New evidence to explain how a common tropical fish mends a broken heart may suggest methods for coaxing the damaged hearts of mammals to better heal, researchers report in the November 3, 2006 issue of Cell, published by Cell Press.
The researchers found that the hearts of zebrafish harbor progenitor cells that spring into action to restore wounded heart muscle. Cells from a membrane layer that surrounds the heart, called the epicardium, follow suit, invading the wounded cardiac tissue and stimulating the growth of new blood vessels.
"Zebrafish can survive pretty massive injury to the heart--the loss of about a quarter of their ventricle," said Kenneth Poss of Duke University Medical Center. The ventricle, which receives blood and then pumps it back out to the body, is one of two chambers that make up the fish heart. "This study gets at some of the important mechanistic questions about how they rebuild the heart, and some of the key factors that contribute."
In contrast to zebrafish, the cardiac damage and scarring caused by heart attacks is a major killer among humans, making "the inability to replace damaged cardiac muscle one of the most prominent regenerative failures of mammals," wrote Alexandra Lepilina and Ashley Coon, the study's first authors.
However, mammalian hearts have been found to contain rare populations of progenitor cells, they added. As in zebrafish, the hearts of adult mammals, including humans, are also housed inside an epicardium, a tissue about which little is known.
"Scientists haven't paid much attention to the epicardium in adults," Poss said. "These findings in fish should encourage more exploration of what adult epicardium can do.
"There is the potential that these cells could be utilized for therapies."
The ability to regenerate tissue is a feature shared among vertebrate species, the researchers said. However, particular animals, including certain amphibians and fish, display an "elevated regenerative spectrum, with many more tissues capable of impressive regeneration," they said. For instance, certain newts or salamanders can regenerate limbs, spinal cord, retina, brain, and heart tissue.
While progenitor cell populations have been identified within most mammalian organs, including skin, skeletal muscle, brain, and heart, these cells vary widely in frequency and the ability to regenerate damaged or lost tissue, they said. In most mammalian organs, progenitor cells can restore cells lost in the course of normal organ function or after minor injury but cannot regenerate after major damage or removal of structures.
"It is believed that the capacity for regeneration is an ancestral condition that has occasionally been lost in the course of vertebrate evolution." Poss said. "Thus, most biologists suspect that the machinery to optimize regeneration from progenitor cells is present, but lies dormant, in mammals."
In an earlier study, Poss and his colleagues found that zebrafish have a unique ability to regenerate cardiac muscle after major injury. They further suspected that illumination of the fishes' ability might offer important insights into "how heart regeneration is naturally optimized."
In the current study, they found that heart regeneration proceeds through two coordinated stages. First, a mass of undifferentiated, pre-cardiac cells form. Those progenitor cells then begin to differentiate and divide, to replace the damaged heart muscle.
In the second step, the epicardium surrounding the heart chambers "lights up" with activity as developmental genes switch on, Poss said. The epicardium expands to rapidly cover the wounded heart muscle.
A subset of those epicardial cells then alters their identity, invading the wound and providing essential new blood vessels to the growing muscle.
They further found that the two-part regeneration process is coordinated by so-called "fibroblast growth factor" (Fgf) signals. Fgf signals are known for their ability to encourage invasive cell behavior, Poss explained.
Indeed, they found, heart muscle cells produce the growth factor, while epicardial cells harbor receptors that are triggered by the signal. When the researchers experimentally blocked the Fgf signal, heart regeneration failed.
"It is tempting to speculate that the ability to mobilize epicardial cells and cultivate such a cardiogenic environment is a primary reason why zebrafish, as opposed to other laboratory models, effectively regenerate [heart muscle]," the researchers concluded. Indeed, they added, mammalian hearts typically show insufficient blood vessel growth after a heart attack.
"Experimental attempts to modify this deficiency are underway, including delivery of growth factors or bone marrow-derived cells that may promote [the formation of new blood vessels]…Success in these pursuits or by directly utilizing epicardial cells or their progenitors could prove favorable for encouraging regeneration from mammalian cardiac progenitor cells."
The researchers include Alexandra Lepilina, Ashley N. Coon, Kazu Kikuchi, Jennifer E. Holdway, Richard W. Roberts, and Kenneth D. Poss of Duke University Medical Center in Durham, NC; C. Geoffrey Burns of Massachusetts General Hospital in Charlestown, MA. This work was supported by grants to K.D.P. from NIH, American Heart Association, March of Dimes, and the Whitehead Foundation.
Lepilina et al.: "A Dynamic Epicardial Injury Response Supports Progenitor Cell Activity during Zebrafish Heart Regeneration."
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