Heart failure afflicts 5.7 million Americans, costs the country
$30.7 billion every year, and has no cures. When heart muscle is
damaged, the body is unable to repair the dead or injured cells.
Scientists at the Gladstone Institutes are exploring cellular reprogramming - turning one
type of adult cell into another - in the heart as a way to regenerate
muscle cells in the hopes of treating, and ultimately curing, heart
‘Two newly identified chemicals improved the speed, quantity, and quality of direct cardiac reprogramming, bringing the technology one step closer to regenerating damaged hearts.’
Gladstone scientists identified two chemicals that
improve their ability to transform scar tissue in a heart into healthy,
beating heart muscle. The new discovery advances efforts to find new and
effective treatments for heart failure.
It takes only three transcription factors - proteins that turn genes
on or off in a cell - to reprogram connective tissue cells into heart
muscle cells in a mouse. After a heart attack, connective tissue forms
scar tissue at the site of the injury, contributing to heart failure.
The three factors, Gata4, Mef2c, and Tbx5 (GMT), work together to turn
heart genes on in these cells and turn other genes off, effectively
regenerating a damaged heart with its own cells. But the method is not
foolproof - typically, only 10% of cells fully convert from scar
tissue to muscle.
In the new study, published in Circulation
scientists tested 5500 chemicals to try to improve this process. They
identified two chemicals that increased the number of heart cells
created by eight-fold. Moreover, the chemicals sped up the process of
cell conversion, achieving in one week what used to take six to eight
"While our original process for direct cardiac reprogramming with
GMT has been promising, it could be more efficient," said senior author
Deepak Srivastava, director of the Gladstone Institute of
Cardiovascular Disease. "With our screen, we discovered that chemically
inhibiting two biological pathways active in embryonic formation
improves the speed, quantity, and quality of the heart cells produced
from our original process."
The first chemical inhibits a growth factor that helps cells grow
and divide and is important for repairing tissue after injury. The
second chemical inhibits an important pathway that regulates heart
development. By combining the two chemicals with GMT, the researchers
successfully regenerated heart muscle and greatly improved heart
function in mice that had suffered a heart attack.
The scientists also used the chemicals to improve direct cardiac
reprogramming of human cells, which is a more complicated process that
requires additional factors. The two chemicals enabled the researchers
to simplify the process bringing them one step closer to better
treatments for heart failure.
"Heart failure afflicts many people worldwide, and we still do not
have an effective treatment for patients suffering from this disease,"
said Tamer Mohamed, first author on the study and a former
postdoctoral scholar at Gladstone. "With our enhanced method of direct
cardiac reprogramming, we hope to combine gene therapy with drugs to
create better treatments for patients suffering from this devastating