Heart attack recovery aided by injecting heart muscle cells that overexpress cyclin D2

“These results suggest that cyclin D2 cardiomyocyte transplantation is a potential therapeutic strategy for heart attack repair,” said study leader Jianyi “Jay” Zhang, MD, Ph.D., chairman of Biomedical Engineering, a joint division of the UAB School of Medicine and the UAB School of Engineering. Photo credit: UAB

In a large animal study, researchers showed that heart attack recovery was helped by the injection of heart muscle cells derived from human-induced pluripotent stem cell lines (hiPSCs) that overexpress cyclin D2. This study, published in the journal Circulation, used a pig model of myocardial infarction that is more similar in size and physiology to the human heart and therefore has a higher clinical relevance for human diseases when compared to studies in mice.

An ongoing challenge facing bioengineering researchers is the heart’s failure to regenerate muscle tissue after a heart attack kills part of its muscle wall. This dead tissue can put strain on the surrounding muscle and lead to fatal heart enlargement.

Heart experts have therefore tried to create new tissue – by applying a piece of heart muscle cells or injecting heart cells – to replace damaged muscle. Similarly, they tried to stimulate the division of existing heart muscle cells near the damaged area. This latest study, conducted by researchers at the University of Alabama at Birmingham, shows progress on both goals.

After the experimental myocardial infarction, the heart tissue around the infarction site was injected with approximately 30 million engineered human cardiomyocytes, which were distinguished from hiPSCs. These cells also overexpress cyclin D2, which is part of a family of proteins involved in cell division.

Compared to the control of human cardiomyocytes, the cyclin D2 cardiomyocytes showed an increased effectiveness in repairing the heart. They multiplied after the injection, and after four weeks the hearts had less pathogenic enlargement, reduced dead muscle tissue size, and improved cardiac function.

Interestingly, the cyclin D2 cardiomyocytes not only stimulated their own proliferation, but also the proliferation of existing myocardial cells around the infarct site of the pig heart and showed angiogenesis, the development of new blood vessels.

“These results suggest that cyclin D2 cardiomyocyte transplantation is a potential therapeutic strategy for heart attack repair,” said study leader Jianyi “Jay” Zhang, MD, Ph.D., chairman of Biomedical Engineering, a joint division of the UAB School of Medicine and the UAB School of Engineering.

This ability of the graft cyclin D2 cardiomyocytes to stimulate the proliferation of nearby cardiac cells present indicated paracrine signaling, a type of cellular communication in which a cell generates a signal that induces changes in nearby cells.

Exosomes – tiny vesicles or tiny vesicles released by human or animal cells that contain proteins and RNA from the cells that release them – are a common form of paracrine signaling.

Zhang and colleagues found that exosomes that they purified from the cyclin D2 cardiomyocyte growth medium actually promoted the proliferation of cultured cardiomyocytes. In addition, the treated cardiomyocytes were more resistant to programmed cell death, known as apoptosis, which is induced by low oxygen levels. The exosomes also induced the proliferation of various other cell types, including human umbilical vein endothelial cells, human vascular smooth muscle cells, and 7 day old rat cardiomyocytes, which have almost undetectable proliferation.

Part of the cargo that exosomes carry is microRNAs or miRNAs. These short pieces of RNA have the ability to interact with messenger RNA in target cells, and they are robust actors in gene regulation in cells. Humans have more than 2,000 miRNAs with different RNA sequences that are believed to regulate a third of the genes in the genome.

The researchers documented which microRNAs were present in the exosomes of the cyclin D2-overexpressing cardiomyocytes and in the exosomes of non-overexpressing cardiomyocytes. As expected, they found differences.

Together, the exosomes of both cell types contained 1,072 different miRNAs, and 651 were common to the two groups of exosomes. However, 332 miRNAs were found only in the cyclin D2-overexpressing cardiomyocytes, and 89 miRNAs were specific for the non-overexpressing cardiomyocytes. In preliminary work to characterize the effects of specific miRNAs, it was shown that a certain miRNA from cyclin D2-overexpressing exosomes stimulates proliferation when it is released into rat cardiomyocytes.

“As the therapeutic potential of exosomes to improve cardiac function becomes clearer, the combination of exosome-mediated delivery of proliferative miRNAs with the transplantation of cyclin D2-overexpressing cardiomyocytes or cell products could result in a promising new strategy for upregulating the proliferation of recipient cardiomyocytes and Reducing heart fibrosis, “said Zhang. “Overall, our data suggest that cardiac cell therapy with cardiomyocytes with increased proliferative capacity could be an effective future strategy for myocardial repair and prevention of heart failure in patients with acute myocardial infarction.”

Treatment with exosomes improves recovery from heart attacks in a preclinical study

More information:
Meng Zhao et al., Cyclin D2 Overexpression Improves Efficacy of Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Myocardial Repair in a Pig Model of Myocardial Infarction, Circulation (2021). DOI: 10.1161 / CIRCULATIONAHA.120.049497 Provided by the University of Alabama at Birmingham

Quote: Recovering myocardial infarction by injecting cardiac muscle cells that overexpress cyclin D2 (2021, May 14), accessed May 14, 2021 from https://medicalxpress.com/news/2021-05-heart-recovery-aided-muscle- cells.html

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