The injection of stem cells into the hearts of patients who have suffered a heart attack can help the heart to heal. Currently clinical trials are underway to test this cardiac stem cell therapy, but a new study published in Nature indicates the cell therapies work in an unexpected way.
Stem cells can differentiate and mature into healthy cells, so it was thought that introducing them into heart tissue would help the hearts heal after a heart attack. While the exact mechanisms involved are not known, it was believed that the stem cells would engraft and differentiate into heathy heart cells to replace the damaged or dead cells. All that was known was that introducing the stem cells was beneficial in some patients.
Stem cell therapy for heart attack patients was first suggested more than two decades ago and over the years there have been many pre-clinical and clinical trials using cardiac stem cells, but the results have been modest at best. Since the exact mechanisms involved were not known, there has been considerable debate as to the best types of stem cells to use, how those stem cells should be introduced, and which patients would be most likely to benefit from the treatment.
The latest research conducted at Cincinnati Children’s Hospital suggests it is not the stem cells themselves that help the heart heal, rather it is the immune response to the introduction of the stem cells that provides the benefits. The researchers found that it did not matter whether healthy or dead stem cells were introduced into the injured hearts of mice, the results were the same.
The latest research helps clarify exactly what is happening when the stem cells are introduced and reveals the mechanism involved, which has eluded cardiologists after decades of cardiac stem cell trials.
The researchers hypothesized that in order for the treatments to be effective, the introduced stem cells would be required to remain in the heart. They conducted a series of experiments to investigate whether five of the most commonly used stem cell types ever engrafted in heart tissue when they were introduced, but none of the five did. Within two weeks of injection into heart tissue, none of the introduced stem cells remained. In many cases, the stem cells were totally eliminated from the heart within a week.
What the researchers did notice, is that when all five types of stem cell were introduced into mice with injured hearts, there was a marked inflammatory response. The researchers found that the innate immune response was triggered regardless of stem cell type, whether the stem cells were alive or dead, and the inflammatory response was also triggered with the introduction of the immune system activator, zymosan. The researchers tested their theory by introducing the innate immune system suppressant, cyclosporine, and the benefits of the stem cells were lost.
Further research showed that the introduction of live or dead stem cells or zymosan resulted in improved muscle mechanical properties, scar reduction, or scar remodeling. The research indicated that the treatments recruited certain subtypes of macrophages, which appeared to be driving the remodeling.
“The innate immune response acutely altered cellular activity around the injured area of the heart so that it healed with a more optimized scar and improved contractile properties,” said Jeffery Molkentin, PhD, principal investigator, director of Molecular Cardiovascular Microbiology a Cincinnati Children’s Hospital Medical Center and professor of the Howard Hughes Medical Institute. “The implications of our study are very straight forward and present important new evidence about an unsettled debate in the field of cardiovascular medicine.”
The researchers also found that the treatment was only effective if the stem cells or zymosan were injected into the part areas of the heart directly flanking the infarct. That is the area where the healing occurs and where the macrophages have their effect.
The researchers at Cincinnati Children’s Hospital are now planning further studies to determine how the healing properties of macrophages can be harnessed.
The study is detailed in the paper – An acute immune response underlies the benefit of cardiac stem-cell therapy – which was recently published in Nature. DOI: 10.1038/s41586-019-1802-2