Stems cells induced into cardiomyocytes integrate into damaged hearts. Credit: H. B. McDonald, BioSerendipity, LLC. Read more

Promising Research into Restoring Heart Function with Stem Cells

Studies with macaques show integration and electrical coupling of stem cell-derived heart muscle cells into damaged hearts.

Heart muscle has limited ability to regenerate. This is why heart attacks cause permanent heart damage. A goal in cardiovascular medicine is to induce healing rather than scarring, especially in patients with large areas of heart damage that compromise heart function. One strategy under investigation is injecting immature heart muscle cells, called cardiomyocytes, into the injured area.

Cardiomyocytes can be produced in culture now. These young heart muscle cells can be generated from either embryonic stem cells (ESCs) or from inducible pluripotent stem cells (iPSCs). Success using these cells in animal models has brought this strategy into clinical trials.

ESCs can form all of the cells of the body. This property is called pluripotency. Under highly controlled culture conditions, ESCs can divide and make more of the same pluripotent cells, or they can turn into any other type of cell and divide to make more of those specific, differentiated cells. The other kind of pluripotent cell is generated by engineering adult cells to become less differentiated and gain the ability to produce other cell types, that is become pluripotent. These adult cells that have been converted into pluripotent cells are the iPSCs. In culture, both ESCs and iPSCs can be made to differentiate into many kinds of cells. Three studies with macaque monkeys suggest that these two kinds of stem cells when converted into cardiomyocytes can be used to repair damaged hearts.

Macaque Study 1

In 2014, Murry and colleagues stimulated human ESCs to form cardiomyocytes in culture, expanded the cells and froze the cells. After causing heart damage in the macaques’ hearts by blocking a blood vessel (an experimentally induced “heart attack”), the researchers thawed and injected the cells into the animals. The human cardiomyocytes were injected directly into the damaged area 2 weeks after the heart attack. The animals had to receive immunosuppressive drugs so that they did not reject the injected human cells.

In this 2014 study, the damage to the heart was relatively small, but the results were impressive. In the one animal studied for 3 months, the human cardiomyocytes had integrated into the damaged area, the cells appeared to be maturing from the embryonic to the adult state, and blood vessels were growing into the area where the human cells had integrated.

Encouragingly, analysis of electrical properties of the hearts showed that the human cardiomyocytes had electrically coupled to the monkey heart cells. Discouragingly, the animals receiving the human cardiomyocytes developed irregular, abnormal heart rhythms (arrhythmias).

This was a very small-scale study with 7 animals. Only one animal that received the human cells was studied for 12 weeks. The others were studied for either 2 or 4 weeks. The main outcomes assessed were whether the injected cells integrated into the hearts and electrically coupled with the macaque heart cells. Both outcomes were positive.

Macaque Study 2

In 2018, Murry and colleagues performed a follow-up study again using human ESCs converted into cardiomyocytes and macaques as the model animal for heart repair. The goals were to determine if the human cardiomyocytes could restore contractile function and to better understand the arrhythmias observed in the previous study.

To measure heart function and contractility, the researchers developed a method for performing cardiac magnetic resonance imaging (MRI) on the monkeys. Among other indicators of heart health, this method enables measurement of left ventricular ejection fraction. Left ventricular ejection fraction measures how much the left ventricle empties with each heart beat and is a key measure of heart function and contractility.

Different from the 2014 study, which involved a relatively small area of damage, this study involved a larger area of damage. Because the cells are human, the animals still required immunosuppressive drugs to prevent rejection of the injected cells. Again, the human cardiomyocytes were injected directly into the damaged area ~2 weeks after the experimentally triggered heart attack. Again, the number of animals in the study was small, so generalizing the results is difficult.

After the induced heart damage, all of the animals had compromised heart function with reduced ability to pump blood. As before, in this second study, the human cells successfully integrated and began to mature from the immature cardiomyocyte state into the adult state. Blood vessels grew into the integrated new tissue. After 3 months, the hearts of the 2 animals receiving the cells had fully recovered pumping ability. In contrast, heart of the control animal continued to decrease in the ability to pump blood.

