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 demonstrated that these intercellular travelers could be derived from endothelial cells, which line the surface of blood vessels and are more abundant and easier to maintain than stem cells. The research is published in Science Translational Medicine.
"Our organ-on-chip technology has progressed to the point where we can now fight drug targets instead of fighting the chip design," said Kit Parker, the Tarr Family Professor of Bioengineering and Applied Physics at SEAS and senior author of the study. "With this study, we have 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 that process actually may cause more damage to the cells in the heart. So-called ischemia-reperfusion injury (IRI) or reoxygenation injury, happens when blood supply returns to tissue 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," said Moran Yadid, a postdoctoral fellow at SEAS and The Wyss Institute for Biologically Inspired Engineering and first author of the paper. "This complex set of processes poses a challenge for the development of effective therapies that can address each of these problems."
That's where the endothelial-derived EVs (EEVs) come in. Because these vesicles are derived from vascular tissue, which is uniquely tuned to sense hypoxic stress, the researchers hypothesized that the cargo they carry could provide direct protection to cardiac muscle.
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 and allow researchers to observe, in real time, the effects of injuries and treatments in human tissue. Here, the researchers simulated a myocardial infarction and reoxygenation on chips that were infused with EEVs and those that were not.
The researchers found that in tissues treated with EEVs, the cardiomyocytes could better adapt to stress conditions and sustain a higher workload. The researchers induced injury by three hours of oxygen restrictions followed by 90 minutes of reoxygenation and then measured the fraction of dead cells and the contractile force of the tissue. The heart tissue treated with EEVs had half as many dead cells and had a contractile force four times higher than the untreated tissue after injury.
The team also found that injured cardiomyocytes that had been treated with EEVs exhibited a set of proteins that was more similar to the uninjured ones compared with untreated cells. "Our findings indicate that EEVs could protect cardiac tissue from reoxygenation injury in part by supplementing the injured cells with proteins and signaling molecules that support different metabolic processes, paving the way for new therapeutic approaches," said André G. Kléber, a Visiting Professor of Pathology at Harvard Medical School and co-author of the study.
MEDICA-tradefair.com; Source: Harvard John A. Paulson School of Engineering and Applied Sciences
