Natural process activating brain's immune cells could point way to repairing damaged brain tissue

October 21, 2012

The brain's key "breeder" cells, it turns out, do more than that. They secrete substances that boost the numbers and strength of critical brain-based immune cells believed to play a vital role in brain health. This finding adds a new dimension to our understanding of how resident stem cells and stem cell transplants may improve brain function.

Many researchers believe that these cells may be able to regenerate damaged by integrating into circuits that have been eroded by neurodegenerative disease or destroyed by injury. But new findings by scientists at the Stanford University School of Medicine suggest that another process, which has not been fully appreciated, could be a part of the equation as well. The findings appear in a study that will be published online Oct. 21 in .

"Transplanting neural into experimental animals' brains shows signs of being able to speed recovery from stroke and possibly neurodegenerative disease as well," said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences in the medical school and senior research scientist at the Veterans Affairs Palo Alto Health Care System. "Why this technique works is far from clear, though, because actually neural stem cells don't engraft well."

Neural stem cells can endure essentially unchanged for decades in two places in the , replicating just enough to meet the routine needs of those regions. In most , they aren't found at all.

While of critical importance to maintaining healthy , true neural stem cells are rare. Far more common are their immediate progeny, which are called , or NPCs. These robust, rapidly dividing cells are poised to travel down a committed path of differentiation to yield new of several different types including neurons.

It's known that treating humans with radiation or drugs that prevent NPC replication causes ("chemo ") and, in children, IQ losses of up to 20 points. Conversely, studies are being initiated to see whether infusing neural stem cells into brains affected by Alzheimer's disease can enhance patients' memory function.

One category of brain cells, microglia, descends not from but from an immune lineage and retains several features of . "Microglia are the brain's own resident immune cells," Wyss-Coray said. Unlike most other mature brain cells, microglia can proliferate throughout adulthood, especially in response to brain injury. They can, moreover, migrate toward injury sites, secrete various "chemical signaling" substances, and gobble up bits of debris, microbial invaders or entire dead or dying neurons.

Microglia normally are distributed throughout the brain—rather small, quiescent cells sprouting long, skinny projections that meekly but efficiently survey large areas that, taken together, cover the entire brain. But if this surveillance reveals signs of a disturbance, such as injury or infection, the microglia whirl into action. They begin proliferating and their puny bodies puff up, metamorphosing from mild-mannered Clark Kent-like reporters to buffed Supermen who fly to the scene of trouble, where they secrete substances that can throttle bad actors or call in reinforcements. Within these activated cells, internal garbage disposals called lysosomes form in large numbers and start whirring, ready to make mincemeat out of pathogens or cellular debris.

In addition to their part patrol-officer, part cleanup-crew status, microglia can also secrete substances that help neurons thrive. They also contribute to the ongoing pruning of unneeded connections between neurons that occurs throughout our lives.

But like immune cells elsewhere, said Wyss-Coray, microglia can be a force for evil if they engage in too much or inappropriate activity. They might, for instance, start to remove healthy cells (as occurs in Parkinson's) or stop cleaning up garbage strewn about the brain (for example, Alzheimer's plaque).

In a series of experiments, Wyss-Coray and his colleagues have shown that NPCs secrete substances that activate microglia. First, the researchers observed that microglia were uncharacteristically abundant and activated in the two regions in the mammalian brain where NPCs reside and new neurons are formed. Wondering whether the NPCs might be causing this increased microglial activity, the investigators incubated mouse microglia in a culture medium in which NPCs had previously been steeped. Two days later, they saw that the microglia had multiplied more, expressed different amounts of various signal molecules and featured more lysosomes. "The microglia were ready for action," said Wyss-Coray.

So they injected NPCs into an area of mice's brains where these cells are normally not found. In the same area in the opposing brain hemisphere, they injected a control solution. Again they found significant differences in microglial proliferation and activity, and more microglia in the NPC-injected side had assumed a "Superman" as opposed to a "Clark Kent" body shape. When they repeated this experiment using only the NPCs' "discarded bath water" rather than NPCs themselves, they got similar results.

Clearly NPCs were secreting something, or some things, that were spurring microglia to action.