Electrophysiological properties and arrhythmias were assessed in the 6 animals that received the cardiomyocytes and the 4 control animals. Both groups had increased occurrence of arrhythmias after the induced heart damage, but no statistically significant difference between the groups occurred throughout the duration of the study. Only one animal receiving cells developed severe ventricular arrhythmias.

The difference in the frequency of the occurrence of arrhythmias in this study and the previous one appeared related to the difference in the size of the damage. However, this study suggested that control animals and animals receiving cells developed arrhythmias for different reasons. The control animals had arrhythmias arising from small site of reentry (the electrical activity stimulates the hearts cells in a place too soon), and animals receiving cells had arrhythmias caused by abnormal impulse generation (cells had abnormal pacemaker activity, the ability to set the heart rate).

Macaque Study 3

A 2016 study performed similar experiments with macaques, but these researchers used the other kind of stem cells, iPSCs, instead of human ESCs. The iPSCs were from immunologically matched, not genetically matched, monkeys. Shiba and colleagues isolated fibroblasts, genetically engineered the cells to make iPSCs, and then cultured the cells under conditions that converted them into cardiomyocytes.

Similar to the studies with human ESCs, the cardiomyocytes were expanded, frozen for storage, then thawed before injection into the animals with experimentally induced heart damage. These animals also required immunosuppressive drugs to prevent rejection of the injected cells. The injected cells integrated with the animal’s hearts, formed heart muscle tissue, and became electrically coupled. Blood vessels grew into the new tissue. Thus, cardiomyocytes from iPSCs were just as effective as cardiomyocytes from ESCs in forming new heart tissue.

These researchers used a method called micro-computed tomography (μCT) to measure the heart’s ability to pump. Animals receiving the cells had improved heart function. All 5 animals receiving cells had arrhythmias 14 days after receiving the cells. In some of the animals, the arrhythmias appeared to resolve over time and were not present at 56 or 84 days.

Collectively, these 3 studies present encouraging results. Cardiomyocytes formed from either ESCs or iPSCs were similarly successful in restoring heart function. When introduced into damaged hearts, the cells integrated into the heart, electrically coupled with the existing heart cells, and became vascularized by new blood vessels. In the 2 studies where function was analyzed, the cardiomyocytes improved heart function. In all cases, the occurrence of arrhythmias is worrisome, and the need for immunosuppressive drugs presents a complicating factor.

Human Studies

Where do we stand on the path to repair of the human heart? A search of ClinicalTrials.gov on 4 November 2019 for “Heart Diseases” and “stem cells” produces 360 results. Various strategies for obtaining stem cells or progenitor cells and using them for heart repair have been attempted. Two reviews (Fisher et al. 2015 and Fisher et al. 2016) of the available human data for the use of stem cells in treating chronic ischemic heart disease, congestive heart failure, and acute myocardial infarction indicate that the data as of 2015 and 2016 are not sufficient to conclude that these treatments are effective. As the FDA warns, avoid unregulated clinics offering stem cell therapies. They are more likely to do harm than good. If you are interested in stem cell therapies for the heart or other organs, search for a clinical trial in your area at clinicaltrials.gov.

Highlighted Articles

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Y.-W. Liu, B. Chen, X. Yang, J. A. Fugate, K. A. Kalucki, A. Futakuchi-Tsuchida, L. Couture, K. W. Vogel, C. A. Astley, A. Baldessari, J. Ogle, C. W. Don, Z. L. Steinberg, S. P. Seslar, S. A. Tuck, H. Tsuchida, A. V. Naumova, S. K. Dupras, M. S. Lyu, J. Lee, D. W. Hailey, H. Reinecke, L. Pabon, B. H. Fryer, W. R. MacLellan, R. S. Thies, C. E. Murry, Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hears of no-human primates. Nat. Biotechnol. 36, 597–605 (2018). PubMed

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