Exosomes and their RNA contents as mediators of therapeutic regeneration

The heart is a terminally‐differentiated organ with a low rate of cellular turnover. Patients who suffer a myocardial infarction (commonly known as a “heart attack”) can lose up to 40% of their functional heart muscle within hours, leaving them prone to death and disability. Once formed, scar does not resolve spontaneously, and, once lost, living heart muscle does not regrow on its own. We challenged that pessimistic dogma using a novel approach: growing regenerative cells from a patient's heart and transplanting those cells back into the zone of injury. In the first‐in‐human CADUCEUS trial, we used magnetic resonance imaging to quantify scar and living heart muscle before and after cardiosphere‐derived cell (CDC) therapy in patients who had suffered moderately large heart attacks. Control subjects randomized to receive standard care behaved according to dogma: scar did not shrink, and living heart muscle did not regrow, over the one‐year period of follow up. In contrast, patients who had received CDCs experienced reduction of scar by about half, and regrowth of substantial amounts (>20 g) of viable myocardium. CADUCEUS was the first controlled study to show evidence of therapeutic regeneration in humans ( Lancet 379 :895–904, 2012). We have since discovered that allogeneic CDCs are safe and effective in preclinical models, prompting initiation of the ongoing ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) clinical trial. Current mechanistic studies focus on the role of exosomes, and their RNA contents, as mediators of the therapeutic benefits, and on macrophages as important effector cells. Support or Funding Information Funded by NIH and by the California Institute for Regenerative Medicine