Stroke is a leading cause of adult disability in the developed world and even more so in the developing world. It afflicts 25 million people worldwide, and the number of new cases is rising seven percent a year as the population ages.

Accident vasculaire cérébral

Stroke is a leading cause of adult disability in the developed world and even more so in the developing world. It afflicts 25 million people worldwide, and the number of new cases is rising seven percent a year as the population ages. In Canada, 50,000 people have a stroke each year. In the United States someone has a stroke every 45 seconds. In North America and Europe, stroke is the third most common cause of death after heart disease and cancer.

There are two types of stroke. The vast majority are ischemic strokes and result from a blood clot or blocked artery. The other kind of stroke is hemorrhagic stroke and results from a burst blood vessel. In both instances, people need immediate medical attention. A brain scan will determine the kind of stroke and whether the patient is eligible for a clot-busting drug that can reverse the stroke damage.

Those who survive a stroke can suffer various degrees of disability depending on which part of the brain has been damaged. Stroke represents a huge burden on the health care system, and on families coping with the aftermath – often lost income, lost independence, caregiving responsibilities and the need for long term care.

Causes

A stroke is caused by an interruption of the blood supply to the brain specifically the loss of oxygen and glucose that are required for brain cells to survive. What goes wrong? Somewhere in the circulatory system there is either a blood clot or sufficient narrowing of the arteries to restrict the flow of blood.

The risk factors for stroke are well known - smoking, high blood pressure, obesity, high blood cholesterol, a sedentary life style, diabetes and stress. Indeed, a diet low in fat and sodium, controlled blood pressure, maintaining a healthy weight and regular exercise are very effective ways to prevent a stroke.

A stroke can happen at any age, but age increases the likelihood of stroke. More women than men die from stroke.

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Symptoms and treatment

Stroke is a medical emergency. The symptoms of a stroke are not difficult to recognize, and with prompt treatment disability can often be avoided. The warning signs are sudden weakness, trouble speaking or sense of confusion, vision problems, an unusually severe headache, and dizziness or sudden loss of balance.

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A small window of opportunity - a long road to recovery

Essentially a stroke is both an event in the central nervous system (the brain) and a condition occurring in the circulatory system - the channels through which blood flows - not unlike a heart attack which damages the heart. A blocked artery can affect many organs, but it has particular and devastating effects on the brain.

Death and disability is common because existing interventions for stroke must be administered within three hours to be effective, in other words, to keep brain cells from dying. Once that window closes, there are no other ways to avoid the neurological impact.

If the patient survives, the long road to recovery begins.

Depending upon which of the two hemispheres is affected, a stroke may impact all sorts of brain functions - the ability to remember, make decisions, speak, move your muscles, reason, do simple calculations, control bodily functions and emotions, understand directions, take in new information, read and write. One of the most common outcomes is weakness or paralysis on one side of the body. Because the damage is localized to particular areas of the brain, therapeutic strategies are also quite specific for recovering certain functions.

Stroke rehabilitation techniques have helped many people restore some functioning by teaching other areas of the brain to compensate for the lost neurons. But until now there has not been a way to replace the lost cells.

How can stem cells help?

Research on the use of stem cells to treat CNS injury and disease is progressing rapidly, partly because the investigations from a range of diseases are all focusing on repairing the brain by replacing or restoring neurons. This includes neurodegenerative diseases, like ALS or Parkinson's disease, genetic disease such as Huntington's disease, as well as brain cancer, spinal cord injury and stroke.

The lack of blood flow to the brain, and the loss of oxygen and nutrients it transports, are what cause brain cells (neurons) to die in the course of a stroke. Because clot-busting drugs need to be administered immediately to be effective, by the time a diagnosis is made, it is often too late.

Stem cells may help doctors extend that window of opportunity to support dying brain cells and reverse the cascade of events that is triggered by stroke. Also, stem cells may be able to replace cells that are irreversibly damaged by stroke.

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Endogenous or exogenous repair?

Until recently, it was believed that once brain cells were lost they could never be replaced. It was not until researchers and clinicians began to document that the brain could reorganize itself and compensate for disease, surgery and injury that there was a significant change in thinking. It is now known that exercise, hormones and an enriched environment facilitate this recovery. It was assumed that in the courses of recovery the brain was establishing new pathways, retraining the surviving brain cells to compensate for lost cells.

Almost ten years ago, Canadian researcher Dr Samuel Weiss discovered that the brain has its own store of stem cells that appear to be active throughout adult life. These are "hidden," as if in reserve, and much of the latest research is devoted to how to coax these stem cells into action. It appears that under certain conditions they can be stimulated to produce new neurons, and brain damage may be reversible.

