Repeated Administrations of Cardiac Progenitor Cells Are Markedly More Effective Than a Single Administration: A New Paradigm in Cell Therapy
Rationale: The effects of c-kitPOS cardiac progenitor cells (CPCs) (and adult cell therapy in general) on left ventricular (LV) function have been regarded as modest or inconsistent.
Objective: To determine whether three CPC infusions have greater efficacy than one infusion.
Methods and Results: Rats with a 30-day-old myocardial infarction received one or three CPC infusions into the LV cavity, 35 days apart. Compared with vehicle-treated rats, the single-dose group exhibited improved LV function after the 1st infusion (consisting of CPCs) but not after the 2nd and 3rd (vehicle). In contrast, in the multiple-dose group regional and global LV function improved by a similar degree after each CPC infusion, resulting in greater cumulative effects. For example, the total increase in LV ejection fraction was approximately triple in the multiple-dose group vs. the single-dose group (P<0.01). The multiple-dose group also exhibited more viable tissue and less scar, less collagen in the risk and noninfarcted regions, and greater myocyte density in the risk region.
Conclusions: This is the first demonstration that repeated CPC administrations are markedly more effective than a single administration. The concept that the full effects of CPCs require repeated doses has significant implications for both preclinical and clinical studies; it suggests that the benefits of cell therapy may be underestimated or even overlooked if they are measured after a single dose, and that repeated administrations are necessary to properly evaluate the effectiveness of a cell product. In addition, we describe a new method that enables studies of repeated cell administrations in rodents.
- cell therapy
- cardiac progenitor cells
- myocardial infarction
- ischemia reperfusion injury
- left ventricular function
- left ventricular remodeling
- Received April 19, 2016.
- Revision received June 27, 2016.
- Accepted June 30, 2016.