The researchers reveal possible mechanisms for the healing power of extracellular...

Extracellular vesicles (EVs) – nanometer-sized messengers that travel between cells to deliver clues and cargo – are promising tools for the next generation of therapies for everything from autoimmune and neurodegenerative diseases to cancer and tissue injury.

Electric vehicles made from stem cells have been shown to help heart cells recover from a heart attack. However, it has remained a mystery how they help and whether the beneficial effects are specific to stem cell-derived electric vehicles.

Now researchers at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have uncovered possible mechanisms for the healing power of electric vehicles and have demonstrated their ability not only to revive cells after a heart attack, but to keep the cells functional in the absence of oxygen during a heart attack.

The researchers demonstrated this functionality in human tissue using a Heart-on-a-Chip with embedded sensors that continuously tracked the contractions of the tissue.

The team also showed that these intercellular travelers may originate from endothelial cells, which line the surface of blood vessels and are more common and easier to care for than stem cells.

The research is published in Scientific translational medicine.

“Our organ-on-chip technology is so advanced that we can now fight drug targets rather than fight chip design,” said Kit Parker, professor of bioengineering and applied physics at SEAS and lead author on the study. “With this study, we mimicked a human disease on a chip with human cells and developed a novel therapeutic approach to treat it.”

Heart attacks, or myocardial infarctions, occur when blood flow to the heart is blocked. Of course, the best way to treat a heart attack is to restore blood flow, but this process can actually cause more damage to the cells in the heart.

An ischemia reperfusion injury (IRI) or reoxygenation injury occurs when blood supply returns to tissues after a period of lack of oxygen.

The cellular response to IRI involves multiple mechanisms such as calcium and proton overload, oxidative stress, mitochondrial dysfunction, and more. These complex processes pose a challenge to the development of effective therapies that can address each of these problems. ”

Moran Yadid, postdoctoral fellow at SEAS and the Wyss Institute for Biological Inspired Engineering and lead author of the work

This is where the endothelial EVs (EEVs) come into play. Because these vesicles originate from vascular tissue specifically designed for hypoxic stress, the researchers hypothesized that the charge they carry could directly protect the heart muscle.

Researchers mapped the entire set of EEV proteins that are or may be expressed by the vesicles.

“Although these vesicles are only 150 nanometers in diameter, surprisingly they contain almost 2,000 different proteins,” said Yadid. “Many of these proteins are related to metabolic processes such as respiration, mitochondrial function, signal transmission and homeostasis. In other words, many processes related to the heart’s response to stress.

“So we believe that instead of a therapeutic molecule, the exosomes contain a cocktail of molecules and proteins that can work together to help the cell maintain homeostasis, deal with stress, modify metabolism, and reduce the extent of injury.” ”

The team tested the effect of EEVs on human heart tissue using the Heart-on-a-Chip model developed by the Disease Biophysics Group at SEAS. Organ-on-chip platforms mimic the structure and function of native tissue, allowing researchers to observe the effects of injuries and treatments in human tissue in real time.

Here, the researchers simulated myocardial infarction and reoxygenation of chips that were infused with EEV and chips that weren’t.

The researchers found that cardiomyocytes in tissues treated with EEV were better able to adapt to stressful conditions and maintain a higher workload. Researchers induced injury by three hours of oxygen restrictions followed by 90 minutes of reoxygenation, and then measured the percentage of dead cells and the force of contraction of the tissue.

The heart tissue treated with EEVs had half as many dead cells and a four times higher force of contraction than the untreated tissue after an injury.

The team also found that injured cardiomyocytes treated with EEVs had a number of proteins that were more similar to the uninjured cells compared to untreated cells. Surprisingly, the team also observed that cells treated with EEVs continued to contract even without oxygen.

“Our results suggest that EEVs could partially protect the heart tissue from reoxygenation injury by supplementing the injured cells with proteins and signaling molecules that support various metabolic processes and pave the way for new therapeutic approaches,” said André G. Kléber, visiting professor of Pathology at Harvard Medical School and co-author of the study.

“Exosomal cell therapies could be beneficial when the traditional model of a molecule, a target, just doesn’t cure the disease,” said Parker. “With the vesicles we deliver, we believe we are taking a shotgun approach to reaching a network of drug targets. With our organ-on-chip platform, we are ready to use synthetic exosomes in therapeutic ways that can be more efficient and amenable to more reliable manufacture. ”