The skin, muscle and bone marrow are alternative sources of stem cells that can make neurons under the right conditions. Dr Freda Miller in Toronto is exploring how to take adult stem cells from such tissues, nourish them with "growth factors" to multiply and differentiate them into nervous system cells and then transplant them back into the brain to regenerate brain tissue. Of course, there are considerable challenges: replacing exactly the types of neurons that have been destroyed and making sure they get to the right area and connect to the surrounding cells.

These two different approaches to using stem cells - known as "endogenous" and "exogenous" repair - are both viable treatments for stroke.

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Healing from within - endogenous repair

Endogenous repair - or "in vivo stimulation" - mobilizes the organism to heal itself. Adult stem cells in the brain (a vestige of the embryonic stem cells that originally developed our brains in utero) may be able to restore neurons lost through stroke. Other stems cells in the body, such as bone marrow stem cells, may be prompted to come out of their hiding places to help the cause.
This approach relies on the ability of certain adult stem cells, in particular those found in the adult brain, to differentiate into the kinds of brain cells that are required. It is a question of "turning on" the stem cells and providing the necessary instructions to rewire the brain after a stroke.

This is currently being done in small trials in the US and Europe by injecting a "growth factor" called G-CSF which mobilizes stem and progenitor cells from the bone marrow into the bloodstream. Once released into the bloodstream they can "home in" on the damaged areas of the brain. These bone marrow cells do not themselves make new nerve cells. Instead, they appear to have a protective effect on neurons and the ability to "switch on" the resident adult stem cells in the brain. This reverses the damage done in an ischemic stroke by sustaining neurons that would otherwise have died, and promoting the generation of new neurons.

These are very exciting and promising developments that underlie a growing optimism regarding stem cell therapy to treat stroke using an endogenous approach. By testing various treatments in non-human primates - such as timing and dosage of G-CSF - the next phase of clinical trials will seek to confirm these findings and refine the treatment regimens.


Picking up the right signals - exogenous repair

 

Exogenous repair, on the other hand, relies on stem cells being created outside of the patient's body in vitro (in a laboratory dish) and transplanted into the patient. Beginning with embryonic or fetal stem cells, this process involves adding growth factors to the mix as they develop. The aim is to multiply and either partially or completely differentiate the cells to become the nerve cell that is needed. This is the point where they can be injected into the patient's brain and either finish their transformation into the type of brain cell that is lacking (in the case of the partially differentiated cells) or participate in repair directly (for the fully differentiated cells).

The Stanford Stroke Center is concentrating on the signalling that helps a transplanted cell to survive and get to the area of damage. According to the investigators, "signals from the damaged cells act as a distress call beckoning the transplanted cells." Subsequent signals help the stem cells differentiate into neurons and the other cells that support brain function once they arrive where they are needed.

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Looking to the Future

Clinical trials are underway to test both the endogenous and exogenous approaches. But there are ethical issues to consider with exogenous repair - the most immediate being that fetal stem cells (from aborted fetuses) are the starting point for much of the current research. Stanford researchers Gary Steinberg and Irving Weissman are working through their company Stem Cell Inc to isolate stem cells from fetal tissue and generate a supply of these cells for use in research into many brain disorders, including stroke.

Stem Cell Therapeutics is a Canadian biotechnology company devoted to using the patient's own stem cells to treat central nervous system diseases. Following success with early trials in the US and Canada, they are expanding their testing of two approved drugs to the treatment of stroke. The first drug in this regimen will increase the number of neural stem cells (NSCs) in the brain of a patient suffering from stroke. The second drug stimulates these new NSCs to become neurons, thus replacing brain cells that were lost or damaged.

In 2009 a UK company called ReNeuron, while failing to achieve FDA approval, achieved UK approval to initiate early clinical trials in Glasgow, Scotland. They will treat patients using a therapeutic dose (about 20 millions cells) of genetically-modified human embryonic stem cells (derived from an aborted fetus). They claim that these cells will not so much replace lost cells as “activate repair pathways” to stimulate new blood vessels and brain cells. This is, in effect, a blending of the two approaches – artificially stimulating the brain through cell transplantation to repair itself.

A recent animal study at Tulane University suggests a similar paradigm shift – that injected stem cells may play a more crucial role in limiting damage than in replacing lost cells. Mice whose blood supply to the brain had been cut off were injected with human mesenchymal stem cells (hMSCs). Usually, when the blood supply is cut off, cells panic, triggering the immune system to go into “overdrive” and produce an immune response (i.e., inflammation) which damages healthy tissue. In this study, MSCs acted like anti-inflammatory agents, reducing damage to nerve cells by 60% by communicating with the mouse cells to calm down and call off the attack on the healthy tissue. Researchers noted that this “dramatic crosstalk” between mouse and human cells was very surprising. They believe the findings may be relevant to other diseases where brain inflammation is involved, such as Parkinson’s and Alzheimer’s.

