Medicine: The Self-Healing Heart
Corn Flakes, X-rays, Viagra, Post-it notes, safety glass, rubber, penicillin and microwave ovens all improbably share a key factor: Each was invented by accident, when “chance,” as microbiologist Louis Pasteur put it, “favor[ed] the prepared mind.”
At the Hadassah–University Hospital on Mount Scopus’s Heart Institute, a chance occurrence six years ago suggested something revolutionary to the prepared minds of Hadassah researchers: Damaged hearts can be urged to heal themselves.
“Until recently, it was ‘known’ that the heart can’t regenerate, and therefore can’t repair itself,” says Dr. Ronen Beeri, director of Hadassah’s Cardiovascular Research Center. “It is only in the past decade that this assumption was challenged. Our finding… suggests a way to renew diseased or damaged heart tissue.”
This is welcome news for millions worldwide. A major health problem, heart disease is the second leading cause of death among 45-to-74-year-olds in Israel, and the leading cause in those over 75. In the United States, it accounts for one in every four deaths, killing 600,000 men and women each year and costing hundreds of billions of dollars annually. Cardiovascular care has been a major focus for Hadassah in Israel and the United States, from the opening of Jerusalem’s Linda Joy Pollin Cardiovascular Wellness Institute for Women to Every Beat Counts: Hadassah’s Heart Health Program.
The accidental discovery that has turned old assumptions on their head came about when Dr. Beeri and fellow researchers Drs. Avishag Korkus-Emanuelov, Jussi Leinonen and Sara Hoss were studying what happens when blood to the heart muscle is obstructed and its valves malfunction.
“Our study was part of ongoing research into myocardial infarction and valvular insufficiency that I began during my fellowship at Massachusetts General Hospital in Boston over a decade ago in collaboration with Dr. Robert A. Levine,” says Dr. Beeri. “To imitate valvular insufficiency, we placed a tube, or shunt, from the left atrium of a sheep’s heart to its left atrial appendage [the muscular pouch on the atrium’s upper left].”
A couple of days after the shunt had been inserted, part of its interior was unexpectedly covered with newly growing tissue. “To our very great excitement, it looked like cardiac tissue,” recalls Dr. Beeri. “It seemed the heart was regenerating itself—something long thought impossible!”
In follow-up studies on mice, the research team found that the left atrial appendage, a pouch whose function has never been understood, contains a reservoir of cardiac stem cells—a stem cell niche—and it was these primitive cells that were responsible for the new tissue, stimulating the heart to repair itself.
Stem cells, the flexible unspecialized progenitors that can develop into any of the more than 200 specialized cell types in the human body, are believed to hold the promise to cure the currently incurable.
Until recently, scientists primarily worked with two kinds of stem cell: those drawn from embryos and those from bone marrow. Then came the discovery of adult stem cells in many of the body’s organs and tissues. Those that Dr. Beeri’s team found in the heart’s left atrial appendage contain proteins that serve as markers for the fetal development of cardiac cells.
“We examined left atrial appendage stem cells from mice, rats and, later, those therapeutically removed from patients with arrhythmic disturbances,” says Dr. Korkus-Emanuelov. “All matured into adult cardiac cells. Some even began beating in the petri dish! It was incredibly exciting. It confirmed what we hoped.”
Dr. Leinonen grew several populations of these cells and watched them differentiate not only into heart muscle cells but also into those for the heart’s tiny blood vessels, its connective tissue and, perhaps most significant, its inflammatory cells, the scouts that apprehend antigens.
These findings were published in the medical journal PLOS ONE. “The indications are revolutionary,” says Dr. Beeri. “It means that the heart contains stem cells that can turn into cells able to stimulate an injured heart to heal itself. And that when they do so, they provide a complete cardiac support package—re-creating the essential blood supply damaged by disease so that new cells can grow.”
The Hadassah team’s startling finding makes sense of two curious observations of the past decade. First, in Britain, new heart cells were found in young patients with inflamed heart muscle: Mechanically supported because their hearts could not pump adequately, they appeared to grow new cardiac cells. Second, children and teens of the 1950s were found to have significantly higher radioactive carbon levels in their heart cells, absorbed from the fallout of atmospheric nuclear and thermonuclear testing during those years. While both observations suggest that the heart may, after all, regenerate itself, they were largely disregarded because of the prevailing wisdom.
The discovery that the heart has its own stem cell niche comes on the heels of several attempts to create replacement heart cells. Researcher Dr. Lior Gepstein at Haifa’s Technion–Israel Institute of Technology developed cardiac cells from embryonic stem cells and created a biological pacemaker; unfortunately, however, the tendency of embryonic stem cells to grow out of control could not be overcome. French Jewish cardiovascular surgeon Philippe Menasche at the Hôpital Européen Georges Pompidou in Paris implanted skeletal muscle cells into heart muscle, but achieved scant improvement and created heart arrhythmias. Most promising, until the accidental growth on the sheep’s heart shunt, was the 2006 discovery by Japanese researcher Shinya Yamanaka that specialized adult cells can be reprogrammed—pushed back into immature cells and then redeveloped into cells for any body tissue. Known as induced pluripotent stem cells, they are more useful for research than in patients as they, too, have a tendency to form tumors.
The new approach to healing the heart opened by the discovery on the shunt, the team believes, is the most promising, though “there is a long way to go before we get to clinical application,” says Dr. Beeri. “We are now studying the signals that summon the heart’s regenerative cells to where they are needed. In simple terms, we put these cells on one side of the petri dish and put different signaling compounds—hormones, chemicals—on the other. By photographing the movement of cells across the dish, we can construct a graph of how they respond to each and eventually create a cocktail that delivers the most effective summons.”
While this is currently the main thrust of the team’s work, they are also investigating other ways of using the heart’s stem cells. “A damaged heart will often remodel itself to try and work better,” explains Dr. Beeri. “If it is pumping inefficiently, it may, for example, take in a larger volume of blood to compensate—which, in the long run, will destroy it. Researchers have tried to prevent this by changing the heart’s geometry, inserting a silicone patch so that the damaged area is bypassed and so prevent the heart harming itself. With the Boston team, we are exploring whether the left atrial appendage can be used in place of the silicone patch: If we spread the pouch over the damaged area, perhaps the stem cells will start growing, leading to a new form of bandaging. While there are no results yet, indications are that it may work.”
As scientists working on the brink of discovery, Dr. Beeri and his colleagues saw the magic in the unexpected growth of tissue on a shunt deep in a sheep’s heart—a chance occurrence that may lead to an easy and effective treatment for one of mankind’s most relentless killers.