Brainssssssss
The brain is a complex organ that controls everything we perceive, learn, and do. It needs a lot of energy, but it cannot make or store it. Instead, it relies on a network of blood vessels that brings oxygen and glucose, a simple sugar important for energy, from the blood. This network is called the brain vasculature.
The vessels within this network have a special structure called the blood-brain barrier (BBB) that protects the brain from harmful substances, such as viruses and bacteria. The BBB is crucial for the health of the neurons, the nerve cells of the brain. If these neurons are damaged or lost, they can cause serious diseases of the brain and nervous system, many of which do not currently have treatments.
Cells and Genes of the Brain Vasculature
As mentioned, neurons are the fundamental nerve cells in the brain. It is important that they remain healthy in order for the brain to stay healthy. Different types of neurons can be classified based on the molecules, or “genes”, that are present in them.
The same holds true for the different types of cells that make up the brain’s vasculature. One type of cell important for the brain’s vasculature is the endothelial cell. The endothelial cell is the main unit that comprises the walls of all blood vessels. Depending on where along the blood vessel an endothelial cell is located determines its identity and the genes that it has or “expresses”. For example, endothelial cells that are part of large blood vessels that carry blood to the brain are called arteriole endothelial cells. In contrast, endothelial cells that are part of large blood vessels that carry blood away from the brain are called venule endothelial cells. These arteriole and venule endothelial cells express different genes.
Creating a Molecular Map of the Human Brain Vasculature
Recent research from our lab worked to address two major unanswered questions in neuroscience: 1) what genes define the brain vasculature cells in humans, and 2) what are the effects of these vascular cells on people with brain diseases? We developed a method to collect cells that make up the human brain vasculature. First, we needed to gather sample brain cells. We did this by collecting some brain tissue, both from brain surgeries as well as post-mortem brains (after-death brains). Then we performed single-nucleus RNA-sequencing, a technique that allows scientists to see what genes are expressed in certain cells. This had not been done before as these genetic tools work in other organisms but were not applicable for human tissue.
In total, we were able to observe about 17,000 brain vascular cells. This included the different types of brain endothelial cells (arteriole, capillary, and venule) mentioned above, as well as a newly discovered population of cells called perivascular fibroblasts.
Uncovering Species-Specific Difference in the Genes of Brain Vasculature
Our experimental approach allowed us to observe distinct populations of cells that comprise the human brain vasculature. We were then able to combine this with a mouse dataset to determine differences in gene expression across two different species. We uncovered that ~16% of genes were unique to one species, either human or mouse. We confirmed these results using a microscope to visualize a group of the human-specific genes. This demonstrated that, indeed, these genes were present only in human brain vascular cell populations and not in mice.
In addition to uncovering new genes that identify human brain vascular cells, we also found differences between mice and humans that could provide insights into treating people with brain diseases. For example, we confirmed that only mice express a gene that is necessary for the transport of certain therapies across the BBB. However, humans do not have this gene and therefore these therapies would not work. Our work allows for researchers to develop drug delivery tools specifically targeted to genes that are known to be present in humans.
Applications of Our Work to Huntington’s Disease
The last part of our study focused on looking at changes in brain vascular gene expression in the context of Huntington’s disease (HD). HD is an inherited neurodegenerative disease caused by a change in the huntingtin (HTT) gene. This devastating disease leads to decline of motor function, cognitive abilities, and ultimately death. To this date, there is no cure for HD nor are there many suitable therapies.
Previous studies have shown that the brain vasculature is affected in HD. However, an extensive look at these changes at a genetic level has not been performed. Using the genetic map we created, we were able to observe the genetic differences in individuals with HD.
Interestingly, we found that many of the genes in the HD endothelial cells were similarly found in HD neurons. We had not seen this in our earlier studies because no molecular map for these cells existed at the time. Our study revealed that a similar pattern of genes that leads to dysfunction in HD neurons is also present in the HD brain endothelial cells. Perhaps these genes contribute to the brain vascular dysfunction that has previously been observed in HD and targeting them specifically could help treat the disease.
The Importance of the Brain Vasculature in Human Disease
Our work provides a resource to the field of neuroscience. The powerful thing about these types of studies is that there is so much information that has yet to be discovered. Many other research groups can download our molecular map and look for genes they find interesting. We highlight the important genes for HD, but others can study different diseases like Alzheimer’s and Parkinson’s disease. This research allowed us to study both the healthy and diseased brain. Additionally, our work could help uncover new approaches for treating currently incurable diseases. Perhaps by better understanding the human brain vasculature, we can now develop specific approaches for treating human diseases.
Written By: Francisco Garcia
Academic Editor: Chemist
Non-Academic Editor: General Practice Lawyer
Original Paper
• Title: Single-cell dissection of the human brain vasculature
• Journal: Nature
• Date Published: 14 February 2022
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