Scientists have discovered how stem cell therapies repair heart tissue — and not by replacing damaged cells with new cells, as previously thought. Instead, injecting stem cells into the injured hearts of mice triggered an inflammatory response that improved the wound healing process by altering the immune response, according to a new paper published on 27 November in Nature (1).
Although available in many clinics, stem cell therapies for the heart remain controversial and there is little evidence they actually work. To date, the results of clinical trials have been uninspiring. Whereas, scientists have demonstrated that injecting stem cells into cardiac tissue after a heart attack can help repair heart tissue in mice. So why don’t we see these effects in humans?
Researchers initially surmised that the short-term effects of stem cells seen in animal studies must be due to stem cells replacing damaged heart cells called cardiomyocytes. However, another study published in 2014 by Prof Jeffery Molkentin’s group concluded that injected stem cells do not become cardiomyocytes.
How do stem cells therapies repair the heart?
To investigate further, the researchers injected two types of heart stem cells currently used in the clinical trials — bone marrow mononuclear cells and cardiac progenitor cells — into the injured hearts of mice. As hoped, heart function was significantly improved in mice that received cell injections compared to the sham group. But unexpectedly, the authors discovered that even dead stem cells offered the same benefits.
The authors explain that the improved wound healing response is actually driven by an inflammatory process triggered by the injected stem cells. And this modified immune response, which involves a type of immune cells called macrophages, was found to enhance the contractile properties and function of the heart muscle.
“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, lead investigator at the Cincinnati Children’s Hospital Medical Center and Howard Hughes Medical Institute, said in a statement. In other words, the inflammatory response triggered by the stem cells produces scar tissue that is more similar to normal tissue and can, therefore, function better.
Even more interesting, the results were mimicked with zymosan, a chemical known to elicit a similar immune response. In fact, zymosan — which binds to certain immune cell receptors — resulted in slightly enhanced and longer-lasting benefits compared to the stem cells.
Then, when macrophage activity was suppressed in some mice, the effects were not observed with either the cells or zymosan.
Re-evaluating how stem cell therapies work
Based on these results, the authors suggest current trials are not properly designed since the cells are typically injected into the bloodstream — to ensure patient safety — and not directly into the heart tissue, which is where the healing process actually occurs and “macrophages can work their magic”.
But this doesn’t mean stem cells cannot be turned into useful heart cells. For instance, other studies have shown that cardiomyocytes derived from embryonic stem cells can repair heart tissue. However, researchers will need to re-evaluate how current clinical trials are performed and which strategies could have safe and beneficial effects in people.
Furthermore, the authors suggest we may not need to inject living cells since the observed therapeutic responses were triggered by inflammation; therefore, the immune response rather than the regenerative capacity of the cells themselves more likely provides benefits. Importantly, the findings might provide new avenues for leveraging the power of stem cells that are less expensive and less time consuming than traditional stem cell therapies.
(1) Vagnozz, R.J. et al. An acute immune response underlies the benefit of cardiac stem-cell therapy. Nature (2019). DOI: 10.1038/s41586-019-1802-2
(2) van Berlo, J.H. et al. c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature (2019). DOI: 10.1038/nature13309