Stroke: how could stem cells help?
Stroke is the second leading cause of death worldwide and the major cause of disability in Europe. A stroke happens when the blood supply to part of the brain is severely reduced, often with severe effects on the body. Depending on the extent of stroke and where it occurs, about a third of stroke sufferers recover quite well, but most still experience some permanent effects and some strokes cause severe disability. Could stem cell treatments help?
Severe reductions in blood flow that occur in strokes can seriously damage parts of the brain or could even be fatal.
Anyone of any age can have a stroke, but age, family health history and lifestyles can affect the risk of having a stroke.
The best treatment for someone suffering a stroke is to get treatment as quickly as possible to restore blood flow.
Brain (neural) stem cells can make any cell in the brain and will naturally repair small amounts of brain damage. Researchers hope that neural stem cell treatments might be able to help stroke victims by partially repairing brain damage.
Scientists want to understand the signals controlling neural stem cells in order to design better treatments.
Researchers are working to develop medications that promote neural stem cells already in the brain to multiply, migrate towards damaged areas and start the repair process.
There are limited numbers of neural stem cells in our brains. Although large numbers of neural stem cells can be made in laboratories with iPSCs, these cells could cause tumours and more brain damage if incorrectly made. Further studies must show that lab-made cells are both safe and effective.
Neural stem cell therapies aiming to rebuild parts of the brain will also require rebuilding the vascular system (to supply blood flow) and reforming the intricate and complex networks between nerve cells. Natural repair processes of neural stem cells may be able to do some of this, but researchers will need to learn much more to assist neural stem cells in this rebuilding process.
Strokes damage large areas of the brain. Although therapies and stem cell treatments may help to restore patients’ motor function and repair parts of the brain, severely damaged areas may be permanently destroyed.
A stroke happens when the blood supply to one or more parts of the brain is reduced or completely blocked. The blockage may be temporary or permanent and it can be caused in two different ways:
- In ischaemic stroke a blood clot obstructs the supply of blood to the brain
- In hemorrhagic stroke a blood vessel bursts and bleeds into the brain
All parts of the brain need to have a good blood supply to work properly. When the flow of blood is restricted or stopped, vital nutrients and oxygen cannot reach the cells in the brain and they are damaged or die. The effects on the body depend on which part of the brain is damaged and how long the blockage remains. A stroke can affect movement, speech, thought processes and memory. It can cause paralysis in one or more parts of the body, or loss of control of bodily functions. About 40% of people affected by stroke will have permanent symptoms that result in them needing special care. Many people’s symptoms improve significantly following a stroke, but only about 10% of patients recover fully.
Anyone of any age can have a stroke, but there are some important risk factors. The chance of having a stroke increases with age, for example. Certain ethnic groups are more at risk and a family history of stroke increases the chance that you may be affected. There are also risk factors that we may reduce through lifestyle changes, such as making sure any high blood pressure is treated, eating a healthy diet low in fat and salt, stopping smoking and staying physically active.
Getting treatment from experienced medical professionals quickly is the most important factor for treating stroke. The sooner the blood flow can be restored, the less damage the brain will suffer and the better the chances of a good recovery. Patients who reach hospital within the first 3-4 hours of the onset of a stroke can be given “clot-busting” medication that significantly reduces disability and improves long-term quality of life. So, medical advice is essential if you suspect a stroke. The Stroke Association provides clear advice on how to recognize the symptoms of a stroke and act quickly.
After a stroke, therapies are focused on helping the brain’s undamaged areas to re-learn lost skills such as walking or talking (termed neurorehabilitation). This involves a wide range of professionals, including neurologists, speech therapists, nurses and physiotherapists. In some cases, healthy areas of the brain can learn to take over from those areas that were damaged by the stroke. Unfortunately, severely damaged parts of the brain cannot recover because the body cannot replace the lost brain cells. This is where scientists hope that stem cells may play a role, helping us to find ways to boost the body’s repair systems.
One reason that helping people recover from a stroke can be difficult is that stroke damages many different types of cells in the brain. This means that, if we want to develop a therapy to replace lost or damaged cells, we need to:
- Learn to grow many different kinds of brain cells, or the appropriate type of stem cells to make the brain cells we need
- Show the cells we can grow work properly
- Understand how to enable these cells to organize themselves in same way as inside the healthy brain, recreating complex connections across different areas of the brain and joining the cells up with the brain’s blood supply
These are huge challenges. Scientists have been working for many years on developing potential ‘cell replacement therapies’ for stroke and continue to do so. However, researchers are also examining alternative ways to use stem cells in stroke treatment. For example, stem cell research may be used in the development of new drugs that could stimulate the brain’s own repair mechanisms, including its own stem cells, to make the new cells that are needed for recovery.
The first studies aimed at developing cell replacement treatments for stroke were done using brain cells derived from a type of tumor called a teratocarcinoma. Researchers found that they could use stem cells from the teratocarcinoma to produce neurons (nerve cells of the brain) in the lab. They then transplanted these lab-grown neurons into the brains of rats after a stroke and showed that the transplanted cells were able to integrate into the rats’ brains. This research led to a clinical trial in 2000 to assess the safety of human-teratocarcinoma-derived neurons transplanted into the brain of stroke patients. However, although this initial clinical study suggested that the transplanted cells survived and might even have had some benefits in a very small number of patients, a further study in 2005 failed to find any improvement in patients. The origin of these cells in a tumour, combined with the lack of improvement shown in patients has led researchers to focus on other possible stem cell sources.
