MADISON – Using neural stem cells derived from the fetal brains of rats, a team of
Wisconsin scientists has devised a rudimentary blood-brain barrier in the lab.
Writing this week (Dec. 19) in the online editions of the Journal of Neurochemistry,
a group led by University of Wisconsin-Madison professor of chemical and biological
engineering Eric V. Shusta describes an experiment in which nascent rat neural stem
cells were used to prod blood vessel cells to assume properties of the blood-brain
barrier.
The blood-brain barrier is an anatomical feature in humans and other animals that
protects the brain from chemicals and other harmful agents, but also limits the
ability of clinicians to administer helpful drugs. It is a feature that can succumb
to diseases such as Alzheimer’s or acute conditions such as stroke, which can leave
the brain vulnerable.
The blood-brain barrier is a critically important structure, Shusta says. Not only
does it physically block the movement of substances between blood and brain, but it
also possesses active properties that enable cells to pump unwanted molecules from
cells back into the bloodstream. What’s more, it has a metabolic function that can
alter the chemical properties of the molecules that do get through to the brain.
“It dictates traffic in and out of the brain,” Shusta explains.
Demonstrating that developing brain cells can release factors that may coax small
blood vessels to exhibit the properties of the blood-brain barrier is important for
a number of reasons. First, it forms a basis for understanding the mechanism that
provides critical protection for the brain. Second, it may lead to insights
regarding ways to overcome a barrier that frustrates neuroscientists, drug companies
and clinicians who would like to sneak drugs past it to treat disease.
“What we have shown is that these neural stem cells have the ability to stimulate
adult blood vessel endothelial cells to display enhanced blood-brain barrier
properties,” Shusta says. “This may lead to new in-vitro models of the blood-brain
barrier.”
That in turn may help researchers devise new therapies to treat brain disease and to
form a clear understanding of how the barrier forms during the course of
development.
“One of the big questions of (brain) development is how does the blood-brain barrier
form and when does it form,” says Shusta. “That’s poorly understood.”
The Wisconsin team, which includes UW-Madison School of Medicine and Public Health
professor and stem cell authority Clive Svendsen, used brain stem cells grown as
“neurospheres” to coax brain endothelial cells – flat cells that line blood vessels
– to form a tighter, more dense barrier to small molecules that would otherwise
diffuse through the blood vessel cells.
What is curious, according to Shusta and Svendsen, is that during development, brain
endothelial cells form an enhanced barrier in the complete absence of astrocytes, a
mature type of cell that serves as the two-by-four of the brain, but which do not
appear in great numbers until birth. Astrocytes provide both structural support and
are critical to the maintenance of the adult blood-brain barrier.
“One of the things we found is that the neural stem cells had a significant effect
on the development of blood-brain barrier properties in the absence of astrocytes,”
Svendsen says. “It is possible these cells take on the role of astrocytes in early
development and may be very important for establishing the initial barrier prior to
the astrocytes taking over and completing the barrier.”
The new work was accomplished by culturing endothelial cells in concert with the
neurospheres. Somehow, the neurospheres prompted the endothelial cells to form
tighter, denser cell-to-cell junctions, enhancing their ability to form a barrier
and exclude small chemical molecules from passing through, a hallmark of the
blood-brain barrier.
Using neural stem cells, Svendsen argues, provides a new way to assess how the
barrier forms in early development, insight that might provide clues about how to
mend the barrier when it is broken through disease or events such as stroke.
“Could neural progenitor cells or stem cells have a role in forming the blood-brain
barrier after damage or disease? The answer seems to be yes,” says Svendsen.
The team will next try to produce similar results using human endothelial cells and
neural stem cells. “That would be very exciting,” Svendsen acknowledges. “We don’t
have a good model for a human blood-brain barrier.”
Development of a human model, presumably, would be of enormous interest to
researchers and pharmaceutical companies as many promising drugs are composed of
molecules too big to pass through the human barrier and thus cannot be used in the
clinic.
In addition to Shusta and Svendsen, UW-Madison postdoctoral fellow Christian
Weidenfeller authored the new study. The study was funded by a grant from the
National Institutes of Health.
