Biologists have uncovered the mechanism by which stem-cell therapies improve heart function. Working in mice, a team of researchers found that the cells prompt an immune response that improves the organ’s function and also discovered how to mimic this repair with a chemical.
Stem-cell therapies for damaged hearts have shown some short-term improvements in animals, but the effect in humans has been limited. At first, scientists theorized that the benefits in mice came from stem cells differentiating into beating heart-muscle cells, called cardiomyocytes. But subsequent studies, including one by Jeffery Molkentin, a cardiovascular biology researcher at the Cincinnati Children’s Hospital Medical Center in Ohio, showed that the cells did not make this transformation.
Today in Nature, Molkentin’s team reports that two common stem-cell therapies trigger immune cells called macrophages that help to repair connective tissue in the damaged area of the heart, which improves its function1.
The team showed that this repair mechanism can also be achieved using a chemical called zymosan, which is known to elicit an immune response.
The findings could have significant implications for the future of stem-cell therapies in humans, a multi-billion dollar industry. Clinics in some countries already offer stem-cell therapies for heart disease — the number one killer worldwide, causing some 17 million deaths a year. But there is limited evidence that they work2. Many scientists also no longer think that the cells used in such therapies are true stem cells because they cannot self-renew, but the term ‘stem-cell therapy’ is still widely used by companies and clinics offering these treatments.
Changing the beat
Molkentin team’s injected two types of cells used in these therapies into the damaged areas of mice hearts that had been temporarily deprived of oxygen, mimicing the conditions of a heart attack. One of these types was mononuclear cells taken from bone marrow, which are among the most commonly used in human clinical trials of stem-cell therapies, the other, cardiac mesenchymal cells. The researchers found that the heart function of the mice that received the cell injections was significantly better than that of mice that received a placebo.
But when the team found that mice that received stem-cell therapies did no better than mice that were given the chemical zymosan. In fact, zymosan maintained its effect for longer than the stem-cell therapies.
To further test the theory that the therapy derives its effectiveness from an immune response, the team injected bits of dead cells into some mice and found that this, too, could improve heart function. The study “suggests that we no longer need to even inject living cells”, says Molkentin.
In other experiments, the researchers suppressed macrophage activity in some mice. In this case, the repair process occurred neither in the mice that received the stem cells nor in those that received zymosan.
Provoking a response
The study is important because it clearly shows that inflammation triggered by the immune system drives the repair-mechanism, says Thomas Thum, a cardiologist at the Hannover Medical School in Germany.
Molkentin says that the results could also apply to stem-cell therapies used for other conditions. Any benefit derived from these cells is likely to come from a local and acute immune response rather than from the regenerative capacity of the cells themselves, he says.
Kory Lavine, a heart-failure cardiologist and immunologist at Washington University in St Louis, says that the study will probably challenge researchers who are pursuing stem-cell treatments for conditions ranging from osteoarthritis to neurodegenerative disease to focus on the role of immune cells in the body, rather than on the power of the therapy.
True stem cells can still be valuable in treating cardiovascular disease, say some scientists. Researchers at the University of Washington in Seattle have shown that cardiomyocytes derived from human embryonic stem cells can help to rebuild heart muscle in monkeys with heart failure3.
Another reason that might shift the focus away from stem-cell therapies is that they are expensive to generate and require time-consuming approval from regulatory agencies. “If there is a chemical off-the-shelf, it would be a much more feasible therapy,” Lavine says.
Vagnozzi, R. J. et al. Nature https://doi.org/10.1038/s41586-019-1802-2 (2019).
Epstein, J. JAMA Cardiol. 4, 95–96 (2018).
Liu, Y. et al. Nat Biotechnol 36, 597–605 (2018).