In todays world, cardiovascular disease is one of the major causes of death. Coronary heart disease and myocardial infarction are the most common ones. In coronary heart disease, the coronary artery fails to supply the adequate amount of blood to the heart which is mostly due to stenosis and atherosclerosis. Whereas in myocardial infarction, when it does not lead to sudden death of the person, it manages to damage a large percentage of cardiomyocytes in the heart which then leads to lowering the contractile capacity below the critical level (Hansson et al., 2009). Currently the use of endothelial progenitor cells in the repair of arteries and damaged parts of the heart has been a very interesting topic of research.
Percutaneous Coronary Intervention (PCI) is the most common treatment for coronary heart diseases. In this stents are most commonly used to open up narrowed arteries for the movement of blood. But the major drawback of this method is restenosis where after about a couple of months of the treatment the narrowing of the arteries is observed again. Multiple trials with Drug Eluting Stents (DES) have shown that they have the potential to highly reduce restenosis but compared to Bare Metal Stents (BMS) the long term prognosis is not improved. DES inhibits the differentiation and movement of the endothelial and smooth muscle progenitor cells which then reduces restenosis and even restricts reendothelialization thus leading to late stent thrombosis (Inoue T et al, 2009).
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This then led to the production of Genous EPC (endothelial progenitor cells) capture stent coated with human CD34 antibodies. These antibodies could capture circulating EPCs. But the drawback of these stents was that CD34 as an antigen was seen to bind to many other cells and not just stem cells. Data from HEALING IIB study in patients with simple lesions and GENIUS-STEMI trial in patients with stent thrombosis elevation myocardial infarction (STEMI) have questioned the potential of the EPC capture stent technology (Garg et al., 2010).
A type of capture stent which binds the EPCs
Current work going on in the lab of Sheila Francis is one of the approaches of pro-healing alternative where they want to produce a pro-healing stent. This work is focused on the use of hTEC cells coated stents. hTEC is human trophoblast derived endovascular cells. These cells are derived from embryonic stem cells (ESCs). They are endothelial in nature and grow in tube like structures as well as express endothelial cell adhesion molecules. The cells are coated on a metal stent in the Heat Robinson system by putting the stents in freezing down tubes along with the cells and incubating them on a rotator. These stents were then ready to be implanted in the artery. A large amount of the inoculum was used for the stents to ensure enough number of cells being retained after the implantation. This method is still in a growing process and current work is going on where these stents have been implanted into pig. After few weeks of the implantation, multiple lesions were seen which were not very pleasant. When checked earlier these cells were found to be non-immunogenic, but the lesions could be the result of immunoreaction as a result of anti-species rejection of the implant which the pig body would have detected at a later stage.
Further work using pig stem cells and then implanting the stent back into the pig heart would be helpful in concluding this matter. Another way to check the cause of the lesions could be to use a small amount of the inoculated cells and see if that reduces the number of lesion. In the presence of a small number of cells initially, the growth factors would encourage the cells to proliferate and these cells might mimic the characters of the cells surrounding them and thus this might even prevent any immunogenic reaction.
The stents seeded with the hTEC can be loaded with VEGF (vascular endothelial growth factor) and some pro-angiogenic factors along with a very small inoculum. This approach might help in having a better outcome as the use of both the cells and the drug might give out a positive result as this technique is still in a growing state.
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After the myocardial infarction, a large number of cardiomyocytes are damaged. These then form the terminally differentiated cells and thus lose their cardiac function and results in heart failure. Currently the most common cure is the entire organ transplant but it is limited to the donors and immune rejection. An alternative to the heart transplant is the replacement of the damaged cardiomyocytes with the new cardiomyocytes (Xu et al., 2011).
The adult heart lacks the capacity to regenerate and thus cell therapy has proved to be a potential treatment after myocardial infarction. A recent work done in mice has shown the direct reprogramming of skin and cardiac fibroblasts into cardiomyocyte-like cells with the help of three transcription factors namely Gata4, Mef2c and Tbx5 (Harvey et al.,2010).
Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are a renewable source for cardiac cells. Cardiac progenitors can be obtained from differentiating ES cells and iPS cells and they are multipotent in nature. iPS cells are made by using somatic cells from the patient thus preventing an immune rejection as the transplant will be autologous to the patient. So the iPS cells are more advantageous than the ES cells as it even saves the trouble of all the ethical issues associated with the ES cells (Xu et al., 2011).
Fig.1: Adapted from Xu H., et al, 2011
iPS cells generated from fibroblasts via pluripotent reprogramming, iPS cells and ES cells induced to differentiate into cardiac lineage in a stepwise manner, ventricular progenitor cells derived from multipotent cardiovascular progenitor cell population used as a source of ventricular myocytes applied for disease modelling and cell based therapies, b. Wnt/Î²-catenin positively control the self-renewal capacity of the Islte1+multipotent cardiovascular progenitor cells. c. progenitor reprogramming. Cardiomyocytes, atrial myocytes obtained by reprogramming towards cardiomyogenesis, d. Direct reprogramming. Generating cardiomyocyte like cells directly from fibroblasts by the overexpression of major cardiogenic transcription factors.
Another approach in curing this condition is to transplant bone marrow stem cells which were then thought to have trans differentiated into cardiomyocytes. There is currently no consensus on whether the bone marrow cells on transplantation have the potential to trans differentiate into the cardiac lineage (Hansson et al., 2009). Several other studies using animal model have suggested that the bone marrow stem cells transplanted into the heart partially repairs the damaged heart. In this process fractionated bone marrow cells are injected into the heart which is autologous for the patient and thus stops any immune rejection to occur. This method is safe and has shown improvement but the findings are not consistent and thus more laboratory trials need to be done on animal models and cell cultures before moving onto further clinical trials.
Even though this type of cell therapy appears safe, but it is a matter of concern where the cells end up after 20 years. These cells have a very mild potential to proliferate. There are many things that are yet to be looked at if this method is to be used clinically as a major treatment for patients who have undergone a myocardial infarction. Things like:
Exactly which specific cells in the bone marrow are forming the cardiomyocytes?
Whether the bone marrow stem cells are actually differentiating into cardiomyocytes and whether they survive for a long time or do they have a specific duration of survival.
What is the optimal delivery system of the cells, direct injection into the heart or into the coronary artery?
Since the blood flow in the artery is heavy, the cells might not reach the ventricle and end up everywhere else except the required location. So because of this reason, a proper delivery method should be figured out.
Do these cells stop the remaining cells of the heart from dying?
As we know that the heart contains its cardiac progenitor cells which are mostly in a quiescent state. It is a possibility that when the bone marrow cells are injected into the heart, they trigger the activation of these quiescent progenitor cells which then come out of their niche and take part in the repair and regeneration of the heart muscles by further proliferation. These cells might even release some substances that would stimulate the existing heart cells to divide and replace the dead cells.
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Heart transplant is a direct cure to this problem but it is limited due to the need of specific donor and the surgery is a long process, whereas if this method is well developed then injecting a few cells would not take that much of time and the person would be free of any immune reactions, thus making the treatment easy and less time consuming. Even though the mechanism of these cells is still not known, the trials should not be stopped just because of this one single reason. It should be continued with a strong parallel work going on to find the exact mechanism of these cells so that once known it can then be launched as the major treatment for repairing the heart after myocardial infarction.