Credit: Reprinted from Liu, B. et al. Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-018-0229-7 (2018), Macmillan Publishers Limited

Pharmacological and surgical interventions after myocardial infarction (MI) improve clinical outcome but do not restore the function of the damaged tissue. Investigators are therefore exploring new strategies for cardiac repair after MI, including the delivery of stem cells or cardiac muscle cells to the injured heart; however, the cells tend to cause arrhythmias, and their effects and mode of action remain unclear. A study describes a new cell-free therapy that improves cardiac recovery after MI in rats through the delivery of exosomes isolated from cardiomyocytes differentiated from human induced pluripotent stem cells (iPS-CMs).

“We asked ourselves if we could achieve the benefits of the cell therapy of the heart without using the cells,” explains lead investigator Gordana Vunjak-Novakovic. Cell transplantations improve cardiac function after MI despite low cell retention in the heart, a ‘hit-and-run’ mechanism that suggests that the cell secretome mediates cardiac repair. Previous studies have shown that extracellular vesicles (EVs) secreted by stem or progenitor cells can improve cardiac repair; Vunjak-Novakovic and colleagues hypothesized that EVs from iPS-CMs (iCM-EVs) would be more therapeutic than EVs from iPS cells (iPS-EVs), given their cardiac-specific components. Bioactive molecules in EVs include microRNAs (miRNAs), and miRNA profiling confirmed that iCM-EVs are enriched in miRNAs that target genes involved in cardiac processes and hypertrophy compared with iPS-EVs.

the cell secretome mediates cardiac repair

Human iPS-EVs and iCM-EVs were packaged into hydrogel patches and placed on the myocardium of rats after MI. iCM-EVs reduced cardiac dilatation and improved function compared with iPS-EVs or no treatment at 2 weeks after MI. Additionally, delivery of iCM-EVs but not iPS-EVs significantly reduced infarct size and cardiomyocyte hypertrophy compared with no treatment at 4 weeks after MI. iCM-EVs were also not arrhythmogenic and reduced apoptosis in the injured heart. “We are very excited about the prospects of this treatment. An advantage of this cell-free approach would be the largely simplified FDA regulatory procedure,” concludes Vunjak-Novakovic.