Stem cells: When will they heal the heart?
It’s been 15 years since a University of Wisconsin-Madison researcher isolated embryonic stem cells — the do-anything cells that appear in early development. It’s been six years since adult human cells were transformed into the related induced pluripotent stem cells.
And yet the early hope to grow “spare parts” — turning stem cells into specialized cells for repairing a failing brain, pancreas or heart, remains mostly promise rather than reality.
Researchers have since found how to transform stem cells into a wide variety of body cells, including heart muscle cells, or cardiomyocytes. But the holy Grail — tissue supplementation or replacement — remains tantalizingly out of reach.
Last week, Why Files attended a symposium on treating cardiovascular disease with stem cells, at the BioPharmaceutical Technology Center Institute near Madison, Wis. We found the picture unexpectedly complicated: as multiple kinds of stem cells are grown and delivered in a bewildering variety of ways to treat a catalog of conditions.
So far, stem cells have not been approved to treat any heart disease in the United States.
Still, the need remains clear. Disorders of the heart and blood vessels, which deliver oxygen and nutrients to the body, continue to kill. “Today, one of every 2.6 Americans will die of some cause related to their heart,” writes Columbia University Medical Center.
Not an easy project
Heart muscle dies when a blood clot blocks the blood supply. Heart muscle does not regenerate, and a major attack can cause death or a lifetime of heart disease.
So why have injections of heart muscle cells grown from stem cells produced only transitory benefits? “There is a battle between the heart and what it is willing to receive,” says Warren Sherman, director of cardiac cell therapy at Columbia University Medical Center.
“Even with normal heart architecture, it’s not a very friendly place for cells to find a home,” Sherman says. “The fluid flow rate is so high that many things get pushed out.” And in the areas that are scarred by heart attack, “there is nothing for the cells to adhere to.”
As a result, “Cell retention rates are just horrible,” Sherman says. “You are lucky, with any [heart] disease, with any delivery method, if you have 5 percent of the cells present 24 hours later.”
The brain or pancreas, two other potential sites of cell therapy, do not suffer from these hindrances.
Researchers have injected muscle cells into blood vessels, inside or outside the heart. They have also injected cells into the muscle of a heart that is still beating. A batch of stem cells can also be seeded onto a “patch,” a fibrous glob that gloms onto the damaged muscle.
Cardiac clinical trials are difficult for a number of reasons:
* Source: Clinical trials have mainly used cardiac cells grown from induced pluripotent stem cells, often grown from the patient’s own skin cells. This process eliminates the risk of immune rejection but can carry the risk of sparking a tumor. Investigators are now exploring a wider range of stem cell sources.
* Differentiation: The methods used to coax stem cells to become heart muscle cells can affect results, and must be standardized before regulatory approval.
* Patients: The criteria for including and excluding patients can affect results. For ethical reasons, trials have focused on the sickest patients, but they tend to have conditions like diabetes that disqualify them from study. Studies that use magnetic resonance machines to quickly assess the results must exclude the many heart patients who carry pacemakers and cannot go near the MR’s super-magnets.
* Patients, again: People are getting quite choosy about joining trials, says Andrea Hunt, vice-president of Baxter International. “The Internet allows people to go far and wide looking for options.” Clinical trials offer hope, but participants are usually not guaranteed to get the actual treatment; up to half get a placebo instead.
* Complexity: Stem cells are vastly more complicated than medicines, says Timothy Kamp, co-director of the Stem Cell and Regenerative Medicine Center at the University of Wisconsin-Madison. “Drug companies say that even a small molecule, from concept to FDA approval, will take 10 or 15 years. And a drug is something we can chemically define, it has a structure, we can purify it. With a cell you are talking about 100,000 molecules all mixed up, dancing a complicated dance. It’s harder to control, but more powerful than a single molecule. This is going to take time to master, to find the right cell for the right job.”
Got the money?
The large, phase III clinical trials needed for FDA approval of a biological treatment typically enroll hundreds of patients at multiple sites, which can be hideously expensive. “Any phase III trial is going to cost at least $100 million, and it goes up from there,” says Hunt.
Even when preliminary results are promising, trials can be torpedoed when the sponsoring company changes its business goals, is bought out, or runs short of money.
For example, the “MARVEL” study, which grew stem cells from the patient’s muscle into early-stage heart muscle cells, or myoblasts, produced “a strong indication of improvement in symptoms and exercise capacity in 21 patients,” says Sherman, who played a role in the trial. “It was safe, but the company [Bioheart, Inc.] was broke … and that’s how it ended. Whether the results were positive or negative, we would have put up a number, and that number still does not exist.”
Stem cell trials must also account for procedures in particular medical fields, said Ann Remmers of Aastrom Biosciences. After a recent stem-cell trial for chronic limb ischemia, which reduces blood flow and can require amputation, “we needed to think through the practice patterns of vascular surgeons. We wanted to treat subjects who had no further options for surgery, but the surgeons we work with are very talented,” and were able to do reparative surgery until shortly before amputation was needed. “The vascular surgeons are making the decisions based on what is best for the patient, and we needed to have thought more about how to integrate the trial into their practice,” Remmers said.
Special stem cell delivery
To date, stem cells have not done much to help people with heart disease. Despite some limited improvement, by six months, the benefits have generally washed out.
“Typically you just give a single dose,” says Eric Schmuck, who works with Amish Raval, an assistant professor of cardiovascular medicine at UW-Madison. “Nobody has done two doses.”
And so Raval and Schmuck are testing a two-dose “prime and boost” strategy. The mesenchymal stem cells they are using originate in the placenta, and are known to fight inflammation, slow down the immune system, and promote blood-vessel growth.
