Jianyi "Jay" Zhang. Photo credit: UAB
Science has long known that recovery from experimental heart attacks is improved by injecting a mixture of heart muscle cells, endothelial cells, and smooth muscle cells. However, results have been limited by poor transplantation and retention, and researchers fear possible tumorigenesis and cardiac arrhythmia.
Research in pigs now shows that the use of the exosomes naturally made from this mixture of heart muscle cells, endothelial cells, and smooth muscle cells, all of which are derived from human-induced pluripotent stem cells, offers regenerative benefits that the injected human-induced pluripotent ones Stem cells correspond. Heart cells or hiPSC-CCs.
Exosomes are membrane-bound extracellular vesicles that contain biologically active proteins, RNAs, and microRNAs. Exosomes are known to be involved in cell-to-cell communication and they are being actively studied as potential clinical therapies.
"The hiPSC-CC exosomes are acellular and thus may enable clinicians to take advantage of the cardioprotective and reparative properties of hiPSC-derived cells while avoiding the complexities associated with tumorigenic risks, cell storage, transport and immune rejection," said Ling Gao, Ph .D. And Jianyi "Jay" Zhang, MD, Ph.D., University of Alabama, Birmingham, co-authors of the study, published in Science Translational Medicine. "Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial repair without increasing the incidence of arrhythmogenic complications and potentially offer an acellular therapeutic option for myocardial injury."
At UAB, Gao was a postdoctoral fellow in biomedical engineering, a joint division of the UAB School of Medicine and the UAB School of Engineering. Zhang is the chairman of the department.
Large animal studies are needed to identify, characterize, and quantify responses to potential treatments. Before this current study, the feasibility of hiPSC-CC exosomes for cardiac therapy was only shown in mouse models and in vitro work.
In the UAB experiments, young pigs with experimental myocardial infarction were injected into the damaged myocardium with one of three treatments: 1) a mixture of cardiomyocytes, endothelial cells, and smooth muscle cells derived from human-induced pluripotent stem cells, 2) exosomes extracted from the three were cell types or 3) homogenized fragments from the three cell types.
The researchers had two primary results from the pig studies. First, they found that measurements of left ventricle function, infarct size, wall loading, cardiac hypertrophy, apoptosis, and angiogenesis in animals treated with hiPSC-CCs, hiPSC-CC fragments, or hiPSC-CC exosomes , were similar and significantly improved compared with animals that recovered without any of the three experimental treatments. Second, they found that exosome therapy did not increase the incidence of arrhythmias.
In experiments with cells or aortic rings grown in culture, they found that exosomes produced by hiPSC-CCs promoted blood vessel growth in cultured endothelial cells and isolated aortic rings. In addition, the exosomes protected cultured hiPSC cardiomyocytes from the cytotoxic effects of serum-free, deoxygenated media by reducing programmed cell death called apoptosis and by maintaining intracellular calcium homeostasis, which has a direct beneficial effect on cardiac conductivity. The exosomes also increased cellular ATP levels, which is beneficial as deficits in cellular ATP metabolism are believed to contribute to the progressive decline in cardiac function in patients with left ventricular hypertrophy and heart failure.
The researchers also found that some of these beneficial in vitro effects can also be mediated through synthetic mimics of the 15 most abundant microRNAs in the hiPSC-CC exosomes. The researchers found that knowledge of the possible role of microRNAs in clinical applications is far from complete.
Heart muscle patches made with human cells improve recovery from heart attack
Ling Gao et al., Exosomes Secreted by hiPSC-Derived Heart Cells Improve Myocardial Infarction Recovery in Pigs, Science Translational Medicine (2020). DOI: 10.1126 / scitranslmed.aay1318
University of Alabama at Birmingham
Treatment with exosomes improves recovery from heart attacks in a preclinical study (2020, September 29).
accessed on September 30, 2020
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