YSM Issue 90.2

neuroscience
NEWS
TARGETED THERAPY FOR BRAIN INJURY
Healing patients with a stroke of genius
►BY JESSICA TRINH
PHOTOGRAPHY BY JARED PERALTA
►A study conducted at Yale University found that the TGF-β1
signaling pathway helps the brain recover following a stroke.
Intracerebral hemorrhage (ICH), a form of stroke, is characterized
by rupturing blood vessels in the brain. Along with a mortality
rate of 40-50 percent, there is no current treatment. Following
the break in blood vessel, the battle is only half over. The immune
system is activated, and macrophages, a form of white blood cells,
rush to the job. Microglia, the resident macrophage, act as the
main defenders and gobble up unwanted particles in the brain.
However, once activated, the microglia can respond in two possible
ways. The classical response is the release of pro-inflammatory
molecules within the brain. The alternative response is the release
of anti-inflammatory signaling factors associated with functional
repair mechanisms in brain tissue. How such strikingly different
responses could be activated in the human brain following ICH
remains unknown.
Lauren Sansing, associate professor in neurology at Yale University,
along with Roslyn Taylor, lead author and researcher in
the Sansing lab, sought to examine the microglial response following
ICH, and to determine the cause behind the activation of
the alternative recovery responses. By studying changes in gene
expression, Sansing and her team could pinpoint the mechanism
behind these responses. To do this, the researchers analyzed the
changes in activation of 780 genes in microglia. They noticed the
most rapid changes in 78 of these genes occurred between days
three and seven following ICH. This time period, called the acute
phase, is marked by edema, the swelling of the brain due to fluid.
With hemorrhage causing damage to the brain, its microglia repair
mechanisms are crucial. The researchers found that by day
seven, microglia activate genes that aid in recovery, releasing anti-inflammatory
molecules instead of pro-inflammatory ones. “It
would make sense that microglia would turn off the inflammatory
process pretty quickly,” Sansing said.
Once the researchers observed these changes in microglia phenotype,
the question became determining what was mediating
the alternative, reparative mechanism. Searching for possible
pathways, researchers found a signaling protein most responsible:
the TGF-β1 pathway. Earlier findings have shown the importance
of this signaling pathway in the development of microglia. “It
wasn’t surprising that TGF-β1 became important in this recovery
phase, but it had never really been identified before,” Sansing said.
Now, they wanted to test whether introducing TGF-β1 protein
would increase the repair functions of microglia. Taylor and her
team studied the inflammatory responses in microglia in cell culture
by treating them with thrombin, a protein-cutting enzyme
which stimulates microglia to react similar to the response following
ICH. They then treated the cells with TGF-β1 protein and
observed the response of microglia. Their results were promising—they
found that inflammation was reduced.
Following their findings of the role of the TGF-β1 pathway
in reducing the inflammation of the classic microglial response,
the researchers treated mice with TGF-β1 protein directly
into the brain and observed the response. They found
that TGF-β1-treatment given within four hours after the occurrence
of ICH resulted in recovered motor function within
a day. Researchers were then interested in how these results
were relevant in human patients.
Applying these findings to human patients, the researchers
found the earlier the TGF-β1 pathway was induced, the higher
the chance of recovery. The researchers measured patients with
the modified Rankin scale, which categorizes severity of stroke
on a seven-point scale. Those with an earlier increased activation
level of the TGF-β1 protein pathway, six to 72 hours after ICH,
had less severe outcomes—and thereby a lower modified Ranking
score—than those with later activation.
By studying the changes in response of microglia, Taylor and
her team have provided promising outlook on the mechanism
behind repair following brain hemorrhage. “I think that our findings
will help provide further insights as to what TGF-β1 may
be doing specifically in microglia in neuroinflammatory diseases,”
Taylor said. While the researchers are still unsure what causes
earlier activation of the TGF-β1 pathway in some patients, the
results support the role of this pathway in repairing brain damage.
Until then, Taylor and her team hope other researchers will
continue brainstorming ways in which the TGF-β1 pathway may
be involved in therapeutic treatment for stroke victims. “The big
question remains whether we can we actually intervene on this
pathway by giving patients TGF-β1 protein,” Sansing said.
www.yalescientific.org
March 2017
Yale Scientific Magazine
9