Posted on Oct 09, 2020, 2 p.m.
Recovery from experimental heart attacks can be improved with an injection of a mixture of heart muscle cells, endothelial cells and smooth muscle cells, but results are limited by poor engraftment and retention, plus there are concerns about potential tumorigenesis and heart arrhythmia.
Recent animal research in pigs has shown that using the exosomes naturally produced from a mixture of heart muscle cells, endothelial cells, and smooth muscle cells derived from human induced pluripotent stem cells yielded regenerative benefits that were the equivalent to the injected hiPSC-CCs.
Exosomes are membrane-bound extracellular vesicles that contain biologically active proteins, RNAs and microRNAs that are well known to participate in cell to cell communication, and are actively studied as potential clinical therapies for a wide range of conditions.
“The hiPSC-CC exosomes are acellular and, consequently, may enable physicians to exploit the cardioprotective and reparative properties of hiPSC-derived cells while avoiding the complexities associated with tumorigenic risks, cell storage, transportation and immune rejection,” said Ling Gao, Ph.D., and Jianyi “Jay” Zhang, M.D., Ph.D., University of Alabama at Birmingham corresponding authors of the study, published in Science Translational Medicine. “Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury.”
Studies involving large animals are required to identify, characterize and quantify all responses to potential treatments, prior to this study the feasibility of hiPSC-CC exosomes for cariad therapy had only been shown to be effective in mouse models and in vitro work.
The UAB studies involving juvenile pigs with experimental heart attacks had 1 of 3 treatments injected into the damaged myocardium: a mixture of cardiomyocytes, endothelial cells, and smooth muscle cells derived from human induced pluripotent stems cells, exosomes extracted from three cell types, and homogenized fragments from the cell types.
There were 2 primary findings from this study. Measurements of left ventricle function, infarct size, wall stress, cardiac hypertrophy apoptosis and angiogenesis in the animals treated with hiPSC-CCS, hiPSC-cc fragments or hiPSC-cc exosomes were found to be similar and significantly improved compared to those that recovered without any of the 3 treatments. Additionally, exosome therapy was found not to increase the frequency of arrhythmia.
During experiments with cells or aortic rings that were grown in culture, exosomes produced by hiPSC-CCs were found to promote blood vessel growth in cultured endothelial cells and isolated aortic rings. The exosomes also protected the cultured hiPSC-cardiomyocytes from the cytotoxic effect of serum-free lox oxygen media by reducing the programmed apoptosis cell death and by maintaining intracellular calcium homeostasis which had a direct beneficial effect on heart conductivity. Additionally, the exosomes also increased cellular ATP content which is beneficial as deficiencies in cellular ATP metabolism are believed to contribute to the progressive decline in heart function in those with left ventricle hypertrophy and heart failure.
Some of the in vitro beneficial effects were found to also be mediated by synthetic mimics of the 15 most abundant microRNAs that were found in the hiPSC-cc exosomes. It was noted that knowledge of the potential role of microRNAs in clinical application requires more research as it is far from complete.
The study: “Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine,” co-authors with Gao and Zhang are Lu Wang, Yuhua Wei, Prasanna Krishnamurthy, Gregory P. Walcott and Philippe Menasché, UAB Department of Biomedical Engineering. Menasché also has an appointment at the Université de Paris, France. Gao is now at Tongji University School of Medicine, Shanghai, China.
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