Extracellular vesicles (EVs) -- nanometer sized messengers that travel between cells to deliver cues and cargo -- are promising tools for subsequent generation of therapies for everything from autoimmune and neurodegenerative diseases to cancer and tissue injury. EVs derived from stem cells have already been shown to assist heart cells recover after a attack , but exactly how they assist and whether the beneficial effect is restricted to EVs derived from stem cells has remained a mystery.
Now, researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have unraveled potential mechanisms behind the healing power of EVs and demonstrated their capacity to not only revive cells after a attack but keep cells functioning while bereft of oxygen during a attack . The researchers demonstrated this functionality in human tissue employing a heart-on-a-chip with embedded sensors that continuously tracked the contractions of the tissue.
The team also demonstrated that these intercellular travelers might be derived from endothelial cells, which line the surface of blood vessels and are more abundant and easier to take care of than stem cells.
The research is published in Science Translational Medicine.
"Our organ-on-chip technology has progressed to the purpose where we will now fight drug targets rather than 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've mimicked a person's disease on a chip with human cells and developed a completely unique therapeutic approach to treat it."
Heart attacks, or myocardial infarctions, occur when blood flow to the guts is blocked. Of course, the simplest thanks to treat a attack is to revive blood flow but that process actually may cause more damage to the cells within 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, like calcium and proton overload, oxidative stress, mitochondrial dysfunction and more," said Moran Yadid, a postdoctoral fellow at SEAS and therefore the Wyss Institute for Biologically Inspired Engineering and first author of the paper. "This complex set of processes poses a challenge for the event of effective therapies which will address each of those problems."
That's where the endothelial-derived EVs (EEVs) are available . Because these vesicles are derived from plant tissue , which is uniquely tuned to sense hypoxic stress, the researchers hypothesized that the cargo they carry could provide direct protection to heart muscle .
The researchers mapped the whole set of EEV proteins that are, or can be, expressed by the vesicles.
"Surprisingly, albeit these vesicles are only 100 and fifty nanometers in diameter, they contain almost 2,000 different proteins," said Yadid. "A lot of those proteins relate to metabolic processes like respiration, mitochondrial function, signaling and homeostasis. In other words, tons of processes that relate to the cardiac response to worry . So, instead of one molecule that's therapeutic, we expect that the exosomes contain a cocktail of molecules and proteins which will , all at once , help the cell maintain homeostasis, affect the strain , modify metabolic action and reduce the quantity 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 performance of native tissue and permit researchers to watch , in real time, the consequences of injuries and coverings in human tissue. Here, the researchers simulated a myocardial infarct and reoxygenation on chips that were infused with EEVs and people that weren't .
The researchers found that in tissues treated with EEVs, the cardiomyocytes could better adapt to worry conditions and sustain a better workload. The researchers induced injury by three hours of oxygen restrictions followed by 90 minutes of reoxygenation then measured the fraction of dead cells and therefore the contractile force of the tissue. the guts tissue treated with EEVs had half as many dead cells and had a contractile force fourfold above the untreated tissue after injury.
The team also found that injured cardiomyocytes that had been treated with EEVs exhibited a group of proteins that was more almost like the uninjured ones compared with untreated cells. Surprisingly, the team also observed that cells treated with EEVs continued to contract even without oxygen.
"Our findings indicate that EEVs could protect cardiac tissue from reoxygenation injury partially by supplementing the injured cells with proteins and signaling molecules that support different metabolic processes, paving the way for brand spanking new therapeutic approaches," said André G. Kléber, a professor of Pathology at Harvard school of medicine and co-author of the study.
"Exosomal cell therapies could be beneficial when the normal model of 1 molecule, one target just won't cure the disease," said Parker. "With the vesicles we administered, we believe we are taking a shotgun approach to hitting a network of drug targets. With our organ on chip platform, we'll be poised to use synthetic exosomes in therapeutic manner which will be more efficient and amenable to more reliable manufacturing."
The research was co-authored by Johan U. Lind, former postdoctoral fellow at SEAS and current professor at the University of Copenhagen, Denmark; Herdeline Ann M. Ardoña, former postdoctoral fellow at SEAS and current professor at the University of California Irvine; Sean P. Sheehy, Lauren E. Dickinson, Feyisayo Eweje, Maartje M.C. Bastings, Benjamin Pope, Blakely B. O'Connor, Juerg R. Straubhaar and Bogdan Budnik.
It was supported by Harvard Materials Research Science and Engineering Center and therefore the National Science Foundation under grant DMR-1420570, and therefore the National Center for Advancing Translational Sciences of the NIH under award numbers UH3TR000522 and 1-UG3-HL-141798-01.
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