Stem cell therapy helps restore heart after a heart attack in an unexpected way. At the same time, damaged and dead cardiomyocytes are not replaced by new cells, as originally assumed.
A new study showed that the basis for stem cell restoration after a heart attack is not the biological processes that are now being studied in ongoing clinical trials, as was originally proposed two decades ago.
An article, published in Nature, reported that injecting living or even dead heart stem cells into the damaged heart of mice provokes an acute inflammatory process, which in turn causes a reaction similar to wound healing, improving the mechanical properties of the injured area.
Indirected by macrophages, immune system cells, the secondary healing process restores cardiac 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 a professor of the Howard Hughes Medical Institute, HHMI.
“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”, – Molkentin said. “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 new article is based on a 2014 study published by the same group of scientists, also in the journal Nature. As in the previous work, the current article shows that the injection of c-kit-positive heart stem cells from the heart into a damaged heart does not work as a method for regenerating cardiomyocytes. The results prompted Molkentin and his colleagues to conclude that it was necessary to “re-evaluate the current planned cell therapy based clinical trials to ask how this therapy might really work.”
An Unexpected Discovery
The study used two types of heart stem cells currently used in clinical trials – bone marrow mononuclear cells and cardiac precursor cells.
Conducting tests and re-checking the data under various conditions, the researchers were surprised to find that in addition to injecting two types of stem cells, the introduction of dead cells or even the inert chemical substance zymosan also improves the condition of the heart, optimizing the healing process. Zymosan is a substance designed to stimulate an innate immune response.
Researchers reported that the stem cell or zymosan treatment tested in this study changed the response of immune cells, significantly reducing the formation of extracellular matrix connective tissue at the sites of injury, as well as improving the mechanical properties of the scar itself.
Molkentin and colleagues also found that stem cells and other therapeutic substances, such as zymosan, have to be injected directly into the area of the heart surrounding a heart attack. This contradicts most past clinical studies in humans, in which, for safety reasons, stem cells were simply inserted into the circulatory system of patients.
“Most of the current trials were also incorrectly designed because they infuse cells into the vasculature”, – Molkentin explained. “Our results show that the injected material has to go directly into the heart tissue flanking the infarct region. This is where the healing is occurring and where the macrophages can work their magic.”
Looking to the Future
Molkentin said his group plans to study the results to find ways to use the healing properties of stem cells and compounds that have been tested. For example, scientists intend to find out how heart stem cells, cell debris and zymosan trigger an acute innate immune response involving macrophages. Molkentin explained that they will test a theory that uses the properties of selective healing of macrophages, including polarizing or biologically queuing macrophages, which have only healing properties.
Further research, he said, could be important for developing future treatment strategies.