Inflammation, not division

The therapeutic effect of stem cells on the heart was explained by inflammation

Polina Loseva, N+1

Scientists have found an explanation for how stem cells help the heart recover after a heart attack. The researchers did not find any cell division in this process (as previously thought), instead, stem cells triggered inflammation in the heart, which prevented the muscle from overgrowing with connective tissue. At the same time, not only live, but also dead stem cells, and even a carbohydrate isolated from yeast, had the same effect. The study is published in the journal Nature (Vagnozzi et al., An acute immune response underlies the benefit of cardiac stem-cell therapy).

Treatment of the heart with stem cells is a controversial technology, which is associated with many scandals. At first, it was proposed to use the organ's own stem cells for treatment. However, in 2018, traces of falsifications were found in the works of their discoverer Pietro Anversa, after which several dozen of his articles were withdrawn from magazines. At the end of 2018, an independent group of scientists re–disassembled the mouse heart into separate cell types and found no traces of stem cells - that is, those that are actually able to divide and heal damage -.

However, in preclinical animal trials, the introduction of several types of stem cells, not only cardiac, improved heart function after injury. Therefore, some research groups have already begun to try this method on humans. Despite this, there is still no consensus among scientists about the mechanism by which stem cells exert their healing effects.

A group of scientists from the Medical Center at the Children's Hospital in Cincinnati, led by Jeffery Molkentin, tracked the reaction of the heart to the introduction of different types of cells.

At first, they worked with healthy mouse hearts. The animals were divided into several groups. The first was injected into the heart stem cells from red bone marrow: this is a mixture of hematopoietic cells and mesenchymal stem cells, which can give different types of connective tissue. The second group got zymosan, a polysaccharide from the yeast cell walls; it is known for its ability to cause inflammation. The third group received the usual saline solution, and the fourth served as a control – they were given an empty injection.

Compared with an empty injection and saline solution, zymosan and red bone marrow cells caused an inflammatory response in the heart: the number of activated macrophages increased by about 4 times: from 10 to 40 percent. But the number of dividing cells in the heart has practically not changed – only by hundredths of a percent.

The mouse heart slice shows how macrophages (colored red and green) flock to the damaged area three days after the researchers injected adult heart stem cells into the area indicated by yellow dotted lines. Picture from Cincinnati Children's Hospital Stem Cell Therapy press release Helps Broken Hearts Heal in Unexpected Way – VM.

Then the researchers set up a second experiment. They injected saline, zymosan, bone marrow cells or cardiac progenitor cells into the heart of mice - it is believed that in some situations they can multiply and give vascular wall cells. But in none of the cases did they detect the appearance of new cells in the heart – stem cells were in no hurry to turn into heart muscle cells. And after two weeks, the stem cells disappeared from the bloodstream altogether.

However, when the researchers switched to experiments with mice after a heart attack, they noticed a therapeutic effect. Both types of cells improved the condition of the heart compared to the control. In the control group, the amount of blood that the heart throws out decreased by 40 percent, and in the experimental groups – by only 20-30 percent. Nevertheless, the scientists concluded that it was not a matter of regeneration at the expense of cells – both zymosan and cells killed by freezing and defrosting had a similar effect.

The authors of the work believe that the work of the heart becomes better due to the inhibition of fibrosis – the overgrowth of the site of damage by connective tissue. At least, the percentage of fibrosis under the influence of zymosan, living or dead stem cells decreased from 40 percent to 30.

Thus, the hypothesis according to which the heart tissue can be restored due to the work of stem cells has once again not been confirmed. But now we have a better idea of exactly how stem cell therapy affects the heart after a heart attack. Based on their results, the authors suggest their colleagues to adjust the protocols and expectations from clinical trials for regenerative heart therapy.

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