A step closer to improving cardiac homing of adipose-derived mesenchymal stem cells.

Myocardial infarction (MI) is a leading cause of death and disability in industrialized countries. MI can lead to the irreversible loss of cardiomyocytes due to prolonged lack of oxygen supply (ischemia) (3). The facts that the mammalian heart itself possesses limited intrinsic regenerative capabilities (6) and, furthermore, that current treatment strategies for heart failure comprise only palliative measures that mitigate symptoms and delay disease progression (2) highlight a current unmet need for new and effective treatment modalities that target the underlying cause of heart failure, which is the loss of cardiomyocytes. Although still controversial (1), increasing evidence suggests that cell therapy has some beneficial effects, which are likely due to still not well-defined paracrine factors being secreted by the injected cells (e.g., mesenchymal stem cells) rather than the injected cells differentiating into cardiomyocytes in vivo (Fig. 1A). The majority of the problems related to cell therapy in general is that most of the injected cells will be washed out of the heart within 1 day after the injection (11). To increase the prolonged retention of the injected cells, a number of strategies have been used (7), with one being improving the homing and survival of injected cells. Resistin is an adipose-derived peptide hormone and has regulatory roles in metabolism (5). A previous study (10) has reported that resistin enhances the homing of endothelial progenitor cells to the synovium, which resulted in promoted angiogenesis in rheumatoid arthritis. Building on this previous observation, He et al. (4) investigated the effects of resistin on cardiac homing by the intravenously injected adipose-derived mesenchymal stem cells (ADSCs) after ischemia-reperfusion (I/R). This study was published in a recent issue of the American Journal of Physiology-Heart and Circulatory Physiology (4). The salient findings of this study are as follows (Fig. 1B): 1) compared with I/R controls, injection of resistin-treated ADSCs significantly increased left ventricular ejection fraction and reduced infarct size; 2) injection of resistin-treated ADSCs increased angiogenesis and reduced loss of cardiomyocytes; 3) resistin treatment promoted myocardial homing of intravenously delivered ADSCs; 4) resistin increased proliferation of ADSCs and enhanced their migratory capacity in vitro; 5) resistin significantly increased the expression of matrix metalloproteinase (MMP)-9 and phosphorylation of ERK1/2, which were abrogated with treatment with the ERK1/2 activation inhibitor U0126 in vitro; and 6) in vivo, cardiac homing of ADSCs treated with resistin was significantly reduced when ADSCs were treated with U0126 in vitro before the injection. He et al. (4) nicely demonstrated the beneficial effects of resistin to cell therapy, which could be further advanced if such a method is applicable to cell types other than ADSCs. Although ADSCs can be easily obtained and expanded, it is still not clear which cell type will be the most beneficial source for cell therapy. More rigorous studies are needed to understand the clear mechanism in which cell therapy actually works in revitalizing failing hearts. As noted by the authors, this study is rather limited in describing the mechanism of action, as only a limited number of genes were screened by quantitative RT-PCR. It would have been more comprehensive if the authors had used highthroughput techniques (e.g., microarrays or RNA-seq) to profile treated cells compared with nontreated cells, which must be validated by other experimental methods, including secretome analysis by protein arrays and/or mass spectrometry. Such comprehensive analysis is extremely important, as the function of resistin is still not completely clear (5), which further complicates the matter as to when such treatment will be used for cell therapy. Although the authors elucidated the possible connection between resistin treatment and the MMP-9-ERK pathway, there is still a long way to go to understand the secreted factors that enhance angiogenesis and protect cardiomyocytes from apoptosis. Finally, it is unknown whether ADSC pretreatment with resistin improves functional perfusion after I/R or simply promotes angiogenesis (via CD31 immunohistochemistry quantification), and this distinction has been shown to be important in postischemic recovery (8, 9). Nevertheless, this is an interesting study that adds further insights into the potential of cell therapy in the near future.