Injection of growth factor reverses heart-attack damage
31 July 2009
Researchers at Children's Hospital Boston have shown that injection
of a growth factor, called neuregulin1 (NRG1), can spur heart-muscle
growth and recovery of cardiac function when injected systemically into
animals after a heart attack.
Injured heart tissue normally can't regrow, but this new work,
published in the July 24 issue of Cell, has laid the groundwork
for regenerating heart tissue after a heart attack, in patients with
heart failure, or in children with congenital heart defects.
After birth, heart-muscle cells (cardiomyocytes) normally withdraw
from the cell cycle — meaning they stop dividing and proliferating. But
the researchers, led by Bernhard Kuhn, MD, and Kevin Bersell of the
Department of Cardiology at Children's, were able to restart the cell
cycle with NRG1, stimulating cardiomyocytes to divide and make copies of
themselves — even though they are not stem cells.
"Although many efforts have focused on stem-cell based strategies,
our work suggests that stem cells aren't required and that stimulating
differentiated cardiomyocytes to proliferate may be a viable
alternative," says Kuhn, the study's senior investigator and a
practicing pediatric cardiologist at Children's since 2007.
When the team injected NRG1 into the peritoneal cavity of live mice
after a heart attack, once daily for 12 weeks, heart regeneration was
increased and pumping function (ejection fraction, assessed on
echocardiograms) improved as compared with untreated controls. The
NRG1-injected mice also lacked the left-ventricular dilation and cardiac
hypertrophy that typify heart failure; both were seen in the controls.
When the researchers also stimulated production of a cellular
receptor for NRG1, known as ErbB4, cardiomyocyte proliferation was
further enhanced, demonstrating that NRG1 works by stimulating this
receptor. They also identified the specific kinds of cardiomyocytes (mononucleated)
that are most likely to respond to treatment.
In 2007, Kuhn and colleagues first demonstrated that the heart has
dormant regenerative capacities that can be reawakened. Kuhn developed a
sponge-like patch, soaked in a compound called periostin that is
abundant in the developing fetal heart (and in injured skeletal muscle)
but scarce in adult hearts.
When the patch was placed over the site of cardiac injury in rats, it
induced cardiomyocyte proliferation and improved heart function (Nature
Medicine 2007; 13:962-9). Similar results were seen in larger
animals, and periostin is now in preclinical development at Children's
Hospital Boston for future application in human patients with heart
The new work adds a second compound to the heart-regeneration
toolbox, and reveals how both periostin and NRG1 work at the cellular
and molecular level, an essential step in predicting possible side
effects. Both compounds ultimately act on the same cellular pathway,
"We applied periostin locally at the site of cardiac injury, but NRG1
works when given by systemic injection — a very promising result that
suggests it may be feasible to use this in the clinic to treat heart
failure," says Kuhn, who won a first prize Young Investigator Award,
from the American College of Cardiology in 2007.
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