The heart: our first organ
About 7 million people around the world have a heart attack each year and heart diseases are the most common cause of death in Europe. A serious heart attack leaves behind damage that the body can never fully repair. Why can’t the human heart heal itself, whilst some other parts of the body like the skin or blood are constantly renewed and repaired? Could stem cell research give us new ways to mend broken hearts?
Heart attacks cause damage to the heart that is never fully repaired.
Contrary to previous thoughts, research shows that heart muscle cells (cardiomyocytes) are slowly made and replaced throughout our life. This process grows slower as we age and is much too slow to repair damage from a heart attack.
Researchers can make cardiomyocytes and pacemaker cells in the lab using embryonic stem cells and induced pluripotent stem cells (iPSCs). Although researchers are hopeful that stem cells may be used to repair heart damage, there are currently no proven stem cell treatments.
It is not known how new cardiomyocytes are made. Some researchers have suggested that there are heart stem cells, but more data is needed to confirm this.
Scientists are also very interested in understanding how hearts in other animals regenerate. This could lead to discoveries that unlock the ability of the human heart to repair itself.
There is ongoing research to find ways to stimulate cells in the heart to multiply and repair damage to the heart naturally.
Studies are being conducted to make cardiomyocytes in the lab that are uniform, predictable and safe for use in transplants.
Medical treatments that affect the heart carry significant risks because the heart is critical for life.
Using pluripotent stem cells, such as iPSCs, to make cardiomyocytes for transplantation requires methods to certify that all the cells are truly cardiomyocytes. If pluripotent cells are accidentally transplanted they could cause cancerous tumours, generate unwanted types of cells or cause other complications.
If cardiomyocytes are correctly made for transplant, an additional complication is making sure that they beat at the same rate as the heart's original cardiomyocytes.
The heart is the first organ to form during development of the body. When an embryo is made up of only a very few cells, each cell can get the nutrients it needs directly from its surroundings. But as the cells divide and multiply to form a growing ball, it soon becomes impossible for nutrients to reach all the cells efficiently without help. The cells also produce waste that they need to get rid of. So the blood and circulatory system, powered by the heart, together form the first organ system to develop. They are essential to carry nutrients and waste around the embryo to keep its cells alive.
Throughout our lives, the heart continues carrying out the vital job of pumping blood around our body. But vast numbers of patients suffer from diseases that impair the heart’s ability to do its job. Once damaged, the adult human heart cannot completely heal. This has led scientists to search for ways to replace damaged cells in the heart. They are looking for an alternative to the only replacement therapy available for heart disease today – heart transplantation.
In the early 2000s, research suggested that cells from the bone marrow might help repair the heart. Mouse bone marrow cells were transplanted into mice that were made to have a heart attack, or myocardial infarction. The results suggested that bone marrow cells could form new heart muscle cells called cardiomyocytes (something that has since been proven wrong). Not surprisingly, the potential for a possible new solution to the enormous problem of heart disease meant these early findings were translated rapidly into clinical trials in humans.
The results from these clinical trials have been mixed: some have shown small improvements in the hearts of patients treated with bone marrow cells, while others found no improvement. The methods used to measure how well the heart is working have differed from one study to the next. While some studies have used modern state-of-the-art imaging technologies to evaluate how much blood the heart is pumping, others have used more old-fashioned imaging techniques based on radiology. These older radiological techniques can sometimes appear to show an increase in heart pumping even if in fact the heart just ‘stiffens’. Overall, even the most successful clinical studies have failed to show an improvement in the heart that is better than using existing medicines.
The original research that suggested mouse bone marrow cells could turn into heart muscle cells (cardiomyocytes) after transplantation has since been proven wrong. The study looked for certain genes in the cells to identify cardiomyocytes in the heart as cells that were thought to have developed from the transplanted bone marrow cells. However, more recent research using different genes to identify the cells has given different results. It is now well established that bone marrow cells do not have the ability to convert into cardiomyocytes when transplanted into the heart. Instead, the bone marrow cells join together (fuse) with the existing cardiomyocytes in the heart. Clinical studies using bone marrow cells have nevertheless continued with the hope that these cells could have other positive effects on the heart.
For some time, scientists believed that the adult heart had no capacity to make new heart muscle cells, or cardiomyocytes, at all. Nuclear bomb tests changed that view. Nuclear bombs were tested above ground from the 1950s until 1963. The explosion of test bombs loaded up the atmosphere with a radioactive type of carbon called C-14. Archaeologists have been using this information for many years to calculate the age of once-living materials based on the amount of C-14 they contain. Biologists have now used this same 'carbon dating' technique to examine the age of cardiomyocytes in living people’s hearts. They have found that on average the cardiomyocytes in an adult human individual are six years younger than the individual themselves. That means that our adult bodies must be making new cardiomyocytes.
Unfortunately, our body's production of new cardiomyocytes declines with age. In the first decades of our lives, about two percent of our cardiomyocytes are replaced every year, but by the time we are in our 70s only a fraction of one percent of the cells are being replaced. In other words, our heart's capacity to make new cardiomyocytes when we need them most, for example when we have a heart attack, is very limited.
