New research at the Weizmann Institute of Science could point to ways of renewing heart cells and eventually lead to new treatments for cardiovascular diseases.
As opposed to blood, hair or skin cells that can renew themselves throughout life, our heart cells cease to divide shortly after birth, and there is very little renewal in adulthood. New research at the Weizmann Institute of Science provides insight into the question of why the mammalian heart fails to regenerate, and demonstrated, in adult mice, the possibility of turning back this fate.
The research appeared in Nature Cell Biology.
Prof. Eldad Tzahor of the Institute’s Biological Regulation Department thought that part of the answer to the regeneration puzzle might lie in his area of expertise: embryonic development, especially of the heart.
Tzahor looked to a protein called ERBB2 – which is well studied because it can pass along growth signals promoting certain kinds of cancer – and which plays a role in heart development.
ERBB2 is a specialized receptor – a protein that transmits external messages into the cell. ERBB2 generally 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.
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 cannot.
Dr. Gabriele D’Uva, a postdoctoral fellow in the research group, 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. Further investigation showed that the difference between a day and a week was in the amount of ERBB2 on the cardiomyocyte membranes.
The team created mice in which the gene for ERBB2 was knocked out only in cardiomyocytes. This had a severe impact and 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 that left little room for blood to enter.
“Too little or too much of this protein had a devastating impact on heart function,” says Tzahor.
The scientists then asked, if one could activate ERBB2 for just a short period in an adult heart following a heart attack, might it be possible to get cardiac cell renewal, without such negative ones 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,” says Tzahor. “As opposed to extensive scarring in the control hearts, the ERBB2-expressing hearts had completely returned to their previous state.”
“ERBB2 is clearly at the top of the chain. We have shown that it can induce cardiac regeneration on its own. But understanding the roles of the other proteins in the chain may present us with new drug targets for treating heart disease,” says D’Uva.
The scientists know that much more research is needed but they’re optimistic.
Tzahor 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.
Profs. Yosef Yarden and Michal Neeman, also of the Biological Regulation Department, Prof. Jonathan Leor of Chaim Sheba Medical Center and Richard P. Harvey of University of South Wales, Australia also contributed to this research.