Stem cells mend the broken heart by activating an acute immune response

Image result for heart attack
Pic courtesy: Wikimedia commons

The heart muscle relies on the incessant flow of oxygen-rich blood to nourish it and keep it pumping. During a heart attack or myocardial infarction, that blood flow is interrupted by a blockage in an artery. Without blood, the area of heart fed by the affected artery begins to die and scar tissue forms in the area. Though the heart is a tough organ, the damaged portion is unable to pump blood efficiently. Over time, this damage can lead to heart failure.

People who have had a heart attack therefore may face a lifetime of maintenance therapy—medications and other treatments aimed at preventing another heart attack and helping the heart work more efficiently. For nearly two decades, scientists have studied how stem cells might repair a damaged heart and restore its function. Stem cell therapies to repair damaged heart tissue are currently being tested in human clinical trials. In these treatments, human stem cells are injected into the heart and this leads to an improvement in heart function.

The mechanism by which stem cells repair the heart remains highly controversial and to date there is no conclusive explanation. Initially, scientists believed that the transplanted stem cells differentiated into heart muscle cells, blood vessels, or other cells damaged by the heart attack. Another idea is that the transplanted stem cells release growth factors and other molecules that promote blood vessel formation (angiogenesis) or stimulate resident cardiac stem cells to repair damage. Additional mechanisms for stem-cell mediated heart repair, including strengthening of the post-infarct scar and the incorporation of donor stem cells with host heart cells, have also been proposed. However a paradigm shifting study by Jeffery Molkentin at The Cincinnati Children’s hospital was published in Nature this week. According to this research the heart repair is actually mediated by activating the body’s innate immune response.

This study suggests that stem cell  therapies may become redundant in repairing cardiac function after a heart attack. Researchers injected different types of stem cells or dead cells or even a chemical called zymosan, which is known to elicit an innate immune response, into an experimental mouse model of heart disease. They saw improvement in heart function regardless of the cell type injected and also with zymosan, and showed that this repair occurs via activation of macrophages which are cells of the innate immune system. The innate immune response acutely altered cellular activity around the injured area of the heart so that it healed with a more optimised scar and improved contractile properties.

Further, as a proof of concept, the researchers suppressed macrophage activity in some mice. In this case, the repair process occurred neither in the mice that received the stem cells nor in those that received zymosan. This suggested that it is the activation of the macrophages which aides in heart repair. They showed that functional benefit of cardiac cell therapy is thus due to an acute inflammatory-based wound healing response that rejuvenates the mechanical properties of the injured area of the heart.

The research also found that stem cells and other therapeutic substances like zymosan have to be injected directly into the hearts surrounding the area of injury. This is in contrast to most past human clinical trials that for patient safety reasons simply injected stem cells into the circulatory system.

Take Home: This study proposes a new concept of how cardiac stem cells improve heart function after a heart attack. This study presents an important new evidence about an unsettled debate in the field of cardiovascular medicine.

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