Researchers at Children's Hospital Boston have taken a significant step towards regenerating heart tissue after a heart attack, in patients with heart failure, or in children with congenital heart defects.
Normally, it is not possible to re-grow injured heart tissue, but researchers have shown that 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.
AdvertisementNRG1 is involved in the initial development of the heart and nervous system,
After birth, heart-muscle cells (cardiomyocytes) normally withdraw from the cell cycle, which means that they stop dividing and proliferating.
But the researchers, led by Dr. Bernhard Kuhn, and Dr. Kevin Bersell, were able to restart the cell cycle with NRG1, stimulating cardiomyocytes to divide and make copies of themselves, despite not being 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," said Kuhn.
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-two conditions seen in the controls.
When the researchers also stimulated production of a cellular receptor for NRG1, known as ErbB4, cardiomyocyte proliferation was further enhanced, which showed 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 developed a sponge-like patch, soaked in a compound called periostin, which when placed over the site of cardiac injury in rats, \induced cardiomyocyte proliferation and improved heart function.
The new study has revealed how both periostin and NRG-1 work at the cellular and molecular level, an essential step in predicting possible side effects.
Kuhn found that 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," said Kuhn.
The study has been published in the journal Cell.