In an ongoing test with pigs, the prime dose is given intravenously shortly after blood flow to part of the heart is stopped, Schmuck says. The resulting inflammation seems to attract the stem cells, which calm the inflammation.
Thirteen days later, 13 injections of the booster dose — totaling about 100 million cells — are squirted into the edge of the damage. “The first dose alters conditions to make the heart more receptive to the second dose,” Schmuck says. “When you reduce inflammation and stimulate blood-vessel growth, the cells have an easier time grafting.”
The experiment is ongoing, but there are early measurements in blood pressure and volume, and heart size and weight, Schmuck says. The treated hearts show a more regular heartbeat, without a systemic immune response.
Curiously, Schmuck doubts that the benefits come from cell replacement. “I think the cells secrete good vibes, juices, that either attract innate stem cells from the heart or help preserve heart muscle cells that are damaged.”
If the study continues to be safe and beneficial, the researchers hope to propose a small human trial of prime and boost within a couple of years.
Meeting your matrix
In the body, most cells grow in a mushy, 3-D world, but in the lab, they grow on hard, flat dishes. This discrepancy may account for some of the difference between real life and lab-life results, says Brenda Ogle, an associate professor of biomedical engineering at the University of Wisconsin-Madison.
Ogle is exploring structures to hold stem cells in a more lifelike configuration, and she finds that mesenchymal stem cells differentiate much as they do on a 2D dish, when held in a lab-built 3D structure of polyethylene glycol.
However, the timing of differentiation is different, Ogle says, possibly due to altered activation of cell-surface receptors, or to the fact that “tissue culture takes place on a stiff, rigid surface,” while the 3D structure is more flexible.
The 3D structure that Ogle is testing contains bits of extra-cellular matrix (ECM) proteins, such as collagen, which normally separates cells. “People used to think of ECM as girders and beams, a structural support for cells,” says Ogle. “We now know that it has other important functions,” such as storing growth factors. “If there is tissue trauma and the ECM breaks down, that may release growth factors that help the tissue respond to damage.”
Ogle’s goal is to build a patch that could stick to the heart and deliver stem cells. Although a disturbing number of cells are flushed away with existing delivery technologies, Ogle’s lab has achieved 70 percent retention by delivering mesenchymal stem cells on a patch made of cow collagen.
Endothelial cells to the rescue?
On the inside, of blood vessels are lined with endothelial cells that help regulate blood pressure, prevent clots, and regulate transport of molecules in and out of blood. Endothelial problems are a cause and symptom of a variety of conditions, including stroke, diabetes and coronary artery disease.
Could endothelial cells play a role in organ regeneration? Yes, says Shahin Rafii, a Howard Hughes Medical Institute investigator at Weill Cornell Medical College. “People think of endothelial cells as inert conduits to deliver oxygen and nutrients. We think maybe they can be the magic bullet, that we can transplant them to promote organ regeneration.”
Like the prime and boost example, the effect is less likely to be cell replacement and more creating a hospitable niche for existing heart cells.
The cells that line capillaries are in a unique position to affect stem cells, Rafii says. “Every stem cell, everywhere, resides next to a capillary. If I tweet a molecule through the capillaries, within seconds, every stem cell in body will know what is going on.”
Rafii adds that endothelial cells trigger growth in organs that are able to regenerate, like the liver and bone marrow. But the regrowth fails if, for example, the endothelial cells come from a different tissue.
Focusing on regeneration is an alternative path to stem-cell therapy, Rafii says. “I argue that if we can engineer organ-specific endothelial cells and transplant them, they will find the right zip code [in the target organ], and cause regeneration.”
If the endothelial cell hypothesis is unusual, so is the proposed source: cells gathered from amniotic fluid during amniocentesis, a common test for fetal health and gender.
“I believe amniotic cells can be used to regenerate bone marrow, lung and liver, if we can solve the immunology problem,” Rafii says. Discarded tissue from the 1 million amniocentesis procedures performed each year in the United States could provide an enormous, diverse stockpile of cells for transformation and transplant.
If Rafii is correct, understanding the signals from endothelial cells could be a significant advance, Kamp says. “Maybe the endothelial cells are telling the heart stem cells and other repair mechanisms to turn on. If you have sick endothelial cells, like with coronary artery disease, those endothelial cells are probably not singing the right song. If we could help them, we could help the heart.”
Nobody can say where, how and when stem cells will become an accepted treatment for cardiovascular disease. But if you combine the extraordinary promise of these cells with the scientific creativity and the profit potential of any treatment that really restores heart muscle, it’s almost inevitable that hearts and blood vessels will eventually benefit from stem cell therapy.
Kamp thinks considerable progress has taken place: “Cell therapies are advancing. We are testing different cell products in patients with heart disease. The real question is what is going to be the right cell for the right job. There are different diseases with different needs, and different cell products and delivery mechanisms. All that has to be worked out, optimized and tested. Clinical trials to develop these take time.”
But patients are still dying, and stem cells are only available from a few small clinical trials within the world regulated by the U.S. Food and Drug Administration. For patients, that’s frustrating, says Sherman, who has been involved with cardiac cell therapy for many years; “I feel greatly for patients out there. We have raised the level of expectation, from the moment stem cells hit the front page, and fairly so, for good reason. Yet it has dragged on, again for good reason, and we still don’t know how to advise them.”
Basic breakthroughs always seem to take too long, Kamp observes. Research into implantable defibrillators, used to stop heart attacks by stabilizing heart electrical rhythms, began in the 1960s, but they were not in wide use by surgeons until the ’90s. “It’s not unusual for these revolutionary technologies to take a decade or more before they start to enter clinical practice.”
— David J. Tenenbaum