Extracellular Vesicles Used to Promote Heart Regeneration in Rats

First generation stem cell therapies largely achieve their results through brief signaling changes, not through any lasting work on the part of the transplanted cells. Those cells in fact die quite rapidly, but the signals they secrete while still alive change the behavior of native cells. This produces benefits such as reduced inflammation or improved regenerative capacity. Given this, why not deliver the signals instead of the cells? It could in principle be an easier, less complex task. Much of cell signaling involves the exchange of extracellular vesicles, tiny membrane-bound packages of molecules. Numerous groups are presently engaged in animal studies of vesicle-based approaches to regenerative therapy, and the one noted here is representative of the type.

The adult human heart cannot regenerate itself after injury, and the death of cardiac muscle cells, known as cardiomyocytes, irreversibly weakens the heart and limits its ability to pump blood. Researchers have turned their focus to stem cell transplantation for cardiomyocyte replacement and recovery of heart function, but studies have shown that implanted stem cells have difficulty surviving and differentiating into cardiomyocytes to repair the damaged muscle. When stem cells were differentiated into cardiomyocytes before implantation, heart function improved, but with a complication: the implanted cardiomyocytes did not contract synchronously with the heart, thus causing potentially lethal arrhythmias (abnormal heart rhythm).

A team of researchres has designed a creative new approach to help injured hearts regenerate by applying extracellular vesicles secreted by cardiomyocytes rather than implanting the cells. Cell-secreted microvesicles are easy to isolate and can be frozen and stored over long periods of time. Such an "off-the-shelf" product has several major advantages over cell therapy-1) it can be used immediately in an acute-care setting, unlike cells that can take months to isolate and grow; 2) it does not cause arrhythmia (which often occurs when cells are transplanted); and 3) the regulatory path towards clinical application is much simpler than for a cell-based therapy.

It is well known from numerous clinical studies that most of the implanted stem cells are washed away within hours of the treatment, but there still are beneficial effects. This has led to the informal "hit-and-run" hypothesis, meaning that the cells deliver their cargo of regulatory molecules before leaving the site of injury. "Consistent with this hypothesis, we postulated that the benefits of cell therapy of the heart could be coming from the secreted bioactive molecules (such as microRNAs), rather than the cells themselves. So we explored whether the benefits of cell therapy of the injured heart could be achieved without using the cells. This way, we would largely simplify the translation into the clinic, and avoid the burden of arrhythmia associated with implantation of contractile cells."

The team derived cardiomyocytes from adult human stem cells and cultured these cells to allow them to secrete extracellular vesicles. The vesicles secreted by undiffereniated stem cells were used for comparison. The researchers then used next-generation sequencing to read their messages and instructions. They found that the extracellular vesicles from cardiomyocytes - but not from stem cells - contained cardiogenic and vasculogenic microRNAs that are very powerful regulatory molecules. The team encapsulated the vesicles in a collagen-based patch that slowly released them over the course of four weeks when implanted onto the injured heart in rat models of myocardial infarction. "We were really excited to find that not only did the hearts treated with cardiomyocyte extracellular vesicles experienced much fewer arrhythmias, but they also recovered cardiac function most effectively and most completely. In fact, by four weeks after treatment, the hearts treated with extracellular vesicles had similar cardiac function as those that were never injured."

Link: http://engineering.columbia.edu/news/cell-therapy-heart-recovery

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