that brain pericytes differ from pericytes in other blood vessels and that they have an active role in maintaining the blood-brain barrier.

“Based on our characterisation, a number of genes with known or presumed function in brain diseases can be associated with specific cell types in brain blood vessels. Our results indicated that more cell types than we previously thought are involved in neuro-vascular diseases such as Alzheimer’s disease and brain tumours. We now have possibilities to study this systematically in different diseases, using the same kind of analysis as we have done here,” says Christer Betsholtz.

The study was a collaboration between researchers at Uppsala University, Karolinska Institutet, and in France, Switzerland, Japan and China.

“A molecular atlas of cell types and zonation in the brain vasculature”, Michael Vanlandewijck, Liqun He, Maarja Andaloussi Mäe, Johanna Andrae, Koji Ando, Francesca Del Gaudio, Khayrun Nahar, Thibaud Lebouvier, Bàrbara Laviña, Leonor Gouveia, Ying Sun, Elisabeth Raschperger, Markus Räsänen, Yvette Zarb, Naoki Mochizuki, Annika Keller, Urban Lendahl, Christer Betsholtz. Nature, online 14 February 2018. DOI: 10.1038/nature25739.

Kerstin Henriksson