A study reports that injecting live or even dead cells into the injured hearts of mice during stem cell therapy triggers an acute inflammatory process. This in turn creates a response to improve the mechanical properties of the injured area. The secondary healing process mediated by macrophage cells of the immune system provided a modest benefit to heart function after a heart attack, according to Jeffery Molkentin, PhD, principal investigator, director of Molecular Cardiovascular Microbiology, a Cincinnati Children's Hospital Medical Center, and professor of the U.S. Board of Heart Disease Hughes Medical Institute (HHMI).
Benefits of stem cell therapy
“The innate immune response acutely altered cellular activity around the injured area of the heart, allowing it to heal with an optimized scar and improved contractile properties,” Molkentin said. “The implications of our study are very simple and provide important new evidence to an unresolved debate in the field of cardiovascular medicine.”
The new paper builds on a study published in 2014 by the same research team, also in Nature. As in this previous study, the current work shows that injecting c-kit positive cardiac stem cells into damaged hearts asRegeneration strategyof cardiomyocytes does not work. The results led Molkentin and his colleagues to conclude that “currently planned cell therapy-based clinical trials need to be reevaluated to ask how this therapy might actually work.”
An unexpected discovery
The study worked with two types of cardiac stem cells that scientists are currently using in clinical trials. These are the mononuclear bone marrow cells and the precursor cells of the heart. When the researchers tested and re-examined their data under different conditions, they were surprised to find that in addition to the two types of stem cells, injecting dead cells or even an inert chemical called zymosan also provided benefits to patients and the heart by optimizing the healing process. Zymosan is a substance that is intended to trigger an innate immune response.
The researchers reported that the stem cell therapy in this study altered immune cell responses. This significantly reduces the formation of additional cellular matrix connective tissue in the injured areas. At the same time, the mechanical properties of the scar itself also improve. The authors concluded: “Hearts injected with stem cells produced a significantly greater change in passive force with increasing stretch, a profile that was more like that of uninjured hearts.”
Molkentin and his colleagues also found that they needed to inject stem cell therapy and other therapeutic substances such as zymosan directly into the hearts around the area of injury. This contrasts with most previous human clinical trials, in which researchers simply injected stem cells into the circulation for patient safety reasons.
“Most current studies have also been designed incorrectly because they infuse cells into the vascular system,” Molkentin explained. “Our results show that the injected material must go directly into the heart tissue flanking the infarct region. This is where the healing takes place and the macrophages can work their magic. The researchers also discovered an interesting finding. Zymosan is a chemical compound that binds to selected pattern recognition receptors to trigger an acute innate immune response. Using Zymosan to treat injured hearts in mice resulted in slightly greater and longer-lasting benefits to injured tissues than injecting stem cells or dead cell debris.
Looking into the future
Molkentin said he and other collaborating scientists will look for ways to harness the healing properties of the stem cells and compounds tested. Noting that cardiac stem cells, cell debris and zymosan triggered an acute innate immune response involving macrophages, Molkentin explained that they will test a theory that exploits the selective healing properties of macrophages. This includes polarizing or biologically arranging macrophages to only have healing-like properties. Further testing could be therapeutically very important to develop future treatment strategies.
