Molecular sleuth identifies and corrects major defects in a blood-brain barrier model

A type of cell derived from human cells that has been widely used for brain research and drug development may have led researchers astray for years, according to a study by scientists at Weill Cornell Medicine and Medicine Columbia University Irving Medical Center.

The cell, called Brain Microvascular Endothelial Cell (iBMEC), was first described by other researchers in 2012, and was used to model the specific lining of capillaries in the brain called the “lump- blood-brain barrier. ” Many brain diseases, including brain cancers as well as degenerative and genetic disorders, could be much more manageable if researchers found drugs over this barrier. For this and other reasons, iBMEC-based models of the barrier have been accepted as an important routine tool in brain research.

However, in a study published on February 4 in the Proceedings of the National Academy of Sciences, Weill Cornell Medicine scientists, in collaboration with scientists at Columbia University ‘s Irving Medical Center and Sloan Kettering Memorial Cancer Center, analyzed the expression patterns of iBMECs genes and found that, of course, cells are not they are endothelial – specific cells that line blood vessels – so they are unlikely to be useful in making correct models of the blood-brain barrier.

“Models of key tissues and structures using stem cell technology could be very useful in developing better disease cures, but as this experience shows, we need to evaluate detail these models before we adopt them, “said co – author Dr. Raphaël Lis, assistant professor of genetics medicine in medicine and a member of the Ansary Cell Institute in the Department of Regenerative Medicine at Weill Cornell Medicine Dr. Lis is also an assistant professor of reproductive medicine at the Ronald O. Perelman and Claudia Cohen Center for Regenerative Medicine at Weill Cornell Medicine.

Since 2007, researchers have known that they can use a combination of transcription factor proteins, which control gene activity, to reprogram normal adult cells, such as skin cells sampled from a patient, into cells that resemble stem cells of the original stage of life. Researchers can then use similar reprogramming techniques to coagulate these cells, called stimulated stem cells, to mature into different cell types – cells that can be examined in the laboratory. to find out about common health and diseases.

The news in 2012 that researchers had made iBMECs, using such methods, was encouraging because the cells appeared to be one of the first cell types specifically associated with tissue created by stem cell methods. The cells appeared to be particularly useful for research, as they were thought to be broadly identical to the endothelial cells of the vascular-blocking blood-brain barrier – which usually block on most molecules in the blood from entering brain tissue. Research using iBMECs to model the blood-brain barrier, to better understand brain diseases and develop new therapies, has been expanded to include many worldwide laboratory.

In attempting to work with iBMECs, the co-operative teams noticed major unexplained differences between these cells and bona fide endothelial cells, for example in their patterns of gene activity. This led them to further study, using advanced methods incorporating the latest single-cell sequencing techniques, to make a close comparison of gene activity in iBMECs and in confirmed human brain endothelial cells.

They found that iBMECs have a predominantly non-endothelial gene activity pattern, with little activity among key endothelial transcription factors or other accepted gene signatures. The cells, they found, also found that normal cell surface proteins were not found in endothelial cells. Their analysis suggested that iBMECs were classified as endothelial cells and represented different cell types called epithelial cells. Epithelial cells participate in the formation of a physical barrier protecting the body from pathogens and environmental stimuli, while supporting the transport of fluids, nutrients and waste. Present in several organs such as the abdomen, lungs or skin, the epithelial barrier, unlike endothelial cells, is not equipped to carry blood.

The researchers noted that the initial studies of iBMECs almost a decade ago placed more emphasis on mechanical properties, such as the barrier of these cells and less on cell identity as they did. expressed through patterns of gene activity.

Generating various human tissues from pluripotent cells is one of the most widely used techniques in laboratories worldwide. This study shows that such methods should be studied carefully to avoid cell misdiagnosis that could lead to erroneous results.

“Previously there were fewer ways to study gene expression images, and there was less understanding of the patterns that make up the identity of specific cell types,” said co-author Dr. David Redmond, assistant professor of computational biology study in medicine and member of the Ansary Stem Cell Institute in the department of Regenerative Medicine at Weill Cornell Medicine.

The team found that by inducing the activity of three known endothelial cell transcription factors, they could reprogram iBMECs to be much more similar to endothelial cells.

“We do not yet have a good ‘blood-brain’ barrier in a lab basin, but I think we are now one step closer to that goal, and we also have an important misunderstanding in the field. corrected, “said first author Tyler Lu, a research expert at the Ronald O. Perelman and Claudia Cohen Center for Regenerative Medicine at Weill Cornell Medicine.

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