21 April 2020
The use of stem cell therapy to repair the damage caused by a heart attack has shown promise in recent clinical trials, but the underlying mechanisms are unclear. A new US study has challenged the prevailing theory.
Scientists had thought that after injection, the stem cells would trigger the production of new heart cells, or cardiomyocytes, strengthening the heart and aiding recovery. But now, Jeffery Molkentin at the University of Cincinnati, and colleagues across the US, have demonstrated that the injection of stem cells into the heart triggers an innate immune response, and that it is this response that facilitates tissue repair. No new cardiomyocytes were formed in any part of the heart.
“We have shown that the injection of living cells, dead cell debris, or even substances that induce inflammation can all uniformly provide a minor healing benefit to the heart by inducing a targeted immune response,” says Molkentin. “This suggests that adult stem cell injections may not be needed in the first place and has significant implications for the treatment of patients after heart attacks.”
The team decided to explore the mechanisms behind using adult stem cells to treat heart tissue injury, which are now commonly studied in clinical trials and have proven to provide a mildly protective effect to the heart. Molkentin and colleagues conducted a series of experiments on mouse models with heart attack injury.
The team split the mouse models into groups, and injected the hearts of the mice with two different types of adult stem cells.
“The body immediately sensed that the injected cells did not belong in the heart, and produced a rapid immune response to kill them,” says Molkentin. “As part of this response, immune cells, called macrophages, accumulated in the heart, clearing the dying ‘foreign’ cells and inducing wound healing activity on the damaged heart tissue.”
Further investigations showed that subtypes of macrophages present in the damaged tissue regions were preferentially altered to ensure that scarring was minimized. The macrophages altered the activity of fibroblasts — cells that generate scar tissue and can remodel the heart — and this enhanced the physical properties of the forming scar.
“This meant the heart healed better with a more optimized scar, meaning that the heart’s contractile properties were improved,” notes Molkentin.
The team then tried injecting mice with zymosan — an inert chemical compound that strongly induces the innate immune response — rather than stem cells. Zymosan triggered the same healing process in the damaged hearts.
Vagnozzi, R.J., Mallet, M., Sargent, M.A., Khalil, H., Johansen, A.K.Z. et al. An acute immune response underlies the benefit of cardiac stem cell therapy. Nature 577, 405-409 (2020). | article