iPSC Therapy in Myocardial Infarction
Case Study:
Repair of Acute Myocardial Infarction by
Human Stemness Factors Induced Pluripotent Stem Cells
Nelson, T. J., Martinez-Fernandez, A., Yamada, S., Perez-Terzic, C., Ikeda, Y., & Terzic, A. (2009).
Overview
Nelson et al. investigated the ability of iPSC to repair acute myocardial infarction in mice. This research was the first to study the efficacy of the use of fibroblast-derived iPSC for cardiac repair. In this study, mouse embryonic fibroblasts were reprogrammed into iPSC using human stemness factors and the iPSCs were injected directly into the site of infarct. This paper investigated the efficacy of iPSCs by studying cardiac muscle performance, morphology and physiology.
Background
Physiology
Heart is mainly made up of three cell types: cardiomyocytes, cardiac pacemaker cells and endothelial cells. Cardiomyocytes are muscle cells that form the striated cardiac muscle in the heart. It lines the atria and ventricles and is responsible for the beating of the heart through muscle contraction. Cardiac pacemaker cells regulate heart beat by conducting electric signal to sitmulate contration. Lastly, the endothelial cells line the blood vessels that provide nutrient to the muscles.
Myocardial Infarction
Myocardial Infarction (MI), also known as heart attack, is characterized by the blockage in coronary arteries, which are blood vessels that support cardiac muscle function. This blockage is usually due to a blood clot composed of mainly fat deposit. As a result, cardiac muscles cease to receive oxygen and nutrients from the blood and cardiomyocytes deteriorate. Cardiac muscle have very limited ability to self-repair. Instead of regenerating cardiac muscle, scar tissue form at the site of infarction as a means of wound healing, which impedes normal heart functions. Over time, such impairment in heart function leads to many other complications in the heart.
What is myocardial Infarction?
Myocardial infarction is usually acute and causes permanent damage to cardiac muscle within minutes. If not treated quickly, it may be lethal. Therefore, treatments need to be done soon after MI takes place. The most common treatments for MI are angioplasty, stent and blood-thinners. Angioplasty and stents serve to open up the blocked artery and restore blood flow by inflating a balloon and inserting a piece of metal mesh inside the artery to keep the structure. Blood-thinners are taken regularly post-MI in order to prevent blood clot formation. However, none of these treatments actually restore muscle function. Therefore, scientists are conducting active research for treatments that may repair and regenerate the damaged cardiac muscles.
Method and Results
In this research, Nelson et al. harvested embryonic fibroblasts from mouse embryos and exposed them to human transcription factors OCT3/4, Sox2, Klf4 and c-Myc. These were also the four transcription factors from Yamanaka et al.’s experiment. Under the exposure to these factors, mouse embryonic fibroblasts obtained pluripotency and became iPSCs. iPSCs were then cultured in differentiation media in order to generate cardiomyocyte progenitor cells. Mice that underwent MI in the left ventricle received injections of iPSCs at the site of infarction. The efficacy of these iPSCs in cardiac repair was analyzed in terms of muscle morphology and function.
Up to 8 weeks after the injections, no tumor was detected and there was a stable growth of differentiated iPSCs in the mice. iPSC-treated mice showed improvements in cardiac contraction. The contractions were synchronized, as shown in Figure 1. The yellow dotted line indicates the endocardium, or the inner wall and the white dotted line indicates the epicardium, or the outer wall of the left ventricle. In Figure 1a and 1b, we can see that the inner and outer wall moved in sync with each other during diastole (relaxation) and systole (contraction). Proteins associated with cardiomyocyte and endothelial cells such as actin and CD31 were also detected in iPSC-treated hearts, indicating regeneration of cardiac tissue.
Figure 1a (left) and 1b (right): Left ventricle motion during systole and diastole
Figure 2: Comparison of MI treated with fibroblasts (no therapeutic effect) and iPSCs
Besides the restoration of function, iPSCs also stopped the structure of heart from deteriorating and preserved cardiac morphology. Figure 2 compares the MI-affected heart treated with fibroblast (with no therapeutic effect) and the one treated with iPSCs. We can see that in the fibroblast-treated heart, there was evidence of aneurysm, or heart enlargement, causing the heart to dilate and lose its shape. As a result, wall thinning also occurs, as shown at the bottom right, where light penetrate the tissue easily. However, in iPSC-treated heart, there was no sign of heart enlargement or wall thinning, indicating that iPSCs preserved heart morphology.
Conclusion
Preservation of heart morphology and the restoration of cardiac muscle function suggested the efficacy of iPSCs in repairing murine cardiac muscle damage due to myocardial infarction. The expression of cardiac-tissue specific proteins also showed the regeneration of cardiomyoctes and endothelial cells. In conclusion, iPSCs are believed to have therapeutic potential in the repair and regeneration of cardiac muscle, though human models are yet to be tested.
If you would like to read more about iPSC therapies in cardiac diseases, please check out the reference for papers and websites on this topic.
Reference
<http://www.closerlookatstemcells.org/stem-cells-and-medicine/heart-disease>
<https://en.wikipedia.org/wiki/Myocardial_infarction>
https://www.youtube.com/watch?v=3_PYnWVoUzM
Nelson, T. J., Martinez-Fernandez, A., Yamada, S., Perez-Terzic, C., Ikeda, Y., & Terzic, A. (2009). Repair of Acute Myocardial Infarction by Human Stemness Factors Induced Pluripotent Stem Cells. Circulation, 120(5), 408-416. doi:10.1161/circulationaha.109.865154
<http://circ.ahajournals.org/content/120/5/408/tab-figures-data>
Figure 1 and 2 credit to the paper
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