ISCRM Researchers Discover “Missing Piece” of the Heart Regeneration Puzzle

Magnification of human stem cell-derived heart muscle cells (cardiomyocytes) stained for contractile proteins (red/green/yellow) and DNA (blue).

Nearly 18 million people die each year from heart disease, making it the leading cause of death in the world. In the United States alone, the annual economic impact of heart disease exceeds $200 billion, a figure that is expected to rise dramatically.

Patients with heart disease experience progressive, significant declines in quality of life marked by reduced activity and higher hospitalization rates. While lifestyle changes and medical treatments are available to slow the progression to end-stage heart failure, none have the ability to restore normal heart functioning.

Heart disease research projects underway at ISCRM are rapidly expanding our understanding about the nature of the human heart and pointing the way to treatments that could soon help people all around the world live longer, healthier lives. In 2018, a study led by ISCRM Director Dr. Chuck Murry demonstrated that stem cell-derived cardiomyocytes could be used to regenerate heart tissue in large primates, a major step toward human clinical trials, which are expected to begin as soon as 2020.

Now, in further evidence of progress, researchers from the University of Washington and the University of Cambridge have made a discovery that could lead to more effective treatments for heart disease

In a new study, recently published in Nature Biotechnology, scientists in Seattle and the UK report that injecting a mixture of cardiac muscle cells plus epicardial-derived cells enhanced heart regeneration in rats.  The mixture built larger muscle grafts with better blood vessels compared to either cell type alone, and this markedly enhanced cardiac function.

“The notion was to see if we could build better heart muscle by including stem cell-derived epicardial cells,” says Dr. Chuck Murry, the Director of the UW Institute for Stem Cell and Regenerative Medicine and co-senior author of the study, along with Dr. Sanjay Sinha at the University of Cambridge. “We found that if we added epicardial cells, the performance of the heart muscle was far superior to anything we had tested previously.”

One key to improved performance – characterized by better cardiomyocyte maturation, increased ability of the heart muscle cells to contract and relax, and enhanced vascularization – is the nature of epicardial cells.

Epicardial cells make up the epicardium, which forms the outer lining of the heart and gives rise to connective tissue – called fibroblasts – and to the smooth muscle cells that are essential for the development of blood vessels. In short, epicardial cells are vital building blocks for the connective tissue that makes cardiac structure and function possible.

It stands to reason that epicardial cells would be well suited to promote the growth of heart muscle tissue. The research team, however, needed to test this hunch by answering two primary questions. First, were epicardial more potent in building heart muscle than other connective tissue cells, like cells derived from skin and bone marrow tissue? Second, if so, could epicardial cells be a missing piece of heart repair? Would it work in practice?

Staining to show proteins in stem-cell derived heart muscle cell

Confirming the first hunch was relatively straightforward. In a series of tissue engineering experiments ex-vivo, epicardial cells clearly outperformed cells derived from other sources, building healthier, stronger muscle.

Testing the hypothesis – that epicardial cells would contribute to muscle tissue growth – was more complex in a living animal. The researchers had to clear a major hurdle: previously, scientists have been unable to successfully transplant epicardial cells and keep them alive in a living heart. Drawing on their expertise in stem cell transplantation, Murry and the ISCRM team coaxed the epicardial cells to engraft with heart cells in rats and to grow into fibroblasts.

The outcome was both logical and exciting: higher cell division rates led to muscle grafts that were three times bigger than grafts grown without epicardial cells.

In a central finding of the study, the research team shows that a monoculture of epicardial cells  was not the most effective approach. Rather, it was a combination of epicardial cells and cardiac muscle cells working together that did more for heart tissue regeneration than any single type of cell could do alone.

Murry emphasized the critical nature of the collaboration with the University of Cambridge. “We lent our know-how in cardiac biology and stem cell-based regeneration. Sanjay Sinha and Johannes Bargehr brought the pivotal missing piece, which was the ability to make the epicardial cells that play a starring role in this study.” As part of the intercontinental partnership, two scientists from the University of Cambridge did two six-month residencies each in the Murry lab to complete work behind the research effort.

Looking ahead, the researchers see several implications for the findings published in Nature Biotechnology. In the broadest sense, the results point to possible new approaches to treating heart disease around the world.

“There are hundreds of thousands of people in the UK living with heart failure – many are in a race against time for a life-saving heart transplant,” says Dr Sanjay Sinha. “But with only around 200 heart transplants performed each year in the UK, it’s absolutely essential that we start finding alternative treatments.”

Sinha’s colleague, Dr Johannes Bargehr, adds, “Our research shows the huge potential of stem cells for one day becoming the first therapy for heart failure. Although we still have some way to go, we believe we’re one giant step closer, and that’s incredibly exciting.”

Murry cited another benefit. “If we can get a graft that is three times bigger, we may be able to treat patients with one-third of the cells. When it comes to bringing a treatment to the clinic someday, that makes a difference in cost-effectiveness.”

Acknowledgements:

This research was funded by the British Heart Foundation, the United Kingdom Medical Research Council, the National Institute for Health Research, and the National Institutes of Health.

The YouTube movie below comparing the stem cell heart graft contractions is from the University of Cambridge and the British Heart Foundation: