Creating a platform to help transplanted stem cells survive after a heart attack

heart

Developing new tools to repair damaged hearts

Repairing, even reversing, the damage caused by a heart attack is the Holy Grail of stem cell researchers. For years the Grail seemed out of reach because the cells that researchers transplanted into heart attack patients didn’t stick around long enough to do much good. Now researchers at Stanford may have found a way around that problem.

In a heart attack, a blockage cuts off the oxygen supply to muscle cells. Like any part of our body starved off oxygen the muscle cells start to die, and as they do the body responds by creating a layer of scars, effectively walling off the dead tissue from the surviving healthy tissue.  But that scar tissue makes it harder for the heart to effectively and efficiently pump blood around the body. That reduced blood flow has a big impact on a person’s ability to return to a normal life.

In the past, efforts to transplant stem cells into the heart had limited success. Researchers tried pairing the cells with factors called peptides to help boost their odds of surviving. That worked a little better but most of the peptides were also short-lived and weren’t able to make a big difference in the ability of transplanted cells to stick around long enough to help the heart heal.

Slow and steady approach

Now, in a CIRM-funded study published in the journal Nature Biomedical Engineering, a team at Stanford – led by Dr. Joseph Wu – believe they have managed to create a new way of delivering these cells, one that combines them with a slow-release delivery mechanism to increase their chances of success.

The team began by working with a subset of bone marrow cells that had been shown in previous studies to have what are called “pro-survival factors.” Then, working in mice, they identified three peptides that lived longer than other peptides. That was step one.

Step two involved creating a matrix, a kind of supporting scaffold, that would enable the researchers to link the three peptides and combine them with a delivery system they hoped would produce a slow release of pro-survival factors.

Step three was seeing if it worked. Using fluorescent markers, they were able to show, in laboratory tests, that unlinked peptides were rapidly released over two or three days. However, the linked peptides had a much slower release, lasting more than 15 days.

Out of the lab and into animals

While these petri dish experiments looked promising the big question was could this approach work in an animal model and, ultimately, in people. So, the team focused on cardiac progenitor cells (CPCs) which have shown potential to help repair damaged hearts, but which also have a low survival rate when transplanted into hearts that have experienced a heart attack.

The team delivered CPCs to the hearts of mice and found the cells without the pro-survival matrix didn’t last long – 80 percent of the cells were gone four days after they were injected, 90 percent were gone by day ten. In contrast the cells on the peptide-infused matrix were found in large numbers up to eight weeks after injection. And the cells didn’t just survive, they also engrafted and activated the heart’s own survival pathways.

Impact on heart

The team then tested to see if the treatment was helping improve heart function. They did echocardiograms and magnetic resonance imaging up to 8 weeks after the transplant surgery and found that the mice treated with the matrix combination had a statistically improved left ventricular function compared to the other mice.

Jayakumar Rajadas, one of the authors on the paper told CIRM that, because the matrix was partly made out of collagen, a substance the FDA has already approved for use in people, this could help in applying for approval to test it in people in the future:

“This paper is the first comprehensive report to demonstrate an FDA-compliant biomaterial to improve stem cell engraftment in the ischemic heart. Importantly, the biomaterial is collagen-based and can be readily tested in humans once regulatory approval is obtained.”

 

A new way to make heart stem cells could potentially repair the damage of heart disease

Today we’re going to talk about heart failure. It’s a sobering topic given that over 20 million people world wide are currently suffering from this disease. Heart failure happens when the body’s heart can no longer pump blood effectively, which can lead to many nasty side effects and inevitably hastens death.

Typical strategies for treating heart failure focus on managing symptoms and delaying disease progression. But for patients, many of whom are elderly, a life of chronic management and frequent hospital stays is daunting. They deserve better.

Here’s where stem cell research could provide new treatments for heart failure. Some stem cells can be coaxed into new heart tissue that could repair damage and restore heart function. While other types of stem cells can release factors that facilitate the development of new blood vessels or that reduce tissue scarring, both of which improve heart function. Some of these treatments are being tested in clinical trials (for instance CIRM is funding a stem cell trial for heart disease sponsored by Capricor Therapeutics), although none have been approved yet.

But there’s good news on this front. Today, the Gladstone Institutes published a study in Cell Stem Cell describing a new method for making transplantable heart stem cells that improved heart function in mice and could potentially treat heart failure in humans.

A new method for making transplantable heart stem cells

The goal of the Gladstone study was to generate a specific type of heart stem cell called a cardiovascular progenitor cell that could survive and develop into the different types of mature heart cells to improve heart function when transplanted into mice.

Using technology previously developed in the lab of Gladstone Professor Sheng Ding, the team used a cocktail of chemicals to turn skin cells into cardiac progenitor cells (CPCs). These cells are like stem cells but specific to the heart and thus can only make heart cells. The CPCs they made had two important qualities: they could be expanded in a culture dish for multiple generations and they could develop into the three main types of adult heart cells (cardiomyocytes, endothelial cells and smooth muscle cells) that are required for heart regeneration.

