A New Approach to Stroke Treatment

---

By Ian Dawe

Every college student contemplating a night on the town has been told that brain cells don’t grow back. Though often ignored by that group, this fact is brought home with ferocious clarity in the case of a stroke. Paths can be built around damaged areas of the brain, and the organ itself can develop ways to compensate function, but re-growing the neurons that were destroyed in the catastrophic injury was long thought to be simply impossible. Through years of rehabilitation, stroke patients can regain some of their lost functions, such as the use of a limb or the ability to speak, but all current approaches are limited by the inability to effectively replace damaged brain cells.

Two Canadian Centres of Excellence, the Stem Cell Network and the Canadian Stroke Network, along with the Canadian Institutes of Health Research (CIHR), are attempting to alter that paradigm. Over the next two years, using a combined $1.8 million in funding and drawing on nine centres across Canada, these three Ottawa, Ont.-based organizations will aggressively examine how brain cells can be regenerated through the Adult Stem Cells to Treat Stroke project. Using a combination of transplantation and growth factor treatment, over 25 researchers will pioneer techniques that could bring new hope to those who have suffered strokes.

“One of the most devastating illnesses we see is stroke,” says Dr. Antoine Hakim, PhD, CEO and scientific director of the Canadian Stroke Network. The reason for this devastation is partly due to the brain damage that results from sudden loss of oxygen to the organ, and partly due to the fact that this damage is irreversible. “We do not have any tools to reconfigure the brain to return function,” Hakim notes, revealing one of the most tragic facts that patients must face.

Historically, stroke patients have been told that essentially they have to find a way to live with the condition, for it can’t be cured. Stroke treatment, therefore, is focused on recovering quality of life, not necessarily repairing the damage. Stem cell research has opened a tantalizing door to the possibility that this maxim can be changed.

Stem cells have as much potential as the research being conducted with them. They are the body’s way of replenishing important cell types, hidden away in special reservoirs like bone marrow. Under the right conditions, the right kinds of stem cells can be coaxed to transform into any type of body cell.

The most well-known stem cell (and the one around which so much controversy has swirled in recent years) is the embryonic stem cell, derived from early-stage embryo tissue. These cells are totipotent, meaning they can be convinced to transform themselves into any kind of cell in the body. Use of these embryonic stem cells is mired in a minefield of ethical issues because they are derived from fertilized eggs. Other stem cells can be pluripotent (able to transform into many types of cells, but not every type) or unipotent (able to become only a single cell type). These are the “adult” stem cells, and the trick that scientists have been trying to play on them for years is to get them to transform into cells not necessarily in their repertoire, such as neurons. Samuel Weiss, PhD of the University of Calgary, one of the lead investigators in this project, believes wholeheartedly that research on embryonic stem cells is valid and should be explored. “The choices (to use adult instead of embryonic stem cells) were made on the level of science,” he explains, but it does have the added benefit of sidestepping the potential ethical firestorm.

The use of adult stem cells has its own challenges, however. Unlike embryonic stem cells, which grow readily in culture and can be frozen down for storage, adult stem cells grow very slowly and are difficult to maintain. Aside from the lack of ethical issues, another compelling reason to explore their use is that they can be taken directly from the patient, producing not only a collection of neurons, but a collection of neurons tailor-made for the injured brain.

Almost 10 years ago, Weiss made the critical discovery that the adult human brain has its own population of stem cells that can be stimulated to change into many different kinds of neurons. Stimulating them in the brain, using various chemical factors including erythropoetin and prolactin, could potentially allow the organ to heal itself, generating new brain cells from “hidden” stem cell populations to replace those that were lost in the stroke. Other techniques are also being developed that can lure the neural stem cells out of their hiding places, help them communicate better with other cells in their environment and generally create a more hospitable environment for the newly generated cells.

The use of growth factors such as these, as many athletes know, carries inherent risks, as does any factor that stimulates cell division. In the wrong context, they have been implicated in types of cancer. But Weiss points out that this kind of treatment would only be used where there has been severe damage or loss of function, and in that context, the risks are worth taking. (Besides, in recent years they have been used in other kinds of therapy without adverse side-effects.)

Other groups in the network supported by this funding use other types of stem cells, including those derived from skin and bone marrow. It was Freda Miller, PhD of Toronto’s Hospital for Sick Children, the Adult Stem Cells to Treat Stroke project’s other lead investigator, who made a breakthrough in 2001 by demonstrating that cells derived from skin were capable of transforming into neurons. Her technique opened the door to a complementary approach to that of Weiss, who uses the brain’s own stem cells.

Taking adult stem cells from other tissues, growing them under the right conditions to transform them into brain cells and transplanting them back into animal brains is another means to the same end: regenerating neural tissue. In fact, researchers hope to be able to transform the cells into not only any brain cell, but the right kind of brain cell, according to the type of brain damage the stroke has produced. Testing the ability of various stem cell types to be transformed, what they can be transformed into and how effective they are in allowing animals to regain function when transplanted will form the second major part of the project. “We’re learning a lot about the bone marrow as a donor organ,” Hakim says. The research teams are constantly coming up with ways to make stem cells from outside the brain “useful to the brain.” He fully expects that the project will teach us much more about how to re-tool these cells.

The next two years offer an enormous opportunity to gain a clear picture of the effectiveness of these approaches. It is Canada’s unique and powerful research capacity that gives this country the chance to lead the way with this science. “It’s our weather,” Hakim says. “The long Canadian winters taught our ancestors how to work better together, and Canadian scientists work together better than anyone else in the world.” The collaborative approach fostered by projects such as this also ensures that all the scientific bases, from the Petri dish to the complete animal, are fully covered.

“We have some of the best people in the world in the three critical areas needed to evaluate this approach,” Weiss notes. These include the molecular biological teams, studying the properties of stem cells in culture, the groups who study stem cell transplantation and stimulation in animal models, and, “most importantly,” according to Weiss, the groups who are able to model strokes in animals.

This third group provides a vital link in the research chain. It is their work that demonstrates not only whether the treatments have rebuilt the structure of the brain or re-populated the damaged areas with the right kinds of cells, but also if this has made any difference in terms of function. “That is what most people want to understand,” Weiss says, noting that recovery of function is one of the primary goals of everyone involved in stroke research, patients and scientists alike. It would make little difference to a patient to know that his or her cells have been re-populated if that led to little or no noticeable effect. The animal models, such as the ones being developed by the Canadian Centre for Behavioural Neuroscience at the University of Lethbridge (Lethbridge, AB), are able to fill that critical gap.

How effective can these techniques be in the treatment of stroke? In two years, researchers will have a pretty good answer to that question. Between these two approaches — transplantation of stem cells derived from other tissues, and treatment of the mature brain to produce new neurons from existing brain stem cells — at least some progress is bound to occur in our understanding of the body’s growth and regulatory systems. Techniques involving adult stem cells will never be the only stroke treatment, nor will they be effective in every case, but they could prove to be an essential addition to the suite of treatment options available.

“It’s not that simple to reconstruct the brain,” Weiss says. “We’re not guaranteeing anything.”

Ronald Worton, PhD, scientific director of the Stem Cell Network, echoes this sentiment. “We all have this gut feeling that stem cells have enormous potential. What we can’t do is guarantee that any given cell will work on any given target.”

To millions of stroke victims, however, guarantees are not necessary. To move from a rehabilitative approach to stroke to an active repair and reconstruction effort would mark a turning point in medicine’s relationship with this disease. With Canada’s unique research groups that, as Hakim says, “have the capacity to make one plus one equal three,” the promise is there. For those struggling to recover from the devastating effects of stroke, sometimes that can be enough.