The heart: our first organ
Heart diseases are the most common cause of death in Europe, and about 7 million people around the world have a heart attack each year. 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 in the heart. Some researchers have suggested that there are heart stem cells but this has recently been shown to be most unlikely.
Scientists are also very interested in understanding how hearts in other animals, like fish or newborn mice, 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.
Researchers are developing methods to make large numbers of 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.
It’s still uncertain how to make lab-made cardiomyocytes for transplantation grow to be fully mature, efficiently integrate into damaged areas of the heart or 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. Thus, the first organ system to develop is the heart, blood and circulatory system, so that nutrients and waste can be transported throughout the growing embryo. The heart continues carrying out this same vital job throughout our lives.
When the heart can’t do its job, people’s lives are at risk. The World Health Organisation states that more people die from heart diseases every year than from any other cause. In 2015, an estimated 31% of all deaths worldwide were due to heart diseases – that’s roughly 17.7 million people.
Once damaged, the adult human heart cannot heal itself like other organs in the body. The only current treatment for a seriously failing heart today is a heart transplant. However, scientists are researching ways that stem cells might help treat heart diseases in the future by repairing or replacing damaged heart cells.
For some time, scientists believed that the adult heart had no capacity to make new heart muscle cells (cardiomyocytes). Believe it or not, nuclear weapon tests from the 1950s and 1960s gave researchers a way to study how fast heart cells are replaced. Nuclear tests created large amounts of a special type of carbon called C-14 in the earth’s atmosphere. Archaeologists regularly use C-14 to calculate the age of once-living materials based on the amount of C-14 they contain, a process called ‘carbon-dating’. Methods for carbon-dating have gotten so accurate that biologists have used this method to determine how old cells are in people that lived through the surge of C-14 generated from nuclear tests. They found that the average age of cardiomyocytes in an adult’s heart are about six years younger than the individual the heart comes from. This means that our adult bodies must be making new cardiomyocytes, just very slowly.
This discovery has created a new field of research to determine where these new cardiomyocytes come from, what biological signals control their production and how this process might be used to treat heart diseases. It now seems most likely that cardiomyocytes themselves can divide to make more cardiomyocytes. If we could somehow enhance this process, we might be able to replace those lost to damage from heart attacks.
Unfortunately, it’s also been shown that our body's production of new cardiomyocytes declines with age. In the first decades of our lives, about two per cent of our cardiomyocytes are replaced every year, but by the time we are in our seventies only a fraction of one per cent of the cells are being replaced.
Clinical trials between 2000 and 2016 have generally focused on using several types of cells, including bone marrow-derived mononuclear cells (BMMCs), hematopoietic stem cells (HSCs), cardiac stem cells (CSCs), and mesenchymal stromal cells (MSCs). It is important to realise that these various cell types come from different sources, have different properties and don’t all behave the same way.
- BMMCs are a mixture of cell types that are taken from bone marrow. These can include white blood cells, progenitor cells that form blood cells or bone/cartilage, MSCs and HSCs. It should be noted that the vast majority of cells in a BMMC sample will be white blood cells and progenitor cells that do not have stem cell properties.
- HSCs are the cells responsible for generating all new blood cells (both red and white cells).
- CSCs were thought to be stem cells found in the heart that could form cardiomyocytes. Although some researchers have reported finding and isolating cells capable of making new cardiomyocytes both in a laboratory dish and in living animal models, others have found it difficult to reproduce these experiments and they have largely been abandoned.
- MSCs are another type of cell sometimes used in cell therapies, but their identity is somewhat controversial. They are also commonly referred to as mesenchymal stem cells (also denoted as ‘MSCs’), though this terminology is being phased out. Research has not proven that MSCs actually have all the properties of true stem cells when in the body. Generally, MSCs are a broad group of progenitor cells that are able to make bone, fat (adipose) and cartilage tissues. MSCs have been isolated from fat, bone marrow, umbilical cord blood, and muscle. However, there is ongoing debate among researchers if the MSCs obtained from these different tissues are really the same. Again, there is not yet a consensus to the precise combination of protein markers that define MSCs.