At the same time, a new technique for replacing lost brain tissue with stem cells was devised by researchers at the University of Nottingham (UK) in 2009. After a stroke, the dead tissue is removed by the immune system leaving a hole. In this study, a tiny biodegradable scaffold full of stem cells was inserted into the holes. Cells multiplied around the scaffold creating new tissue, blood vessels and fibres rather than dispersing into surrounding areas. The researchers found it only took 7 days to fill the holes with new tissue when the cells had a structure to cling to.

These studies suggest that stem cells may help in several different ways to treat stroke. What is clear is that we now know enough to begin to use stem cells to reverse the damage done by stroke, although it will be some time before these therapies are routinely available.

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Canada

According to the Canadian Stroke Network, stroke afflicts one Canadian every 10 minutes. This statistic has prompted an aggressive strategy of research, education, prevention and treatment which includes the efforts of the Canadian Stroke Network, the Heart and Stroke Foundation and the Stem Cell Network.

Canadian stem cell therapy for stroke has focused on adult stem cells as alternative sources for neural progenitor cells. Human skin (most recently neonatal foreskin), muscle cells, bone marrow cells, fat cells (or adipose tissue), cells in the lining of the nose and intestines have all demonstrated the capacity to make neural cells. In the case of skin and olfactory (from the nose) stem cells, the ability to make neural cells is something that they actually did during embryonic development and that they retain the ability to do in the adult. In the case of bone marrow or fat cells, their apparent ability to make nerve cells is called plasticity, a term used to describe something that these cells normally do not do, but can be induced to do in the right conditions.

Dr Freda Miller, at the University of Toronto, has discovered how to isolate skin-derived precursor cells (SKPs) that come from the same “niche” in the developing embryo that neural cells are derived from. These cells can differentiate into several kinds of neural cells, including Schwann cells which play an important role in many nervous system diseases. When her team tried transplanting SKPs found in human skin into laboratory animals that modeled the damage caused by stroke, these cells were able to become Schwann cells. They have recently used this same strategy to enhance recovery following spinal cord injury. This research is also complementing discoveries that use stem cells to treat Parkinson’s disease and multiple sclerosis – all diseases requiring neurological repair.

Dr Samuel Weiss at the University of Calgary, who first discovered adult brain stem cells nearly a decade ago, is involved in clinical trials to test the safety of a new drug regimen that appears to prompt the brain to regenerate neurons and restore motor function. He has demonstrated that adult neural stem cells are active throughout life and can generate all three kinds of brain cells – leading to the possibility that transplantation of neural stem cells can provide all the necessary cells to repair neurological damage.

Both endogenous and exogenous approaches are being pursued, and significant funding and collaboration in the area of stroke is part of the Canadian Stroke Strategy.

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Links

General Information

Canadian Stroke Network
Canadian Stroke Strategy
Heart and Stroke Foundation
National Institute of Neurological Disorders and Stroke
American Stroke Association

Research

Stem Cell Network

www.bioscienceworld.ca/ANewApproachtoStrokeTreatment

Borlongan, CV and Hess, DC, New hope for stroke patients: mobilization of endogenous stem cells, CMAJ, 174(7), p 954.

Clinical Trials

Stem Cell Therapeutics

Articles of Interest

Regenerative Medicine. Department of Health and Human Services. August 2006. Chapter 3: Repairing the Nervous System with Stem Cells

Scientific American (9/16/08): “Can Stem Cells Block Stroke Damage: Yes, but in a surprising way

“Stem Cell Repair Kit for Stroke” MIT Technology Review, 3/9/09


GLOSSARY

endogenous repair
Stimulating stem cells that normally reside in the body to help repair damaged organs or tissue. Endogenous repair is sometimes called “in vivo stimulation.”

exogenous repair
Stem cells can be cultivated in vitro (in a petri dish or laboratory culture) to multiply almost indefinitely. When these cells are harvested and transplanted into living tissue, they gravitate to the site of injury and replicate the cell that is needed.

hemorrhagic stroke
A stroke that results from a burst blood vessel.

in vitro

Experimentation in a laboratory culture or petri dish, rather than in a living organism.

in vivo
Experimentation done on living tissue rather than in a controlled environment. Both clinical trials and animal research are forms of in vivo research.

ischemic stroke
A stroke that results from a blood clot or blocked artery.

mesenchymal stem cell (MSC)
Stem cells that are responsible for the early development of the skeleton, muscles, joints, cartilage, fat cells and other tissue. A small population of adult MSCs reside in the bone marrow and are responsible for producing mesenchymal progenitor cells, which spawn replacement cells for damaged tissue.

plasticity
The ability of stem cells in one adult tissue to generate cell types of another tissue. Adult stem cells appear to have considerable plasticity under certain conditions, which makes them useful for cellular therapy.