Brain stem cells, known as neural stem cells, are one of the main types of stem cell being studied in relation to treating stroke. These stem cells are able to divide and multiply, and to form all the different types of cells in the brain. They can be obtained from fetal tissue and from certain parts of the adult brain, but both these sources provide a very limited number of cells. These cells also have the disadvantage that they are not identical to the patient’s own cells, meaning they might be rejected upon transplantation unless drugs are given to suppress the patient’s immune system. In addition, the use of fetal tissue is the subject of ethical debate, while obtaining neural stem cells from an adult brain requires a major operation and carries significant risks for the donor.
Despite the challenges associated with obtaining neural stem cells, some promising results have been achieved in studies on rodents. This research suggests that when injected into the brain, neural stem cells can move selectively towards damaged areas. Once there, the cells can help replace damaged tissue and encourage the brain’s own repair mechanisms into action by releasing substances that reduce inflammation and improve survival of existing neurons. Transplanting neural stem cells into the brain nevertheless remains a very difficult and long-term challenge.
Other research suggests that an alternative approach may also be useful. There is some evidence that certain chemicals can be used to encourage the neural stem cells that are already in the brain to divide, multiply and move towards damaged areas. This may open up new ways to treat stroke by using medication.
Embryonic stem cells and induced pluripotent stem (iPS) cells have been used to grow neural stem cells in the lab in large numbers. Both embryonic stem cells and iPS cells are pluripotent – they can make all the different types of cells in the body. Learning how to control this process to produce neural stem cells addresses some of the problems faced by researchers looking for a source of cells for treatments. However, the powerful properties of embryonic stem cells and iPS cells also mean they have the ability to form tumors, a risk that must be dealt with before we do clinical trials of potential new treatments in people with stroke.
The first uses of embryonic stem cells in stroke research date back to 2005, when neural stem cells produced from embryonic stem cells were injected into rat brains. The transplanted neural stem cells were seen to produce different types of specialized neurons (nerve cells) inside the brain. In 2006 a research group from Germany demonstrated that neural stem cells made in this way not only survived and made new nerve cells inside the brain, but the neurons they produced could also make connections to existing neurons of the brain. During 2008 and 2009 different research groups demonstrated that transplanted neurons produced from human embryonic stem cells were able to integrate into rat brains after they had undergone an ischemic stroke. The scientists observed an improvement in the movement of the animals after the transplant. Recently, a study led by groups from Sweden and Germany reported similar results in mice and rats using neural stem cells made from human iPS cells.
Despite these promising laboratory results, much more research is needed before it will be possible to consider using embryonic stem cells or iPS cells for stroke treatment in patients. Scientists need to understand precisely how to guide the pluripotent stem cells to produce only the type of neural cell required, to produce methods for transplantation that will be safe and effective and to study the long-term impact of transplants.
Mesenchymal stem cells (MSCs) are one of the most commonly used types of stem cell in clinical trials on stroke to date. They can be easily obtained and grown from a patient’s bone marrow and can produce fat, cartilage and bone cells. Mesenchymal-stem-cell-like cells can also be derived from other sources such umbilical cord and adipose (fatty) tissue, though the exact identity and nature of these cells is still the subject of some scientific debate.
MSCs from bone marrow and cells obtained from adipose tissue have been injected into the brain or into a vein in the leg of rats with stroke-like brain damage. In these studies, animals that received injected cells showed a decrease in the size of the damaged area of the brain compared to animals that were not given an injection. The injected cells appear to move to the damaged area of the brain, but this is not thought to be essential for a beneficial effect since MSCs cannot make new brain cells. Instead, the researchers carrying out such studies think the injected MSCs produce and release substances that reduce inflammation and stimulate self-repair within the brain. More research is needed to understand fully how this might work before effective therapies can be developed.
In 2005 a group of researchers in South Korea reported a clinical trial with five patients who received an injection of MSCs into their brains. After one year, the results suggested that the injection of MSCs was safe but there was no clear evidence that the cells had improved the patients’ condition. The same scientists reported a similar study in 2010 in which a larger number of patients had been given MSCs and studied for the following five years. The results were very similar to the first study. The question therefore remains open as to whether MSCs are able to provide a benefit to stroke patients.
No stem cell therapies are yet available for stroke. Researchers around the world are using different types of stem cells to study how the brain works and to investigate how the damage caused by stroke may one day be repaired. Some early stage clinical trials are underway. These include the PISCES trial bythe UK-based company ReNeuron, which has grown neural stem cells from fetal tissue. In 2012 they reported the results of a very early stage clinical trial to test the safety of injecting these cells into the brains of five patients. None of the five patients experienced any adverse effects. ReNeuron is now applying to the UK government for permission to start a trial with a larger group of patients to investigate whether transplantation of this type of neural stem cell has a beneficial effect. The public clinical trials registry clinicaltrials.gov lists at least a further 25 clinical trials investigating the use of stem cells of one type or another to treat stroke patients. Most of these are taking place in China and the USA, though there are also a small number of trials in Europe.
There are still many open questions about the possible use of stem cells to treat stroke. For example: What is the ideal source of stem cells? How should they be transplanted or can the stem cells already inside the patient’s brain be used? How many cells are needed and what would be the right time to carry out a treatment after stroke? What are the specific conditions needed to grow the right type of cells to high purity and safety standards? Ongoing research aims to answer these and other important questions.
Lead image of a ct scan showing some stroke damage on the left, by Wellcome Images. Additional images of chronic stroke by Wellcome Photo Library, Wellcome Images, of neurons grown from embryonic stem cells by Q-L. Ying & A. Smith, Wellcome Images and of transplanted mouse neural stem cells by Yirui Sun, Wellcome Images.