A number of clinical trials have occurred since 2000 to examine safety and effectiveness of various cell therapies for heart diseases. These trials have reported a mixture of results. Many times it can be difficult, even for researchers, to understand results that are observed in trials, particularly if a trial has a small number of participants. Generally, many early clinical studies that showed encouraging results used small patient groups and may have used methods that are not as accurate as more modern methods. When these smaller studies were followed by larger randomised and controlled clinical trials, most outcomes showed treatments provided patients with little improvement, if any at all. Overall, even the most successful clinical studies have failed to show an improvement in the heart that is better than using existing medicines.
It is now well established that cells isolated from bone marrow 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, such as BMMCs and HSCs, have nevertheless continued with the hope that these cells could have other positive effects on the heart.
Clinical studies may not have yielded a proven therapeutic approach, but they have shown that several cell treatment methods are safe. They have also allowed researchers to learn why cell therapies for the heart currently don’t work very well. The largest problem appears to be that cells applied in treatments do not stay in the damaged areas of the heart. This is because the cells don’t survive and/or integrate with the heart tissue. Researchers are currently trying to address these issues to improve the chances for successful cell therapies. Unfortunately, individuals should be aware that the field of research examining stem-cell-based heart treatments has had a large number of published results retracted because data was manipulated to support positive conclusions and outcomes.
Basic research: There are many laboratories and clinics studying a wide range of topics about the heart and stem cells. Many of these laboratories study areas considered ‘basic research’, which means that their investigations teach scientists about how the heart, heart cells and stem cells function, but may not directly result in new therapies. However, this basic research is essential for creating the foundation of knowledge needed to propose and develop new treatments.
Therapeutic research: Developing therapies for diseases of the heart and damage to heart tissue begins with studies on cells and animals to test the effectiveness and safety of new ideas for treatments. Lots of laboratory evidence must be collected before a clinical trial may be conducted on people. Clinical trials test whether a new treatment is safe, effective and better than what is already available. There are many clinical trials in progress to examine stem cell treatment of the heart, some more notable ones are briefly described below. A more comprehensive list of studies investigating stem cells to treat the heart can be found at clinicaltrials.gov. (Please note that this public website only lists clinical trials. It does not check if the listed clinical trials are safe, scientifically sound or carried out by reputable institutions.)
Results of ESCs for heart failure show that clinical grade human ESCs can be used to clinical-grade cardiovascular progenitor cells that are safe for transplantation (clincaltrials.gov | NCT02057900)
Bone Marrow-derived Mononuclear Cells(BM-MNC) heart (clincaltrials.gov | NCT01569178)
COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial. NCT01167751).
Embryonic stem cells and induced pluripotent stem cells (iPS cells) are both used to grow heart stem cells (cardiac stem cells, CSCs) and heart muscle cells (cardiomyocytes) in laboratories. Researchers have found multiple methods to make cardiomyocytes and these processes are constantly being modified and adjusted to make better quality cells. There have been several recent and exciting advances in this area. One group of researchers have reported using growing conditions with three specific components to make high quality cardiomyocytes from human iPS cells. Several groups have developed systems to grow large numbers of cardiomyocytes at the same time. Having large numbers of cells will be essential for treating patients because it is estimated that treatments for heart attacks will likely require ~1,000,000,000 cells per patient. Other researchers have been advancing methods to make CSCs. The idea behind making CSCs is that when these cells are transplanted they will make all the cardiomyocytes and other cell types needed to repair the heart.
While the advances in growing cardiomyocytes and CSCs are promising steps towards cell-based treatments, there is still lots of work to be done. Researchers have noticed that the cardiomyocytes grown in labs don’t yet fully mature into functioning heart muscle, although recent research has shown ways in which this might be achieved. Determining how to grow cells that are fully functional will be critical to developing cell-based regenerative medicines.