Scientists made a new type of heart stem cell that can turn into the three main types of adult heart cells. (Image: Yu Zhang)

Gladstone scientists made a new type of heart stem cell that can make the three main types of adult heart cells. (Image: Yu Zhang)

Because of their ability to replicate and to become adult heart cells, they named these cells induced expandable cardiovascular progenitor cells or ieCPCs. They transplanted ieCPCs in mice that had suffered a heart attack and were pleased to see that 90% of engrafted cells (the ones that survived and stuck around) developed into functioning heart cells that worked seamlessly with the existing heart cells to improve the damaged heart’s ability to pump blood. From a single injection of one million ieCPCs, the improvements in heart function lasted for three months.

In a Gladstone News Release, first author on the study, Yu Zhang, explained why ieCPCs are better for transplantation into damaged hearts than adult heart cells like cardiomyocytes or the muscle cells of the heart:

“Scientists have tried for decades to treat heart failure by transplanting adult heart cells, but these cells cannot reproduce themselves, and so they do not survive in the damaged heart. Our generated ieCPCs can prolifically replicate and reliably mature into the three types of cells in the heart, which makes them a very promising potential treatment for heart failure.”

Another benefit to ieCPCs was that they did not generate tumors when transplanted. This can happen with non-heart stem cells or with cells derived from pluripotent stem cells.

What does the future hold for ieCPCs?

A heart attack can kill more than one billion heart cells, and while the heart has some regenerative ability, it cannot replace that many cells on its own. The Gladstone study is exciting because it provides a new population of heart stem cells that can be expanded in a dish to generate a large donor population of stem cells for transplantation.

Senior author Shen Ding spoke to the robustness of their new stem cell technology:

Sheng Ding

Sheng Ding

“Cardiac progenitor cells could be ideal for heart regeneration. They are the closest precursor to functional heart cells, and, in a single step, they can rapidly and efficiently become heart cells, both in a dish and in a live heart. With our new technology, we can quickly create billions of these cells in a dish and then transplant them into damaged hearts to treat heart failure.”

Additionally, their new method opens the doors for generating patient-specific stem cell treatments.

“Because these cells are generated from skin cells, it opens the door for personalized medicine, using a patient’s own cells to treat their disease.”

Sheng Ding’s lab is one to watch if you follow research in stem cell biology and regenerative medicine. We recently blogged about a different but equally important study from his lab where he made functional pancreatic beta cells from skin as a potential cell therapy for diabetes. I hope that his team will ultimately be able to translate their current research in both diabetes and heart disease towards clinical applications in humans.

Stem cell stories that caught our eye: new ways to reprogram, shifting attitudes on tissue donation, and hockey legend’s miracle questioned

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Insulin-producing cells produced from skin. Starting with human skin cells a team at the University of Iowa has created iPS-type stem cells through genetic reprogramming and matured those stem cells into insulin-producing cells that successfully brought blood-sugar levels closer to normal when transplanted in mice.

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left). [Credit: University of Iowa]

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left).
[Credit: University of Iowa]

The cells did not completely restore blood-sugar levels to normal, but did point to the possibility of achieving that goal in the future, something the team leader Nicholas Zavazava noted in an article in the Des Moines Register, calling the work an “encouraging first step” toward a potential cure for diabetes.

The Register discussed the possibility of making personalized cells that match the genetics of the patient and avoiding the need for immune suppression. This has long been a goal with iPS cells, but increasingly the research community has turned to looking for options that would avoid immune rejection with donor cells that could be off-the-shelf and less expensive than making new cells for each patient.

Heart cells from reprogramming work in mice. Like several other teams, a group in Japan created beating heart cells from iPS-type stem cells. But they went the additional step of growing them into sheets of heart muscle that when transplanted into mice integrated into the animals own heart and beat to the same rhythm.

The team published the work in Cell Transplantation and the news agency AlianzaNews ran a story noting that it has previously been unclear if these cells would get in sync with the host heart muscle. The result provides hope this could be a route to repair hearts damaged by heart attack.

Patient attitudes on donating tissue. A University of Michigan study suggests most folks don’t care how you use body tissue they donate for research if you ask them about research generically. But their attitudes change when you ask about specific research, with positive responses increasing for only one type of research: stem cell research.

On the generic question, 69 percent said go for it, but when you mentioned the possibility of abortion research more than half said no and if told the cells might lead to commercial products 45 percent said nix. The team published their work in the Journal of the American Medical Association and HealthCanal picked up the university’s press release that quoted the lead researcher, Tom Tomlinson, on why paying attention to donor preference is so critical:

“Biobanks are becoming more and more important to health research, so it’s important to understand these concerns and how transparent these facilities need to be in the research they support.”

CIRM has begun building a bank of iPS-type stem cells made from tissue donated by people with one of 11 diseases. We went through a very detailed process to develop uniform informed consent forms to make sure the donors for our cell bank knew exactly how their cells could be used. Read more about the consent process here.

Mainstream media start to question hockey legend’s miracle. Finally some healthy skepticism has arrived. Hockey legend Gordie Howe’s recovery from a pair of strokes just before the holidays was treated by the general media as a true Christmas miracle. The scientific press tried to layer the coverage with some questions of what we don’t know about his case but not the mainstream media. The one exception I saw was Brad Fikes in the San Diego Union Tribune who had to rely on a couple of scientists who were openly speaking out at the time. We wrote about their concerns then as well.

Now two major outlets have raised questions in long pieces back-to-back yesterday and this morning. The Star in hockey-crazed Canada wrote the first piece and New York Magazine wrote today’s. Both raise serious questions about whether stem cells could have been the cause of Howe’s recovery and are valuable additions to the coverage.