Stressing cells to improve transplant outcomes and cardiac function

by Chris Kamel

There's a scene in The Simpsons, after Homer suffers from a heart attack, where he paraphrases Friedrich Nietzsche's famous words, "That which does not kill us makes us stronger." Those words, in this situation, are overly optimistic. After an ischemic event like a heart attack or a stroke, not only is there massive cell death and tissue damage, but the affected area remains a harsh environment due to poor blood supply and oxygen shortage. Despite the promise of regenerative stem cell transplants, the damaged heart remains hostile and massive death of transplanted cells represents a major challenge. There are two approaches to beating this problem: improve the transplant environment, or improve the hardiness of the cells.

Nietzsche, of course, was a philosopher not a biologist, but he was prescient of a possible solution. For over 20 years, scientists have studied the concept of preconditioning. As described in Nature Reviews Neuroscience, preconditioning is:

“Presenting a stressful but nondamaging stimulus to cells, tissues or organisms to promote a transient adaptive response so that injury resulting from subsequent exposure to a harmful stimulus is reduced.”

In other words, in particular situations, a cellular insult that doesn't kill it makes it stronger.

Recent research, published in Antioxidants and Redox Signaling is the latest in a line of attempts to harness preconditioning response to improve stem cell transplants (reviewed here). In their experiments, the group pre-treated mesenchymal stem cells with the drug diazoxide as a preconditioning agent and found that the cells had better survival after oxygen-glucose deprivation both in the short and long term (i.e. 24 hours after removal of the drug). The preconditioned cells also showed increased levels of pro-survival molecules, including dependence on NF-κB activation, a protein known to be involved in preconditioning response. When injected into a rat model of heart attack, the preconditioned cells showed improved survival seven days post-transplant, increased activation of pro-survival factors, and improved cardiac function compared to non-preconditioned cells or sham transplant. Six weeks after transplant, the hearts treated with preconditioned cells continued to perform better than the other groups and showed increased blood vessel formation and reduced area of tissue damage - all signs that the damaged heart is being repaired.

With stem cell transplants to repair heart damage already making their way through clinical trials, and the difficulties scaling up cells for use, methods for improving transplant survival and efficiency are certainly welcome. Harnessing NF-κB dependent preconditioning is one strategy for prepping stem cells for survival in certain harsh transplant micro-environments.