A new mechanism for healing hearts

Stem cell therapy helps hearts recover from heart attacks in an unexpected way

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CINCINNATI—Stem cell therapy does helps hearts recover from a heart attack — although not for the reasons originally proposed two decades ago that are the basis of ongoing clinical trials today. This is the conclusion of a study published today in Nature, which shows an entirely different way that heart stem cells help the injured heart, and not by replacing damaged or dead heart cells.
This study reports that injecting living or even dead heart stem cells into the injured hearts of mice triggers an acute inflammatory process, which generates a wound healing-like response to enhance the mechanical properties of the injured area.
According to Jeffery Molkentin, Ph.D., principal investigator of the study, director of Molecular Cardiovascular Microbiology at Cincinnati Children’s Hospital Medical Center and a professor of the Howard Hughes Medical Institute (HHMI), the secondary healing process mediated by macrophage cells of the immune system provided a modest benefit to heart function after heart attack.
“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 Molkentin. “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 paper builds on a 2014 study published by the same research team, also in Nature. Like the earlier study, the current paper shows that injecting c-kit positive heart stem cells into damaged hearts doesn’t regenerate cardiomyocytes.
The findings made Molkentin and his colleagues conclude that there is a need to “re-evaluate the current planned cell therapy based clinical trials to ask how this therapy might really work.”
The study worked with two types of heart stem cells currently used in the clinical trials, bone marrow mononuclear cells and cardiac progenitor cells. As researchers went through the process of testing and re-verifying their data under different conditions, they were surprised to discover that in addition to the two types of stem cells, injecting dead cells or even an inert chemical called zymosan provided benefit to the heart by optimizing the healing process.
The researchers reported that stem cells or zymosan therapies tested in this study altered immune cell responses that significantly decreased the formation of extra cellular matrix connective tissue in the injury areas, while improving the mechanical properties of the scar itself.
The authors noted that “injected hearts produced a significantly greater change in passive force over increasing stretch, a profile that was more like uninjured hearts.”
Molkentin and his colleagues found that stem cells and other therapeutic substances like zymosan need to be injected directly into the hearts surrounding the area of infarction injury. Most previous human clinical trials have injected stem cells into the circulatory system for patient safety reasons.
“Most of the current trials were also incorrectly designed because they infuse cells into the vasculature. 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,” Molkentin explained.
The researchers pointed out an interesting finding involving zymosan, a chemical compound that binds with select pattern recognition receptors to cause an acute innate immune response. Using zymosan to treat injured hearts in mice resulted in a slightly greater and longer-lasting benefit on injured tissues than injecting stem cells or dead cell debris.
Molkentin and the collaborating scientists plan to follow up the findings by looking for ways to leverage the healing properties of the stem cells and compounds they tested.
Since heart stem cells, cell debris and zymosan all triggered an acute innate immune response involving macrophages in the current paper, Molkentin said that researchers will test a theory that harnesses the selective healing properties of macrophages. This includes polarizing or biologically queuing macrophages to only have healing-like properties. Further testing could be very important for developing future treatment strategies.  

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