A huge mission: Upstate scientist explores how stem cell therapy may repair brain damage from stroke or Alzheimer’s
Li-Ru Zhao‘s father, Jintian Zhao, was in his mid-60s in 1973 when a blood clot clogged a vessel in his brain and he suffered a stroke. Doctors in China, where he lives, suggested acupuncture or physical therapy in the first six months of recovery. They said after six months, nothing would help.
“My research challenges this notion,” says Zhao, an Upstate scientist engaged in one of the most promising new fields of medicine: stem cell factor therapy.
Zhao, MD, PhD, is an associate professor of neurosurgery in Upstate‘s biomedical sciences and neurosciences programs.
She appreciates studying neurological diseases because so many are considered incurable. “I feel my mission is so huge,” she explains. She also loves the challenge of discovering new things.
“The purpose of science is to search for the truth, to answer the questions we do not know.”
Zhao began searching for stroke answers two decades ago.
In the late 1990s, she worked alongside a famous stroke researcher at Lund University Wallenberg Neuroscience Center in Sweden. She focused on acute stroke research and then segued into studying stroke recovery.
Zhao and her husband, Weiming Duan, MD, PhD, then relocated to the University of Minnesota, where she continued her work.
Search for answers to stroke begins
One of her colleagues in Minnesota was studying the use of bone marrow stem cells for the treatment of leukemia. That gave Zhao the idea to see whether bone marrow stem cells could play a role in stroke recovery.
In her study, she transplanted human bone marrow stem cells into the brains of rats afflicted by stroke. She witnessed remarkable recovery. As exiting as the results were, Zhao had to learn why and how this happened. She hypothesized that the stem cells, once injected, released factors that were responsible for rewiring the brain for permanent recovery.
In 2002, her husband received a job offer at Northwestern University, in Chicago. She moved with him and continued her research, working to prove her hypothesis. She experimented with embryonic stem cells at Northwestern. Again, she saw remarkable repair from stroke. But this time, about a quarter of her test animals developed tumors.
Embryonic stem cells have the ability to become any type of cell, but embryonic stem cell transplantation has a risk of generating cancerous tumors. For embryonic stem cells to be helpful to her, Zhao would have to figure a way around their propensity for tumor formation.
A pair of research colleagues at Northwestern who specialized in hematology suggested she instead try using stem cell factors.
“I had the same question in my mind,” Zhao admits.
A clue in human aging?
Bone marrow stem cell factors are naturally occurring substances, released by bone marrow stem cells, that are capable of stimulating cell growth and healing. As people age, they have fewer of these factors. Zhao suspects that could help explain why younger people tend to recover from stroke more fully than older people.
Biotech firms sell stem cell factors as drug formulations. Two types of bone marrow stem cell factors – SCF, stem cell factor, and G-CSF, granulocyte colony stimulating factor — have been used in combination to reduce the damage from heart attacks. Researchers at that time had not looked at using these factors for stroke recovery.
Zhao experimented using SCF and G-CSF individually. She also used the two factors together and discovered they were synergistic in neural network generation and in stroke recovery. That is, they work better together than either work apart.
She began considering the timing.
Research for brain repair
During the first six months of recovery after a stroke, patients will have some degree of recovery without any sort of intervention, Zhao says, explaining that this spontaneous recovery is due to brain plasticity – the brain‘s ability to change throughout life. Injecting SCF and G-CSF factors seems to enhance brain plasticity and enhance the formation of new neural networks, which are crucial for recovery.
After she demonstrated the benefit of SCF and G-CSF in brain repair when the growth factors were injected at several hours or several months post-stroke, Zhao wondered whether SCF and G-CSF injected six months after a stroke would enhance recovery. Using multiple approaches, including brain imaging in live animals, her research team found that SCF and G-CSF together seemed to improve motor function recovery.
Through their research, she and her team located the brain cells that respond to the stem cell factor treatment. Neurons have receptors for both SCF and G-CSF. “That is the basis to suggest bone marrow stem cell factors affect brain structure and brain function,” Zhao explains.
Live brain imaging data have shown that considerably more neural networks form in brains that receive the treatment of bone marrow stem cell factors.
Turning to Alzheimer‘s
Zhao relocated again in 2004 with her husband to Louisiana State University Health Sciences Center.
When a large grant arrived for research on Alzheimer‘s disease, Zhao wondered whether the work she was doing on stroke repair could also be useful in Alzheimer‘s treatment.
She set up experiments and soon saw that stem cell factors lead to recovery in Alzheimer‘s disease, too. The amyloid plaques that accumulate between neurons and are the hallmark of Alzheimer‘s were fewer in the animals that received stem cell factor injections.
“This was very, very exciting,” Zhao recalls.
She also saw similar results in her laboratory using stem cell factors to treat a rare type of stroke and dementia with genetic roots.
“All the data put together actually validated what I was doing and made me feel more confident” that stem cell factors work for brain repair in a variety of diseases.
Understanding the potential
When Zhao‘s father-in-law suffered a severe stroke in 2010, her husband relocated to Beijing to care for him. Zhao accepted a position at Upstate in 2013.
Here, she has conducted experiments on the use of stem cell factors to treat traumatic brain injury. They work, in the lab, just as they worked for stroke and Alzheimer‘s.
Like so many other scientists in the field of stem cell research, Zhao is on the cusp of something potentially huge — but in the early stages.
Stem cell-related therapies “hold significant promise for transformative and potentially curative treatments for some of humanity‘s most troubling and intractable maladies,” says Food and Drug Administration Commissioner Scott Gottlieb, MD.
He continues: “Recent advances in our basic knowledge of the pathways involved in tissue damage and regeneration have combined with remarkable progress in adult stem cell biology to put us at a genuine inflection point in the history of medicine. The prospect of clinical tissue repair strategies is a tangible reality.”
Before Zhao can move her work forward with a clinical trial in humans, she must first determine exactly how the stem cell factors work and what amount is needed for effectiveness.
So, she continues her research in search of a repair for brain damage.
This article appears in the winter 2018 issue of Upstate Health magazine.