The discovery that the adult heart does make new cardiomyocytes, although at a very low rate, has opened up a new field of research and created fresh hope that it may be possible to make a patient’s damaged heart produce new cells to repair itself. Researchers are trying to find out where new cardiomyocytes come from, and to understand how production of these new cells is controlled in the healthy body. Several research groups have suggested that there might be heart stem cells in the adult heart that are making the new cardiomyocytes. However, there is no consensus amongst scientists about the identity of heart stem cells and their existence has not yet been confirmed.
Cardiomyocytes can be made in the lab from stem cells that are not found in the heart:
- Embryonic stem cells can be used to make cardiomyocytes quite easily in the lab, though many challenges remain before these cells could be used in patients.
- Researchers have also made cardiomyocytes from induced pluripotent stem cells (iPS cells), a type of stem cell that can be created in the lab by reprogramming skin cells. Since iPS cells can be made from the patient’s own skin, it may eventually be possible to make heart cells that exactly match the patient and would not be rejected if transplanted back into the body.
However, there are many challenges still to be addressed. For example, any beating heart cells transplanted into a patient's heart would need to beat with the rest of the heart. It is also vital to learn how to obtain ONLY the right cells for transplantation. Both embryonic stem cells and iPS cells are known as pluripotent – they can make all the different types of cell found in the body. Unfortunately, when these very unspecialized cells are transplanted into adult individuals, they tend to form tumours. It is therefore very important to be able to separate the pluripotent stem cells from the specialized cells they can produce, like cardiomyocytes. Only the cardiomyocytes should be transplanted into the patient. One strategy that can be used to pick out cardiomyocytes is to identify a unique combination of proteins that is always found on the surface of the cells, very much like a bar code. Methods like this for selecting a particular type of cell very accurately and reliably are an area of current research.
The future holds many questions and hopes. Will we be able to stimulate the heart to generate new muscle in adult patients without transplanting cells? Will we be able to make cardiomyocytes in the lab and select out specialized subtypes of cells for transplantation, for example pacemaker cells to generate biological pacemakers? How could these transplanted cells be made to work in concert with the patient's heart? To answer these questions and develop new therapies, more research is needed to understand the heart and the mechanisms that control the generation of new heart cells. For example, studies in zebrafish are providing new clues: the adult zebrafish heart has a remarkable capacity to regenerate (or repair). Recent research has also shown that the hearts of newly born mice can regenerate, but they lose this ability as the mouse matures. Current studies are investigating how this change in the ability of the heart to repair itself happens; an improved understanding of this process may eventually reveal new possibilities for treating patients by turning on the heart's own repair mechanisms.
This type of work to develop new cell- or regeneration-based therapies will take time. In the shorter term, researchers hope to use cardiomyocytes grown in the lab to test or identify new medicines for the heart.
Sometimes the arteries that feed into the heart narrow gradually over time, as a result of a cumulative accumulation of an obstruction (made up of fatty, fibrous material). The amount of blood that can flow through the artery, and reach the heart, is reduced. Because blood carries oxygen, the heart is not able to receive the amount of oxygen it needs. Chronic disease often leads to heart attack, when the material at the narrowing of the artery tears and a blood clot forms, suddenly reducing the flow of blood to the heart further.
An acute myocardial infarction (heart attack) occurs when an area of the heart muscle dies or is damaged due to an inadequate supply of oxygen. Most commonly, a blood clot forms in one of the coronary arteries, the blood vessels that supply blood to the heart. This clot prevents blood, and consequently, oxygen from reaching the heart cells in that area, leading to their death.
Until a few years ago, scientists thought that it was impossible to repair a damaged heart. The discovery of possible cardiac (heart) stem cells at the beginning of this century opened up new possibilities to use stem cells to repair hearts that have been injured through heart attacks (acute myocardial infarction) or chronic disease (chronic coronary artery disease). Several early studies in animals suggested that transplanting bone marrow stem cells into injured hearts would indeed partially repair these hearts. Later studies have shown that transplanted bone marrow cells do not produce new heart muscle cells. Research is ongoing to understand exactly what affect the bone marrow cells do have on the heart.
There are many ongoing clinical trials of bone marrow transplants to treat heart disease, particularly heart attacks (acute myocardial infarction). Generally speaking, in these trials patients who have suffered a heart attack are given preparations of their own bone marrow stem cells – these are called autologous transplants. These clinical trials have demonstrated that this treatment is safe and some have recorded small improvements in heart function, but it has not been proven that bone marrow cells have a significant enough positive effect to improve on existing medical approaches. Many scientists feel that the findings of the different studies are not consistent and a lot of questions remain about their clinical relevance and long-term effects of the transplants. Consequently, scientists feel that continued laboratory research is needed, using both animal models and cells grown in the laboratory, in order to progress the development of potential new therapies.
Some of the questions scientists are trying to answer include what source of cells can be used to obtain replacement heart muscle cells. For example, researchers are investigating the possibility of using heart muscle cells grown from embryonic stem cells, or made by 'reprogramming' adult specialised cells. Both techniques produce a mixture of types of cells so it is also critical to develop methods for obtaining pure heart muscle cells from these sources.
Cell images by Stefan Jovinge. Lead image of human heart by Gordon Museum/Wellcome Images. Nuclear testing photo courtesy of National Nuclear Security Administration / Nevada Site Office.