In the United States, someone has a heart attack every 40 seconds (according to the CDC). Scary, right? Cardiovascular diseases are the number 1 cause of death globally, according to the World Health Organization (WHO), and there isn’t a definite cure for it because of the myriad of factors that result in the occurrence of a heart attack, from obesity to tobacco use. But did you know that in a heart attack, little particles called vesicles keep your cells functioning without oxygen?
Extracellular vesicles (EV) are extremely small, membrane-enclosed particles that travel between cells for delivery and response initiation. These EVs have lots of potential as next-generation therapies for all kinds of diseases, from neurodegenerative diseases like Alzheimer’s to even cancer! Why? Some of them are derived from stem cells, which are cells that have the potential to become different types of cells in your body. These specific EVs have already been shown to help heart cells survive heart attacks and revive cells after one, but until now, we didn’t know how, which prevents us from using these particles as medical therapies.
Luckily, researchers from Harvard University’s John A. Paulson School of Engineering and Applied Sciences (SEAS) have uncovered the specific mechanisms that power this cell-healing process. To demonstrate how it works, they used a heart-on-a-chip, which was developed by Harvard researchers, that emulated human tissue and tracked tissue contractions. Let’s take a look at the study and how this revival process works.
What They Found
Myocardial infarctions, or more commonly known as heart attacks, are caused by the blockage of blood flow to the heart. Obviously, the best treatment for a heart attack is to restore blood flow, but this can actually damage your heart cells! Sometimes, when blood starts to flow after a period of time without oxygen, an ischemia-reperfusion injury (IRI), or reoxygenation injury, can occur. According to Moran Yadid, a postdoctoral fellow at SEAS and first author of the paper, which can be found here, “The cellular response to IRI involves multiple mechanisms, such as calcium and proton overload, oxidative stress, mitochondrial dysfunction and more.”
If we can’t restore blood flow without being injured, how do we treat heart attacks properly? That’s where the EVs come in. Earlier, I said EVs derived from stem cells have been shown to help heart cells recover after a heart attack, but the researchers at Harvard have found a different type of EV that can perform the same recovery tasks and is easier to maintain. These vesicles are derived from endothelial cells, which form a layer that lines the surface of blood vessels. Because endothelial-derived EVs (EEVs) come from the tissue of blood vessels, which can sense when oxygen levels are depleted, the researchers at SEAS thought that the particles they carry could protect cardiac muscle (muscle in your heart).
To test their hypothesis, the scientists mapped out every possible protein that the EEVs could contain. Here’s what they found:
“Surprisingly, even though these vesicles are only a hundred and fifty nanometers in diameter, they contain almost 2,000 different proteins,” said Yadid. “A lot of these proteins relate to metabolic processes like respiration, mitochondrial function, signaling and homeostasis. In other words, a lot of processes that relate to the cardiac response to stress. So, rather than one molecule that is therapeutic, we think that the exosomes contain a cocktail of molecules and proteins that can, all together, help the cell maintain homeostasis, deal with the stress, modify metabolic action and reduce the amount of injury.
To test the effect of these EEVs on heart tissue, the researchers used a heart-on-a-chip, which was constructed by SEAS’ own Disease Biophysics Group. This chip mimics the structure and function of human tissue and allows researchers to observe the effects of any treatments on this tissue.
From these tests, the researchers found that cardiac muscle cells adapted better to stressful conditions when the tissues were treated with EEVs. To test how they would hold up to injury, they removed oxygen for 3 hours, reoxygenated the cells for 90 minutes, and recorded the contractile force of the tissue and the fraction of dead cells. The tissue with EEVs had a much higher contractile force and half as many dead cells. Additionally, they found that the cells with EEVs continued to contract even without oxygen.
After more research is conducted, researchers and medical professionals can start developing new cell therapies that use these extracellular vesicles. This EEV study even shows that these tiny particles can help treat heart attacks! If we start finding vesicles derived from other types of cells for other diseases like Alzheimer’s and different cancers, we may even cure these diseases. The future is bright for exosomal (another word for EV) cell therapies, as sometimes, traditional treatments just don’t cut it. Until then, all we can do is follow the latest research and stay informed.