Naumova et al. reply:

We appreciate the comments from Malliaras and Marbán1 describing their work on developing imaging markers of therapeutic efficacy2 that was not mentioned in our review3. Owing to the page limitation, we were not able to cite all the literature published on this topic. We of course agree that magnetic resonance imaging (MRI) is a valuable technology for evaluating the efficacy of cell therapy, heart contractility, myofiber architecture and infarct size, especially in large-animal models. However, validation of imaging markers requires control measurements, especially in the assessment of gadolinium-contrast kinetics. As these measurements were reported only for cell-treated animals2, it remains unclear whether treatment changes the clearance rate in the scar. Decreases in vascular permeability and reduced extravasation after stem cell transplantation have been reported in controlled studies4,5, indicating that there is experimental evidence rather than a mere theoretical concern regarding these potential confounding factors. Nevertheless, we agree that there was a good correlation between scar size as determined by MRI and histology at the end of the study by Malliaras et al.2, suggesting that cell-induced scar shrinkage may indeed be a real phenomenon.

The claimed growth of 10–15 g of new myocardium2 was not as well substantiated. Although there was not an increase in myocyte diameter, cell length was not measured and morphometric estimates of cell number were not obtained. Furthermore, although cell cycle activity was increased threefold, the overall rates were quite low (6 proliferative cells per square millimeter). It remains unclear how such a low rate of proliferation could lead to such a large increase in myocardial mass. Considering the heart's well-known proclivity to generate polyploid cardiomyocytes without cell division, a more conservative interpretation of the data would seem prudent until more definitive evidence is available. Still, if the heart did undergo replacement of infarct mass by new cardiomyocytes, it would probably manifest the changes the authors reported by MRI. Additionally, if 10–15 g of new myocardium really were generated through cell division, this should be easy to show by conventional histology techniques, such as BrdU pulse-labeling or cumulative labeling experiments. We look forward to seeing such studies in the future. In the meantime, we are intrigued by the potency of cardiosphere-derived cells to effect cardiac repair but remain cautious about their proposed mechanisms of action.