Guards of the blood-brain barrier identified

Pericytes crucial to protecting central nervous system

Of all the body’s organs, the brain is the most like Area 51: Entry to the region is severely restricted, thanks to a barricade of cells and molecules known collectively as the blood-brain barrier. Increased surveillance by scientists has now pinpointed the barrier’s senior operatives, cells that are tasked with monitoring the razor wire–like barricade that keeps all but a select few from entering the brain.

In two papers published online October 13 in Nature, scientists report that specialized cells called perictyes are crucial in the blood-brain barrier’s development and its maintenance in adulthood. A better understanding of how these pericytes function could help elucidate why some people fare especially poorly after traumatic brain injury or get particular neurological diseases such as cerebral palsy, scientists say.  And new research could also lead to tricks for selectively opening or closing the blood-brain barrier, letting in medications that might combat diseases such as Alzheimer’s.

One of the new studies demonstrates that pericytes are necessary for cementing the barrier’s cells into a nearly impenetrable wall surrounding blood vessels in the central nervous system. The work also establishes a timeline: In mice, the blood-brain barrier develops well before birth, researchers from Stanford and the University of California, San Francisco report. Pericytes also appear to keep the barrier’s cells on lockdown, dialing down the activity of genes that, if left to their own devices, would spur the transport of molecules across the barrier and into the brain.

The second new study establishes that pericytes play a key role in regulating the blood-brain barrier in adult mice and also identifies a drug that appears to slow the transport of molecules across a leaky blood-brain barrier. In mutant mice lacking functional pericytes, the leukemia drug imatinib quickly halted the willy-nilly passage of molecules into the brain, researchers from Sweden and Germany report.

“We are now doing experiments with imatinib-like substances,” says Christer Betsholtz of the Karolinska Institute in Stockholm, who led the second study. “We would like to understand how imatinib is closing the barrier.”

Pericytes are found all over the body: Wherever there are blood vessels, there are pericytes around them. For a long time researchers thought that pericytes’ primary task was to help control flow in blood vessels. But around the blood vessels of the retina and the blood-brain barrier, pericytes are especially plentiful; in the last decade these cells have come under increased scrutiny as regulators of these important barriers.

The importance of the blood-brain barrier cannot be understated, says Norman Saunders of the University of Melbourne in Australia. Not only does the barrier block access by baddies such as bacteria and parasites, it also prevents the unchaperoned entry of electrically charged molecules called ions. Since brain cells communicate via electrical impulses, the barrier literally keeps the brain from going haywire, Saunders says.

“If it weren’t for the blood-brain barrier, our sensory experience would be reduced to a series of flashes and bangs,” says Saunders, recalling a quip of his late colleague and blood-brain barrier research giant Hugh Davson.

While pericytes were definitely on the short list of key regulators of the blood-brain barrier, many researchers were focusing on astrocytes, the star-shaped brain cells that help the brain’s thinking cells, neurons, do their thing. But research suggests that astrocytes don’t develop until after birth, which led some people to erroneously conclude that the blood-brain barrier therefore also doesn’t develop until infancy.

The new research firmly establishes that the blood-brain barrier is developed before birth, and that pericytes have a lot to do with that development. The cells also keep the barrier operating during adulthood. Mice genetically engineered to have fewer working pericytes have leakier blood-brain barriers, both teams report. This increased permeability seems to be partially due to structural problems — the normally supertight junctions between the barrier’s cells become cocked and crooked.

But more important than the dysfunctional junctions is the misbehavior of the barrier’s import and export machinery. Without pericytes, the barrier’s cells take up many more molecules from the blood than they should, and dump those molecules into the brain. This includes molecules associated with the immune system — substances that cause swelling and inflammation — a healthy response in most body tissues but not in the brain, says Richard Daneman of the University of California, San Francisco, who led one of the studies.

“A major function seems to be keeping the immune system out,” he says. “You don’t see immune cells in the brain — but in certain disease scenarios, multiple sclerosis, strokes — you get damage from the immune system in the brain.”

A malady that strikes people with diabetes may also be related to pericyte problems. After years with the disease, pericytes associated with the blood vessels around the retina start to disappear, says Andrius Kazlauskas of the Schepens Eye Research Institute at Harvard Medical School. Once the cells are gone, immune system molecules can invade, inflammation occurs and a person can’t see, says Kazlauskas. The condition is known as diabetic retinopathy.

“This work says that keeping the pericytes happy, keeping them alive, is likely to keep the vasculature happy,” he says. “That’s huge; conceptually, that’s a breakthrough. It is really intolerable for vision when the retina swells.”

Also intriguing is evidence that the leukemia drug imatinib slowed leakage, Kazlauskas says. Perhaps related drugs will eventually have a place in treating diabetic retinopathy.

In the future, there may even be genetic tests that tell people how healthy their pericyte population is, says neuroscientist Joan Abbott of the blood-brain barrier group at King’s College London. “We’ve been puzzled as to why some people after brain trauma do better than others,” Abbott says.  If some people are born with fewer or faulty pericytes due to genetics, their blood-brain barriers may be leaky from the start.

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