Supercharging the brain’s self-healing cells

You ask your daughter to pass the salad, but the word that comes out is shoe. You need a walker to move around your living room. You’re having trouble recognizing familiar faces.  

A stroke can cause significant brain damage that severely impacts a person’s quality of life. Speech, mobility, memory, thought processes and mood can all take a hit. But what if a new treatment could supercharge the stem cells that your brain produces at the injured site — in the critical few days following a stroke — and repair the damage? 

With research funding from Heart & Stroke donors, Dr. Jing Wang is working to boost the brain’s intrinsic healing power. At the Ottawa Hospital, where she is a senior scientist, Dr. Wang and her team are tracing the molecular processes triggered by an ischemic stroke, which occurs when a clot blocks blood flow in the brain. What they’ve found points to an exciting possibility: a natural process within the brain that could be enhanced to generate new brain cells and restore function.  

Dr. Wang, a neurobiologist and associate professor of cellular molecular medicine at the University of Ottawa, explains where this power comes from, and how it could potentially help the brain heal itself after stroke. 

What happens to the brain during a stroke? 

A stroke deprives the affected region of the brain of oxygen and energy, causing massive cell deaths in the surrounding brain tissue. If you get to treatment quickly, blood flow can be restored. So, a lot of people survive the acute stage of stroke. Some are lucky and make a full recovery. But many are left with permanent brain damage.  

During a brain injury such as a stroke, a lot of things are happening at the lesion site. One is a surge of neural stem cells.

What are neural stem cells, and why are they significant? 

A stem cell is like a seeding cell. It not only can renew itself; it can also generate an offspring daughter cell.  

Neural stem cells are stem cells found in the adult brain. They have the capability of generating new brain cells, including neurons, but this capacity is limited.  

The neural stem cells that are induced and appear at the site of brain injury only surge for a very short window, probably three to seven days. After that, these induced neural stem cells diminish. That means we have a fleeting, but powerful, opportunity to harness their healing potential.

Where do these injury-induced neural stem cells come from? 

They are transformed from other types of non-neuronal cells. What we're interested in is a type of cell called a pericyte, which is wrapped around a blood vessel. Normally, pericytes are a major component of the blood-brain barrier. But we found that injury can trigger their growth into stem cells.

How could neural stem cells potentially repair brain damage caused by stroke? 

We found they can generate a neuron at the stroke site, but at a very low rate — we estimate about 4%. We’re studying how we can promote the neuron production from these induced neural stem cells, which only surge within the short window after injury before they disappear. Can we drive them to become newborn neurons in the lesion site to help repair the tissue right away?  

How are you studying the healing potential of these neural stem cells?

We are approaching it in two ways. One way is in the culture dish. We start by isolating pericytes in a dish. Then we mimic the conditions of a stroke by depriving them of oxygen and glucose.

We can then apply different tools to this culture, for example, throwing in a drug to see if it can speed up the pericyte to generate a neural stem cell. Once the neural stem cells are there, we can manipulate the second phase, to drive these stem cells to become neurons in the dish.

The other approach is through genetic manipulation in vivo. As we learn more about proteins involved in this process, we can use genetics to either knock down or overexpress certain molecules in vivo. Eventually, we hope to speed up neuron production in this way.

What have you found in your research so far?

We’ve looked at one drug, metformin, which is approved for treating type 2 diabetes. When we applied it to injury-induced neural stem cells, we sped up their rate of generating neurons. We were thrilled by this discovery, and we’re now moving to the next phase: creating a localized drug‑delivery system that can release metformin directly at the injury site to encourage new neuron growth from the injury‑induced neural stem cells.

What are you looking at next in the laboratory?

In our Heart & Stroke work, we want to further identify what molecules are essential to drive this pathway.

We are looking at two proteins: HIF1-alpha and HIF2-alpha, which play different roles in transforming pericytes into neural stem cells — and then generating neurons from those stem cells. We believe that, especially if we can inhibit HIF1-alpha, these neural stem cells could generate many more neurons.

We have strong preliminary data, and this funding will allow us to expand to much deeper work over the next four or five years, to define the specific role of these proteins using our genetic models. From there we hope to identify what kind of drug by targeting the function of the proteins would be most effective in helping generate more neurons to repair damaged brain tissue.

If this stage of your research is successful, how could this treatment be delivered to the patient?

The drug could simply be injected into the peritoneum (body cavity) or simply administered through an intravenous drip.

Alternatively, we are currently developing a local drug delivery system in collaboration with chemical engineer and neurosurgeon to release drug treatment locally at the injury site, which is suitable for some devastating strokes requiring emergency surgery to release brain pressure due to swelling.

What could your discoveries mean to someone who has a stroke?

Ultimately, we hope to allow those patients to regain the function they lost during brain damage. That could mean a return to work, walking without assistance or maintaining independence.

What does it mean to you to have support from Heart & Stroke donors?

Support from donors is a constant reminder that our research is ultimately about the people living with long-term consequences of heart disease and stroke — the patient, their family, their community.

Donor support motivates us. We want to advance scientific understanding, but we also want to move closer to therapy that can improve long-term outcomes and quality of life for survivors.