Factor fixes damaged hearts

A growth factor injected into adult mice spurs heart muscle cells to proliferate, helping heal heart attack damage

Jul 23, 2009
Kelly Rae Chi
A growth factor injected into adult mice with damaged hearts can stimulate differentiated heart cells to proliferate, promoting regeneration after heart attack, according to a study published tomorrow (July 24) in Cell. The study is "a big advance," linkurl:Doug Sawyer,;https://medschool.mc.vanderbilt.edu/facultydata/php_files/show_faculty.php?id3=16376 a cardiologist at Vanderbilt University Medical Center in Nashville, Tennessee, who was not involved in the research, told The Scientist. Heart muscle cells are known to proliferate during fetal development, but were previously thought to differentiate terminally soon after birth. During the last 15 years, however, an increasing body of evidence has hinted that these cells can re-enter the cell cycle and regenerate. Bernhard Kühn, a linkurl:pediatric cardiologist;http://www.childrenshospital.org/cfapps/research/data_admin/Site2562/mainpageS2562P0.html at Children's Hospital Boston, and his colleagues gave mice an intraperitoneal injection of neuregulin1 one week after inducing heart attacks, and then administered daily injections for 12 weeks. Two weeks after the final injection, they examined the heart tissue to see whether the damage caused by the heart attack had been ameliorated. "We stopped treating the mice cold turkey and said, 'Look, if this is true regeneration, it should be there two weeks later,'" Kühn said. Indeed, electrocardiographs showed that in treated mice, ventricle chambers of the heart recovered more, both structurally and functionally, than in mice given control injections.Neuregulin1's effect is mediated through its receptor, ErbB4. When researchers genetically inactivated ErbB4 in young mice, the animals' heart muscle cells stopped entering the cell cycle and proliferating. Kühn and his group also found that adding neuregulin1 to adult heart muscle triggered roughly 0.6% of cells to divide over a nine-day period. "The effect is not huge, but it's way above baseline," said linkurl:Chuck Murry,;http://www.pathology.washington.edu/research/labs/murry/people.php director of University of Washington's Center for Cardiovascular Biology in Seattle, who was not involved with the study. "It seems that cumulatively these effects could be physiologically meaningful."In the mammalian heart, roughly 25% of muscle cells contain one nucleus, whereas the remaining 75% contain two or more. Tracing proliferation in vivo, the group showed that neuregulin1 prompted 14% of mononucleated cells to make new DNA -- a sign of proliferation. Only 3% of multi-nucleated cells treated with the factor synthesized DNA. "It's now starting to look like [mononucleated cells] have a special function in the heart," Murry said. "It's changed the way that I think about these cells."Sawyer noted that the strength of the study was in demonstrating elements of the mechanism behind heart cell proliferation in adult animals. "The exciting part, in my mind, is that the ligand itself is also in clinical trials," he said. In 2006, researchers from Zensun, a Chinese biotechnology company, showed that a human recombinant form of neuregulin1 improved heart function in rats and dogs. The company has since started testing neuregulin1-- dubbed Neucardin -- as a treatment for congestive heart failure in Phase 2 and Phase 3 clinical trials in China and Australia, and is set to start a Phase 2a trial in the US. Kühn and his group is further examining the molecular and cellular details of how neuregulin1 promotes proliferation. They are also characterizing the factor's effects on heart regeneration in pigs. A linkurl:study published earlier;http://www.ncbi.nlm.nih.gov/pubmed/19342590 this year in Science by Swedish researchers showed that in humans, roughly 1% of heart muscle cells renew each year, and less than half of the total number of heart cells are exchanged over a person's lifetime.Whether the new results will translate into humans is an "enormous question," said linkurl:Barry Greenberg,;http://cardiology.ucsd.edu/Default.aspx?tabid=51 director of the Advanced Heart Failure Treatment Program at the University of California, San Diego, School of Medicine, who did not participate in the study. "But at least it provides us with a potentially exciting new pathway to explore for treating patients with heart failure."The movie shows a differentiated mononucleated cardiomyocyte expressing a GFP tagged H2B fusion construct. Time-lapse video microscopy shows this cardiomyocyte undergoes karyokinesis (nuclear division), followed by cytokinesis (cellular division). This mononucleated cardiomyocyte completes the cell-cycle giving rise to two daughter cardiomyocytes. Credit: K. Bersell et al., Cell 138:257-70, July 24, 2009
**__Related stories:__***linkurl:The regenerative heart;http://www.the-scientist.com/blog/display/55086/
[13th October 2008]*linkurl:A waiting trial;http://www.the-scientist.com/article/display/54071/
[January 2008]*linkurl:Making a play at regrowing hearts;http://www.the-scientist.com/article/display/24104/
[August 2006]