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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


Snapshots of Life: Growing Mini-Brains in a Dish

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Brain grown in a lab dish

Credit: Collin Edington and Iris Lee, Department of Biomedical Engineering, MIT

Something pretty incredible happens—both visually and scientifically—when researchers spread neural stem cells onto a gel-like matrix in a lab dish and wait to see what happens. Gradually, the cells differentiate and self-assemble to form cohesive organoids that resemble miniature brains!

In this image of a mini-brain organoid, the center consists of a clump of neuronal bodies (magenta), surrounded by an intricate network of branching extensions (green) through which these cells relay information. Scattered throughout the mini-brain are star-shaped astrocytes (red) that serve as support cells.


Sleep Gene Linked to Migraines

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Oil painting of a woman holding her head, frowning

“Migraine.” This oil painting, by Dr. Emily Bates, was created while she was collecting data for this publication. As a migraine sufferer, this painting describes how migraines feel to her.
Credit: Emily Bates

Migraines—pounding headaches sometimes preceded by a visual “aura,” and often coupled with vomiting, nausea, distorted vision, and hypersensitivity to sound and touch—can be highly debilitating if recurrent and prolonged. They affect millions of Americans and an estimated 10–20 percent of the global population. Yet what predisposes individuals to them is somewhat of a mystery. Though there are certainly environmental triggers, the tendency for migraines to run in families suggests that there’s likely an inherited component. Recently, a team of NIH-funded researchers, one of whom regularly suffered from migraines herself, found a gene that plays a part.


Mice Learn Better with Help from Human Brain Cells

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Photo image of human astrocytes

Human astrocytes in a mouse brain
Source: Steven Goldman, M.D., Ph.D., University of Rochester Medical Center

What happens when you implant human glia—a type of brain cell that protects and nurtures neurons—into the brains of newborn mice? Well, it turns out these glia mature into multi-talented astrocyte cells that provide nutrients, repair injuries, and modulate signals just like they do in a human brain. They even assume the same complex star shape!

We know the cells in question are indeed human astrocytes because they produce a group of specific proteins, which are tagged with a combination of dyes that together appear yellow in this image. In contrast, the mouse cells are blue.

This all looks very pretty, but you might wonder what impact these human astrocytes have on mouse cognition. Researchers found mice that received the implants were better able to learn and remember than those that didn’t. In short, the human cells seem to have made the mice smarter.

Interestingly, human astrocytes are larger, more complex, and more diverse than their counterparts in other species. So, perhaps these cells may hold some of the keys to our own unique cognitive abilities.

Reference:

Forebrain Engraftment
by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice. Xiaoning Han, Michael Chen, Fushun Wang, Martha Windrem, Su Wang, Steven Shanz, Qiwu Xu, Nancy Ann Oberheim, Lane Bekar,  Sarah Betstadt,  Alcino J. Silva, Takahiro Takano, Steven A. Goldman, and Maiken Nedergaard. Cell Stem Cell 12, 342–353, March 7, 2013.

NIH support: the National Institute of Mental Health; and the National Institute of Neurological Disorders and Stroke