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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

Macrophage-mediated wound healing responsible for cardiac stem cell therapy

Stem cell therapy has been thought to regenerate heart cells by replacing damaged or dead heart cells. However, a latest research study has identified inflammatory-based wound healing as the mechanistic basis for cardiac stem cell therapy.

Stem cells have been under test in various clinical trials to regenerate damaged heart tissue. However, the mechanistic reason or the underlying biologic effect which leads to cardia tissue regeneration is lacking.

In the present study published in Nature, Dr Jeffery Molkentin and team at the Cincinnati Children’s Hospital Medical Center investigated the mechanistic basis for cardiac cell therapy in mice after a cardiac injury. An earlier study by the same group in 2014 found that injecting heart stem cells into damaged hearts failed to regenerate cardiomyocytes. This prompted the team to investigate the real reason how the stem cells work inside the heart.

The team injected live cardiac stem cells into the injured heart of mice and found that while heart function was enhanced, it was not associated with new cardiomyocyte production. Heart function was also enhanced when dead stem cell debris were injected. In both cases, the injection triggered an acute inflammatory process, which in turn generated a wound healing-like response to enhance the mechanical properties of the injured area. Interestingly, a similar immune response was also observed when zymosan, a substance known to induce innate immune response, was injected into the damaged heart in mice.

Further research identified macrophage cells as the mediators of the secondary healing process observed in these mice. The macrophage response altered cardiac fibroblast activity, reduced border zone extracellular matrix content, and enhanced the mechanical properties of the injured area leading to cardiac repair.

Thus, findings from the study demonstrate that an acute inflammatory-based wound healing response is indeed responsible for the functional benefit of cardiac cell therapy.

The team also found that stem cells and zymosan had to be injected directly into the hearts surrounding the area of infarction injury to have a beneficial effect. This contrasts with most past human clinical trials that injected stem cells into the circulatory system rather than close to the heart.

Dr Molkentin, Principal Investigator of the study commented: “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. Our results also 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. The implications of our study are very straight forward and present important new evidence about an unsettled debate in the field of cardiovascular medicine.”

Source: An acute immune response underlies the benefit of cardiac stem-cell therapy, Vagnozzi RJ et al., Nature, November 2019; DOI

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