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blood-brain barrier

Making Personalized Blood-Brain Barriers in a Dish

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Credit: Vatine et al, Cell Stem Cell, 2019

The blood-brain barrier, or BBB, is a dense sheet of cells that surrounds most of the brain’s blood vessels. The BBB’s tiny gaps let vital small molecules, such as oxygen and water, diffuse from the bloodstream into the brain while helping to keep out larger, impermeable foreign substances that don’t belong there.

But in people with certain neurological disorders—such as amyotrophic lateral sclerosis (ALS) and Huntington’s disease—abnormalities in this barrier may block the entry of biomolecules essential to healthy brain activity. The BBB also makes it difficult for needed therapies to reach their target in the brain.

To help look for solutions to these and other problems, researchers can now grow human blood-brain barriers on a chip like the one pictured above. The high-magnification image reveals some of the BBB’s cellular parts. There are endothelial-like cells (magenta), which are similar to those that line the small vessels surrounding the brain. In close association are supportive brain cells known as astrocytes (green), which help to regulate blood flow.

While similar organ chips have been created before, what sets apart this new BBB chip is its use of induced pluripotent stem cell (iPSC) technology combined with advanced chip engineering. The iPSCs, derived in this case from blood samples, make it possible to produce a living model of anyone’s unique BBB on demand.

The researchers, led by Clive Svendsen, Cedars-Sinai, Los Angeles, first use a biochemical recipe to coax a person’s white blood cells to become iPSCs. At this point, the iPSCs are capable of producing any other cell type. But the Svendsen team follows two different recipes to direct those iPSCs to differentiate into endothelial and neural cells needed to model the BBB.

Also making this BBB platform unique is its use of a sophisticated microfluidic chip, produced by Boston-based Emulate, Inc. The chip mimics conditions inside the human body, allowing the blood-brain barrier to function much as it would in a person.

The channels enable researchers to flow cerebral spinal fluid (CSF) through one side and blood through the other to create the fully functional model tissue. The BBB chips also show electrical resistance and permeability just as would be expected in a person. The model BBBs are even able to block the entry of certain drugs!

As described in Cell Stem Cell, the researchers have already created BBB chips using iPSCs from a person with Huntington’s disease and another from an individual with a rare congenital disorder called Allan-Herndon-Dudley syndrome, an inherited disorder of brain development.

In the near term, his team has plans to model ALS and Parkinson’s disease on the BBB chips. Because these chips hold the promise of modeling the human BBB more precisely than animal models, they may accelerate studies of potentially promising new drugs. Svendsen suggests that individuals with neurological conditions might one day have their own BBB chips made on demand to help in selecting the best-available therapeutic options for them. Now that’s a future we’d all like to see.

Reference:

[1] Human iPSC-Derived Blood-Brain Barrier Chips Enable Disease Modeling and Personalized Medicine Applications. Vatine GD, Barrile R, Workman MJ, Sances S, Barriga BK, Rahnama M, Barthakur S, Kasendra M, Lucchesi C, Kerns J, Wen N, Spivia WR, Chen Z, Van Eyk J, Svendsen CN. Cell Stem Cell. 2019 Jun 6;24(6):995-1005.e6.

Links:

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

Stem Cell Information (NIH)

Svendsen Lab (Cedars-Sinai, Los Angeles)

NIH Support: National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences


Blast Off! Sending Human Tissue Chips into Space

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Tissue Chips in Space

Credit: Josh Valcarcel, NASA

A big challenge in unlocking the mysteries of aging is how long you need to study humans, or even human cells, to get answers. But, in partnership with NASA, NIH is hoping that space will help facilitate this important area of research.

It’s already known, from what’s been seen in astronauts, that the weightless conditions found in space can speed various processes associated with aging. So, might it be possible to use the space station as a lab to conduct aging experiments?


Exercise Releases Brain-Healthy Protein

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ExerciseWe all know that exercise is important for a strong and healthy body. Less appreciated is that exercise seems also to be important for a strong and healthy mind, boosting memory and learning, while possibly delaying age-related cognitive decline [1]. How is this so? Researchers have assembled a growing body of evidence that suggests skeletal muscle cells secrete proteins and other factors into the blood during exercise that have a regenerative effect on the brain.

Now, an NIH-supported study has identified a new biochemical candidate to help explore the muscle-brain connection: a protein secreted by skeletal muscle cells called cathepsin B. The study found that levels of this protein rise in the blood of people who exercise regularly, in this case running on a treadmill. In mice, brain cells treated with the protein also exhibited molecular changes associated with the production of new neurons. Interestingly, the researchers found that the memory boost normally provided by exercise is diminished in mice unable to produce cathepsin B.


Creative Minds: A New Chemistry for Aging Research?

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Tony Wyss-Coray

Tony Wyss-Coray / Credit: Stanford School of Medicine

Basic scientists have long studied aging by looking inside of cells. While this research has produced many important leads, they are now starting to look outside the cell for the wealth of biochemical clues contained in the bloodstream.

To introduce you to this exciting frontier in aging research, this blog highlighted a while back the work of Tony Wyss-Coray at Stanford School of Medicine, Palo Alto, CA. He and a colleague had just received a 2013 NIH Director’s Transformative Research Award to explore the effects of exercise on the brains of mice. Their work, in fact, produced one of Science Magazine’s Breakthrough Discoveries of 2014. Their team showed that by fusing the circulatory systems of old and young mice to create a shared blood supply, the young blood triggered new muscle and neural connections in the older mice, while also improving their memories.

As fascinating as this theoretical Fountain of Youth was, Wyss-Coray recognized a critical limitation. He had no way of knowing how factors secreted by the young mouse could actually cross the blood-brain barrier and rejuvenate neurons. To solve this unknown, Wyss-Coray recently received a 2015 NIH Director’s Pioneer Award to build a potentially game-changing tool to track the aging process in mice.