Repeated administrations of cardiac progenitor cells are superior to a single administration of an equivalent cumulative dose

BACKGROUND We have recently found that 3 repeated doses (12×106each) of c-kitPOScardiac progenitor cells (CPCs) were markedly more effective than a single dose of 12×106cells in alleviating postinfarction left ventricular dysfunction and remodeling. However, since the single-dose group received only one third of the total number of CPCs given to the multiple-dose group, it is unknown whether the superior therapeutic efficacy was caused by repeated treatments per se or by administration of a higher total number of CPCs. This issue has major clinical implications because multiple cell injections in patients pose significant challenges, which would be obviated by using 1 large injection. Accordingly, we determined whether the beneficial effects of 3 repeated CPC doses can be recapitulated by 1 large dose containing the same total number of cells. METHODS AND RESULTS Rats with a 30-day-old myocardial infarction received 3 echo-guided intraventricular infusions, 35 days apart, of vehicle-vehicle-vehicle, 36×106CPCs-vehicle-vehicle, or 3 equal doses of 12×106CPCs. Infusion of a single, large dose of CPCs (36×106cells) produced an initial improvement in left ventricular function, but no further improvement was observed after the second and third infusions (both vehicle). In contrast, each of the 3 doses of CPCs (12×106) caused a progressive improvement in left ventricular function, the cumulative magnitude of which was greater than with a single dose. Unlike the single dose, repeated doses reduced collagen content and immune cell infiltration. CONCLUSIONS Three repeated doses of CPCs are superior to 1 dose even though the total number of cells infused is the same, possibly because of greater antifibrotic and anti-inflammatory actions.