Several other challenges to using lab-grown heart cells for medical treatments are also being addressed. For example, any beating heart cells transplanted into a patient's heart would need to beat with the rest of the heart. Another challenge in creating cell-based treatments is getting lab-made cells to integrate and survive in the damaged parts of the heart. Most studies show only a small number of cells survive after cell transplants, but some new methods have been developed in various laboratories to encourage the cells to make larger patches of new heart muscle. It is also vital to learn how to obtain ONLY the right cells for transplantation. Both embryonic stem cells and iPS cells are pluripotent, meaning they can make all the different types of cell found in the body. Unfortunately, pluripotent cells also have the potential to grow into cancerous tumours if they are not restricted. It is very important to create procedures to separate pluripotent stem cells from CSCs and cardiomyocytes before cells are used for transplantation.
The future holds many questions and hopes. Will we be able to make high-quality and mature cardiomyocytes in the lab for transplantation? How will we make sure that transplanted cells correctly integrate and survive in only the damaged heart? Will we be able to ensure that transplanted cells work in concert with heart muscle still there? One day, will we be able to stimulate the heart to regenerate itself without transplanting cells? More research is needed to answer these and other questions that will aid development of new therapies.
By better understanding the development, function and repair of the heart we may also learn how to promote the heart to heal itself. Researchers are learning clues about how biology naturally repairs and regenerates the heart in other animals. Zebrafish have a remarkable ability to regenerate their hearts if they are damaged. Also, the hearts of newborn mice can regenerate, but mice lose this ability as they mature. Current studies are investigating how biology is able to naturally regenerate the heart in these animals as well as others. Understanding regeneration in other animals may reveal how to make better cardiomyocytes for transplantation or it could lead to discovering how to turn on natural repair mechanisms in the human heart. 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, arteries that feed into the heart gradually narrow over time. This is caused by the accumulation of obstructing material (typically fatty, fibrous material). Narrowing of arteries reduces blood flow to the heart. Because blood carries oxygen, less blood flow means that the heart receives less oxygen to work. Chronic coronary artery disease often leads to heart attack when the material at the narrowing of the artery tears and a blood clot forms, which can fully block blood flow to parts of the heart.
The heart, like all muscles, needs oxygen to work. The blood pumped by the heart carries oxygen throughout the body, including to the heart itself. An acute myocardial infarction (heart attack) occurs when heart muscle cells (cardiomyocytes) die or are damaged due to a lack of oxygen. The most common form of heart attack occurs when a blood clot forms in one of the coronary arteries, which supply blood to the heart. This clot blocks blood from reaching areas of the heart, causing cardiomyocytes to die in those areas.
Until a few years ago, scientists thought that it was impossible to repair a damaged heart. Studies suggesting that cardiac (heart) cells may be able to divide in heart muscle itself has led to new ideas for how stem cells might be used to repair injured heart muscle. This will hopefully also lead to new treatments for individuals who have suffered from a heart attack (acute myocardial infarction) or chronic coronary artery disease. Currently there are no proven stem cell treatments for any type of heart disease. Although several early studies suggested that transplanting bone marrow stem cells might help repair damaged hearts, later studies have not supported this. Researchers are also investigating the use of other types of stem cells for treating the heart, such as embryonic stem cells and induced pluripotent stem cells (iPS cells). There are many clinical trials currently using stem cells of different kinds to treat heart disease. Please note that just because a treatment is offered through a ‘listed’ clinical trial does not mean that treatment will work or that it is safe. Most listed clinical trials are using bone-marrow-derived stem cells and methods that have not been proven to work. There have been cases where individuals have been hurt by unproven stem cell treatments. Many questions remain about the clinical relevance and long-term effects of transplants being offered. Scientists generally feel that continued laboratory research is needed to develop new therapies that are safe and effective.
Interview with Christine Mummery: A physicist's take on stem cell biology
Fact sheet on Regeneration: what does it mean and how does it work?
How carbon dating works from How Stuff Works
Heart Hub, from the American Heart Association
National Heart Lung and Blood Institute, National Institutes of Health, USA
World Health Organization (WHO) page on cardiovascular diseases
This factsheet was created by Stefan Jovinge, coordinator or the EC funded project CardioCell.
Reviewed in 2015 by Christine Mummery.
Edited and updated in 2018 by Ryan Lewis.
Reviewed in 2019 by Christine Mummery.
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.