Using sophisticated lab techniques, the team monitored purified NPCs plus several other cell types found in the brain and assessed nearly 60 different substances known to have powerful cell-to-cell signaling properties. Several such substances, it turned out, were secreted in much larger amounts by NPCs than by the other cell types: most notably, vascular endothelial growth factor, or VEGF—a well-known molecule produced by many cell types throughout the body. VEGF stimulates the formation of blood vessels and exerts a beneficial effect on neurons. Conversely, drugs that block VEGF (such as Avastin) are frequently used to combat cancer because tumors require an immense blood supply in order to grow quickly.

VEGF is also known to boost microglial proliferation. Because it is produced in such volumes by NPCs, Wyss-Coray's team wanted to see if VEGF alone could mimic any of the changes wrought by NPCs or their culture-medium-borne detritus. So they injected VEGF into mice's right brain hemisphere, and saline solution into the left—again with the same outcomes. Taking the opposite tack, the team injected NPC-saturated medium devoid of the cells, as they had done earlier. But this time they first used various laboratory techniques to deplete the fluid of the VEGF secreted by its former inhabitants. Doing this almost completely reversed its microglia-activating effects.

"All of this strongly suggests that VEGF produced by NPCs is playing a strong role in influencing microglial behavior," said Wyss-Coray. "This is important, because in all neurodegenerative diseases we know of we see microglia out of control." The new finding may open the door to reprogramming misbehaving microglia to play better with other .

Explore further: Gardening in the brain: Specialist cells prune connections between neurons

Related Stories

Gardening in the brain: Specialist cells prune connections between neurons

July 21, 2011
Gardeners know that some trees require regular pruning: some of their branches have to be cut so that others can grow stronger. The same is true of the developing brain: cells called microglia prune the connections between ...

Key signal prepares immune cells to defend skin, brain

August 10, 2012
(Medical Xpress) -- Scientists at Washington University School of Medicine in St. Louis have identified the molecular signal that triggers the development of immune cells that patrol the skin and brain.

Study examines role of microglial cells as both defenders and fighters in the nervous system

October 16, 2012
(Medical Xpress)—In many pathologies of the nervous system, there is a common event - cells called microglia are activated from surveillant watchmen into fighters.  Microglia are the immune cells of the nervous system, ...

Locating ground zero: How the brain's emergency workers find the disaster area

May 24, 2012
Like emergency workers rushing to a disaster scene, cells called microglia speed to places where the brain has been injured, to contain the damage by 'eating up' any cellular debris and dead or dying neurons. Scientists at ...

Recommended for you

Worms learn to smell danger

October 17, 2017
Worms can learn. And the ways they learn and respond to danger could lead scientists to new treatments for people with neurodegenerative diseases.

Team finds training exercise that boosts brain power

October 17, 2017
One of the two brain-training methods most scientists use in research is significantly better in improving memory and attention, Johns Hopkins University researchers found. It also results in more significant changes in brain ...

'Busybody' protein may get on your nerves, but that's a good thing

October 17, 2017
Sensory neurons regulate how we recognize pain, touch, and the movement and position of our own bodies, but the field of neuroscience is just beginning to unravel this circuitry. Now, new research from the Salk Institute ...

Mechanism explains how seizures may lead to memory loss

October 16, 2017
Although it's been clear that seizures are linked to memory loss and other cognitive deficits in patients with Alzheimer's disease, how this happens has been puzzling. In a study published in the journal Nature Medicine, ...

Study shows people find well-being more so from special places than from mementoes

October 16, 2017
(Medical Xpress)—A team of researchers at the University of Surrey has found that people experience a feeling of well-being when thinking about or visiting a place that holds special meaning to them. They also found that ...

fMRI scans reveal why pain tolerance goes up during female orgasm and shows brain does not turn off

October 13, 2017
(Medical Xpress)—A team of researchers at Rutgers University has determined why women are able to tolerate more pain during the time leading up to and during orgasm. In their paper published in the Journal of Sexual Medicine, ...

2 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

Tausch
not rated yet Oct 21, 2012
The hallmark (indicator) of neurodegenerative diseases is 'out-or-control' microglia.

Removing a hallmark universal indicator of neurodegenerative diseases makes no sense. Reprogramming a diagnostic tools indicate nothing is wrong makes no sense.
Tausch
not rated yet Oct 21, 2012
Reprogramming a diagnostic tool to indicate nothing is wrong makes no sense.
Typo correction.

To me Wyss-Coray's suggestion to reprogram is counterproductive.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.