(photo credit: INGIMAGE)
The possibility that mammalian -- including human -- heart cells could eventually regenerate after suffering damage from heart attacks has been brought closer by scientists from the Weizmann Institute of Science who induced mouse heart cells to take a step backwards so they can be renewed.
When a heart attack strikes, heart muscle cells die and scar tissue forms, paving the way for coronary insufficiency and cardiovascular diseases, which are one of the leading causes of death around the world, partly because the cells in our most vital organ do not get renewed.
Unlike blood, hair or skin cells that can renew themselves throughout life, heart cells stop dividing soon after birth, with very little renewal in adulthood. But the new discovery, by Prof. Eldad Tzahor of the Rehovot institute’s biological regulation department offers insight into the question of why the mammalian heart fails to regenerate and opened up the possibility of reversing this in adult mice. This research appeared on Monday in the journal Nature Cell Biology
Tzahor thought that part of the answer to the regeneration puzzle might lie in his area of expertise -- embryonic development, especially of the heart. In fact, a protein named ERBB2, which is well studied because it can pass along growth signals promoting certain kinds of cancer, plays a role in heart development.
ERBB2 is a specialized receptor – a protein that transmits external messages into the cell. ERBB2 usually works together with a second, related, receptor by binding a growth factor called Neuregulin 1 (NRG1) to transmit its message. NGR1 is already being tested in clinical studies for treating heart failure.
Dr. Gabriele D’Uva, a postdoctoral fellow on Tzahor’s team, wanted to know exactly how NRG1 and ERBB2 function in heart regeneration. In mice, new heart muscle cells can be added up to a week after birth; newborn mice can regenerate damaged hearts, while seven-day-old mice already cannot. D’Uva and research student Alla Aharonov observed that heart muscle cells called cardiomyocytes that were treated with NRG1 continued to proliferate on the day of birth; but the effect dropped dramatically within a week, even with ample amounts of NRG1. They then found that the difference between a day and a week was in the amount of ERBB2 on the cardiomyocyte membranes.
The team then produced mice in which the gene for ERBB2 was knocked out only in cardiomyocytes; this had a severe impact, as the mice had hearts with walls that were thin and balloon-like – a cardiac pathology known as dilated cardiomyopathy. The conclusion was that cardiomyocytes lacking ERBB2 do not divide, even in the presence of NRG1.
Next, the team reactivated the ERBB2 protein in adult mouse heart cells, in which cardiomyocytes normally no longer divide. This resulted in extreme cardiomyocyte proliferation and hypertrophy – excessive growth of the individual cardiomyocytes – leading to a giant heart (cardiomegaly) that left little room for blood to enter. Tzahor explained: “Too little or too much of this protein had a devastating impact on heart function.”
The team reasoned that If one could activate ERBB2 for just a short period in an adult heart following a heart attack, it might be possible to cause the renewal of heart cells without negative results such as hypertrophy and scarring. Testing this idea, the team found that they could, indeed, activate ERBB2 in mice for a short interval only following an induced heart attack and obtain nearly complete heart regeneration within several weeks. “The results were amazing,” said Tzahor. “As opposed to extensive scarring in the control hearts, the ERBB2-expressing hearts had completely returned to their previous state.”
They investigated the regenerative process through live imaging and molecular studies and found that cardiomyocytes “de-differentiate” -- revert to an earlier form -- something between an embryonic and an adult cell, which can then divide and differentiate into new heart cells. In other words, the ERBB2 took the cells back a step to an earlier, embryonic form; and then stopping its activity promoted the regeneration process.
Tzahor warned that clinical trials of patients receiving the NRG1 treatment might not be overly successful if ERBB2 levels are not boosted as well. He and his team plan to continue researching this signaling pathway to suggest ways of improving the process, which may, in the future, point to ways of renewing heart cells.
Because this pathway is also involved in cancer, well-grounded studies will be needed to understand exactly how to direct the cardiomyocyte renewal signal at the right place, the right time and in the right amount. “Much more research will be required to see if this principle could be applied to the human heart, but our findings are proof that it may be possible,” he says.
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