One of regenerative medicine’s greatest goals is to develop new treatments for stroke. So far, stem cell research for the disease has focused on developing therapeutic neurons — the primary movers of electrical impulses in the brain — to repair tissue damaged when oxygen to the brain is limited by a blood clot or break in a vessel. New UC Davis research, however, shows that other cells may be better suited for the task.
Published today in the journal Nature Communications, the
large, collaborative study found that astrocytes — neural cells that
transport key nutrients and form the blood-brain barrier — can protect
brain tissue and reduce disability due to stroke and other ischemic
“Astrocytes are often considered just
‘housekeeping’ cells because of their supportive roles to neurons, but
they’re actually much more sophisticated,” said Wenbin Deng, associate
professor of biochemistry and molecular medicine at UC Davis and senior
author of the study. “They are critical to several brain functions and
are believed to protect neurons from injury and death. They are not
excitable cells like neurons and are easier to harness. We wanted to
explore their potential in treating neurological disorders, beginning
Deng added that the therapeutic potential of
astrocytes has not been investigated in this context, since making them
at the purity levels necessary for stem cell therapies is challenging.
In addition, the specific types of astrocytes linked with protecting and
repairing brain injuries were not well understood.
The team began
by using a transcription factor (a protein that turns on genes) known
as Olig2 to differentiate human embryonic stem cells into astrocytes.
This approach generated a previously undiscovered type of astrocyte
called Olig2PC-Astros. More importantly, it produced those astrocytes at
almost 100 percent purity.
The researchers then compared the effects of Olig2PC-Astros, another
type of astrocyte called NPC-Astros and no treatment whatsoever on three
groups of rats with ischemic brain injuries. The rats transplanted with
Olig2PC-Astros experienced superior neuroprotection together with
higher levels of brain-derived neurotrophic factor (BDNF), a protein
associated with nerve growth and survival. The rats transplanted with
NPC-Astros or that received no treatment showed much higher levels of
To determine whether the astrocytes impacted
behavior, the researchers used a water maze to measure the rats’
learning and memory. In the maze, the rats were required to use memory
rather than vision to reach a destination. When tested 14 days after
transplantation, the rats receiving Olig2PC-Astros navigated the maze in
significantly less time than the rats that received NPC-Astros or no
The investigators used cell culture experiments to
determine whether the astrocytes could protect neurons from oxidative
stress, which plays a significant role in brain injury following stroke.
They exposed neurons co-cultured with both types of astrocytes to
hydrogen peroxide to replicate oxidative stress. They found that, while
both types of astrocytes provided protection, the Olig2PC-Astros had
greater antioxidant effects. Further investigation showed that the
Olig2PC-Astros had higher levels of the protein Nrf2, which increased
antioxidant activity in the mouse neurons.
“We were surprised and
delighted to find that the Olig2PC-Astros protected neurons from
oxidative stress in addition to rebuilding the neural circuits that
improved learning and memory,” said Deng.
The investigators also
investigated the genetic qualities of the newly identified astrocytes.
Global microarray studies showed they were genetically similar to the
standard NPC-Astros. The Olig2PC-Astros, however, expressed more genes
(such as BDNF and vasoactive endothelial growth factor, or VEGF)
associated with neuroprotection. Many of these genes help regulate the
formation and function of synapses, which carry signals between neurons.
experiments showed that both the Olig2PC-Astros and NPC-Astros
accelerated synapse development in mouse neurons. The Olig2PC-Astros,
however, had significantly greater protective effects over the
In addition to being therapeutically helpful, the Olig2PC-Astros showed no tumor formation, remained in brain areas where they were transplanted and did not differentiate into other cell types, such as neurons.
“Dr. Deng’s team has shown that this new method for deriving
astrocytes from embryonic stem cells creates a cell population that is
more pure and functionally superior to the standard method for astrocyte
derivation,” said Jan Nolta, director of the UC Davis Institute for
Regenerative Cures. “The functional improvement seen in the brain injury
models is impressive, as are the higher levels of BDNF. I will be
excited to see this work extended to other brain disease models such as
Huntington’s disease and others, where it is known that BDNF has a
Deng added that the results could lead to stem cell treatments for many neurodegenerative diseases.
creating a highly purified population of astrocytes and showing both
their therapeutic benefits and safety, we open up the possibility of
using these cells to restore brain function for conditions such as
Alzheimer’s disease, epilepsy, traumatic brain disorder, cerebral palsy
and spinal cord injury,” said Deng.
Peng Jiang of UC Davis and
Shriners Hospitals for Children was the study lead author. Deng and
Jiang’s co-authors were Chen Chen, Olga Chechneva, Seung-Hyuk Chung and
David Pleasure of UC Davis and Shriners Hospitals for Children;
Quanguang Zhang and Ruimin Wang of the Medical College of Georgia;
Mahendra Rao of the National Institutes of Health (NIH) Center for
Regenerative Medicine; and Ying Liu of the University of Texas Health
Source: UC Davis Health System