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endothelial cells

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


Regenerative Medicine: Making Blood Stem Cells in the Lab

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Endothelial cells becoming hematopoietic stem cells

Caption: Arrow in first panel points to an endothelial cell induced to become hematopoietic stem cell (HSC). Second and third panels show the expansion of HSCs over time.
Credit: Raphael Lis, Weill Cornell Medicine, New York, NY

Bone marrow transplants offer a way to cure leukemia, sickle cell disease, and a variety of other life-threatening blood disorders.There are two major problems, however: One is many patients don’t have a well-matched donor to provide the marrow needed to reconstitute their blood with healthy cells. Another is even with a well-matched donor, rejection or graft versus host disease can occur, and lifelong immunosuppression may be needed.

A much more powerful option would be to develop a means for every patient to serve as their own bone marrow donor. To address this challenge, researchers have been trying to develop reliable, lab-based methods for making the vital, blood-producing component of bone marrow: hematopoietic stem cells (HSCs).

Two new studies by NIH-funded research teams bring us closer to achieving this feat. In the first study, researchers developed a biochemical “recipe” to produce HSC-like cells from human induced pluripotent stem cells (iPSCs), which were derived from mature skin cells. In the second, researchers employed another approach to convert mature mouse endothelial cells, which line the inside of blood vessels, directly into self-renewing HSCs. When these HSCs were transplanted into mice, they fully reconstituted the animals’ blood systems with healthy red and white blood cells.


Bright Lights, Cool Science

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Photo of the developing brain of a live zebrafish

Photo Credit: Jennifer Peters, Ph.D., and Michael Taylor, Ph.D. at the Cell and Tissue Imaging Center at St. Jude Children’s Research Hospital.

This may look like a tangle of holiday lights, but it’s actually a peek inside  the developing brain of a live zebrafish. NIH-supported researchers created this award-winning picture by labeling the brain’s endothelial cells with fluorescent proteins and then using a confocal microscope to snap 3-D images as the cells assembled into the blood-brain barrier. So why are these guys taking photos of fish brains? They want to gain a better understanding of how the blood-brain barrier develops. And that’s  important because a major hurdle in the treatment of many brain disorders is figuring out better ways to move drugs and other therapies from the bloodstream and into the brain.