By injecting a protein into mice with heart damage, researchers in Boston have shown that it’s possible to cause adult heart-muscle cells to proliferate and cardiac function to improve. The approach could eventually prove valuable for heart-attack patients who have lost cardiac-muscle cells and some cardiac function, especially since existing therapies are unable to regenerate or restore these lost cells.
Several large research groups are working on techniques to regenerate heart tissue or shore up heart function using stem cells, and some of these projects have reached clinical trials. The Boston team’s work, led by Bernhard Kühn at Children’s Hospital Boston, instead focuses on stimulating adult heart cells, an alternative approach that could, in theory, lead to less invasive and less expensive treatments.
Kühn’s work is “very exciting” in that it involves using “protein therapy to harness cardiac regeneration,” says Roger Hajjar, director of the cardiovascular research center at Mount Sinai Medical Center in New York, who was not involved in the research.
For years, the prevailing dogma was that adult cardiac cells do not regenerate. Some researchers have shown, however, that at least some cardiac cells are, in fact, capable of dividing. But following a heart attack, they do not proliferate sufficiently to repair the resulting damage. Kühn’s work suggests a novel way in which they could be stimulated to do so.
Repair job: The green spots in this video show the division of cardiac-muscle cells as a result of the experimental treatment.
Credit: Bernhard Kühn/Cell
In a study published today in the journal Cell, Kühn and colleagues first showed that a protein called neuregulin1 can cause fully mature heart-muscle cells from mice to divide and proliferate in a petri dish. The researchers then injected this protein into mice with heart damage. After 12 weeks of daily injections, the animals’ hearts showed less hypertrophy, or enlargement, and improved function. For instance, the hearts had about a 10 percent increase in ejection fraction–the fraction of blood pumped out of the left ventricle with each beat. The treatment “didn’t make the damage go away completely,” says Kühn, “but it did make the heart work significantly better.”
Going forward, one potential worry is that Kühn’s team injected the protein systemically, meaning that it traveled throughout the animals’ bodies. In addition to the heart, cells in the breasts and nervous system also express receptors for the therapeutic protein, which raises the risk of unwanted cell division. “We were nervous about the treated mice developing breast tumors or producing milk,” Kühn acknowledges. “We did not see abnormalities when we looked at the breasts macroscopically. But we plan to study breast and nervous tissue,” more closely in future research, he says. A therapy that could be injected directly into the blood would be relatively easy and inexpensive to administer, he notes.
However, others say that systemic injections would be too risky in people, especially since cancer cells might already be present in some patients. If this therapy were to move forward, it would be “extremely important to deliver the protein locally,” says Hajjar.
A few previous studies have also shown that proteins injected into animal models can cause division of adult heart cells and improvement in cardiac function. In 2007, Kühn found that a different molecule, a protein called periostin, also caused some cardiac-muscle cells to proliferate, improving heart function. In 2006, another group at Children’s Hospital Boston used a regimen with a protein called fibroblast growth factor and found that it too resulted in heart-cell proliferation, reduced scarring, and improved function.
Most animal and human studies have focused, however, on various kinds of stem cells. Many researchers believe that the adult heart contains a small number of tissue-specific stem cells, which could potentially play a role in regeneration and repair. Piero Anversa of Brigham and Women’s Hospital in Boston recently began phase-one trials for an approach in which cardiac stem cells are isolated from patients, expanded in the lab, and then reinjected. Anversa has shown that a cocktail of growth factors, injected into dogs, causes native cardiac stem cells to differentiate into mature cells and improve heart function. Meanwhile, Eduardo Marban, director of the Cedars-Sinai Heart Institute in California, has pioneered a related technique. His team removes small pieces of tissue from patients’ hearts, grows a collection of cells, including cardiac stem cells, and then injects the cells into patients’ coronary arteries.This work is also in phase-one trials.
Other researchers are focusing on stem cells derived from bone marrow. And in other research conducted in pigs and, preliminarily, in humans, the use of bone-marrow cell therapy has improved heart function.
One advantage of cell therapy is that the cells could be administered less often, in theory, than a drug or protein therapy, says Joshua Hare, director of the Interdisciplinary Stem Cell Institute at the University of Miami, although the administrations would also likely be more invasive. Several cell-therapy approaches are also further along in the research process and could potentially be available to patients sooner.
Still, there may be some overlap in how protein therapy and cell therapy could work in the heart. Some of the benefits of cell therapy may come from stimulating endogenous pathways similar to or the same as the one targeted by Kühn, says Hare. It’s possible that part of the underlying biology is similar, he adds, and “we just have to figure out the best way to manipulate it.”