Researchers regenerate heart cells in mice
Tuesday, April 21, 2015
Myocardial infarction (MI) causes irreversible necrosis of heart muscle secondary to prolonged ischemia. Scar tissue begins to build almost immediately, leading to the loss of contractile myocardium, which is a frequent cause of chronic heart failure.
However, a new study suggests there may someday be a way to stimulate the body into regenerating heart cells after MI.
Cardiovascular diseases are leading causes of death globally. This is due, at least in part, to the fact that cardiomyocytes do no regenerate. Unlike other body cells that renew themselves throughout life, a human's heart cells stop dividing during infancy.
Research at the Weizmann Institute of Science provides new insight into why mammalian heart cells fail to regenerate, and even demonstrated that it was possible to reverse this fate in adult mice. The research results, published this month in Nature Cell Biology, may eventually help clinicians reduce cardiomyopathy and stimulate cell regeneration in heart attack patients.
The protein ERBB2 plays an important role in heart development. Because it can pass along certain growth signals that promote the growth of certain types of cancer, scientists have closely studied this specialized receptor.
ERBB2 typically works together with Neuregulin 1 (NRG1) to transmit external messages into the cells. Researchers were already conducting clinical studies testing NRG1 as a treatment for heart failure, but this new study may prompt scientists to include ERBB2 in future studies.
The Weizmann Institute of Science researchers wanted to learn more about the role NRG1 and ERBB2 play in heart regeneration. Mice are similar to humans in that only the youngest mice can regenerate new heart muscle cells. Newborn mice can regenerate damaged heart cells while mice that are seven days old cannot.
The researchers saw that cardiomyocytes treated with NRG1 proliferated on the mouse subject's date of birth, but that the effect declined dramatically within seven days, even when the scientists used generous amounts of NRG1. When the researchers looked closer, they noticed an association between the amount of ERBB2 and the difference of cardiomyocyte membrane regeneration.
The team then created knockout mice, deactivating ERBB2 only in cardiomyocytes. These mice developed dilated cardiomyopathy, with thin and balloon-like heart walls. This led the researchers to conclude that cardiomyocytes lacking ERBB2 do not divide, even with copious amounts of NRG1.
The researchers then reactivated ERBB2 in adult mouse cardiomyocytes, in which these heart cells should no longer divide. ERBB2 reactivation caused extreme cardiomyocyte proliferation and hypertrophy that resulted in cardiomegaly. The scientists surmised that having too much or too little ERBB2 has a serious effect on heart function.
The team then wondered if activating ERBB2 in an adult heart for only a short period following an MI would result in cardiomyocyte renewal without hypertrophy and scarring. To test the idea, the researchers induced myocardial infarction then activated ERBB2 for a short interval. They discovered nearly complete heart regeneration within weeks. Instead of extensive scarring seen in the control hearts, the treated hearts had returned to their previous states.
Live imaging and molecular studies suggest cardiomyocytes can "dedifferentiate," or revert to an earlier form somewhere between embryonic and adult cell. These dedifferentiated cells can divide and differentiate into new cardiomyocytes.
In other words, activating ERBB2 brought cells back to an earlier form, then deactivating it promoted the regeneration process.
This process could someday bring new hope to the 750,000 Americans who suffer a heart attack each year. Further research into the effects of ERBB2 may help these patients recover from the cell death associated with heart attack and reduce their risk for developing chronic heart failure.
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