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Repairing hearts

Upon activation, a novel population of resident cardiac cells forms new muscle after damage.

By | June 8, 2011

Mouse heartCOURTESY OF THE BRITISH HEART FOUNDATION

A newly identified type of resident progenitor cell in the outer layer of heart tissue can be coaxed to proliferate, migrate into heart muscle, and transform into cardiomyocytes, according to new research published this week in Nature.

The research, which was conducted using mice, suggests that the human heart could be encouraged to repair itself after a heart attack by stimulating a pool of resident adult progenitor cells—a therapy that would be preferable to cell transplantation, which runs the risk of host immune rejection and limited survival of the transplanted cells.

"What this work shows is that there is an inherent capacity for the heart to repair itself," said Peter Weissberg, medical director of the British Heart Foundation, which funded the study, at a press conference. "The cells are already there, they just need to be tweaked and primed and scaled up."

Other studies have failed to successfully track the migration of resident cardiac stem cells or to identify a switch that activates them. The authors of the Nature paper "really solved these two problems," said Mark Mercola, director of the Muscle Development and Regeneration Program at the Sanford-Burnham Medical Research Institute in California, who was not involved in the study.

Paul Riley and colleagues at University College London had previously shown that thymosin ß4 (Tß4), a small protein originally identified in the thymus, can induce a population of progenitor cells in heart tissue's outer layer, called the epicardium, to form blood vessels and trigger the formation of new fibroblasts and muscle cells in mouse embryos. "We thought, if [Tß4] is essential and necessary for embryonic epicardial development, then might it be sufficient to trigger the equivalent in the adult epicardium?" said Riley. "How the heart is built in an embryo can tell you an awful lot about how to repair one in the adult."

New cardiomyocytes shown in red, integrating with existing cells in greenCOURTESY OF THE BRITISH HEART FOUNDATION

The team "primed" the hearts of adult mice with Tß4 hoping to turn on that embryonic potential. The peptide switched on Wt1, a classical epicardial marker gene, which the scientists labeled with green fluorescent protein to track the movement of the cells. The team then induced a heart injury in the mice, and observed the cells proliferating and moving into the injury site within the heart muscle, where they formed mature cardiomyocytes. The cells formed attachments with neighboring muscle cells, becoming electrically coupled and functional.

The team monitored the mice for a month using MRI to observe the success of the new cardiomyocyte integration. The mice pre-treated with Tß4 had less scaring at the site of injury, less dilation and thinning of the heart walls—a classic sign of heart failure—and a better ability to pump blood than control mice whose hearts were injured but did not receive Tß4.

Currently, the team is looking for other small molecules that might spur the progenitor cells to form new cardiomyocytes even more efficiently, as Tß4 stimulated the generation of only a limited number of new heart cells. They are also testing human tissue samples in vitro to see if Tß4 stimulates human cells in the same way. The research "opens up lots of questions," said Mercola, "but it's a nice block added to the pyramid [of heart regeneration research]."

Repairing hearts from thescientistllc on Vimeo.

If the research does extrapolate to humans, it might be a step toward therapies in which individuals at high risk for cardiac maladies could take a preventive pill to prime their heart for repair in case of an attack. The team only saw new cardiomyocyte formation if the heart was treated before the injury with Tß4, so "if we thought about any kind of therapeutic application, it's going to have to be a preemptive strike," said Riley.

N. Smart, et al., “De novo cardiomyocytes from within the activated adult heart after injury,” Nature, DOI: 10.1038/nature10188, 2011.

 

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