Quo vadis, progenitor? Progenitor cell homing in chronic ischemic heart disease.

Autologous cell therapy to improve ischemic cardiac dysfunction after myocardial infarction is an attractive therapeutic approach and an area of intense basic and clinical research efforts. Although a number of randomized clinical trials on autologous cell treatment for acute myocardial infarction have shown at least transient improvements in left ventricular function, other trials did not find significant benefits of cell therapy. In chronic ischemic heart disease, the results are still more controversial. Today, despite all efforts, the precise cell types and the mechanism of action conferring therapeutic effects are still a matter of scientific debate. However, it is becoming more and more evident that 1 important variable in the yet unsolved therapeutic formula is the question of cell homing to the site of action and, related to this, the proper timing of cell administration. In other words, homing and retention of circulating cells at the site of action is the sine qua non of therapeutic cell therapy. A study appearing in this issue of the Journal of Cardiovascular Pharmacology has addressed the issue of cell homing in the chronic phase after myocardial infarction. In this nonrandomized study, 7 patients in the chronic phase after myocardial infarction (ie more than 1 year after the event) received autologous peripheral CD34 cells by intracoronary infusion into the infarct-related artery, and cell homing of radiolabeled CD34 cells was studied by positron emission tomography/computed tomography, which combines the high sensitivity of positron emission tomography with high spatial resolution of computed tomography to precisely localize labeled cell populations. In addition, endothelial function of the coronary arteries was evaluated at the time of cell infusion and 3 month later. The main findings of the study are that, first, only a small percentage of cells (3.6%) homed to the myocardium and, second, there was no change in endothelial function after CD34 autologous transfer. Together with another recent study, these finding demonstrate low progenitor cell homing in the chronic phase of ischemic heart disease. This contrasts with findings in the immediate postinfarction period, which demonstrated much higher homing rates of CD34 cells. The recent studies raise some important points about studying stem cell homing in the clinical arena. Let us take a closer look. First, procedural aspects need to be considered. In principle, the labeling technique must be adequate for the cell type studied: the authors used 18-fluorodeoxyglucose (FDG) for cell labeling, but labeling efficacy was only 5.2%, which contrasts sharply with a labeling efficacy of 65% using 111In-oxine, a single photon emission computed tomography tracer, which was used by the authors in a previous study. Although 111Inoxine is carried into the cells via a lipophilic chelator, FDG uptake is coupled to the metabolic state of a cell. Quiescent stem cell populations (cells were not mobilized for collection) with low metabolism might thus not be adequately labeled with FDG. However, another study using 111In-oxine labeling of infused cells found comparably low homing values in chronic infarct patients, although the cell types used in that study probably represent more mature proangiogenic cells. So the homing behavior of true stem cells remains a field with open question. Second, patient selection is crucial. For progenitor cells to home to sites of action, there needs to be a stimulus for homing and retention. Ischemia, overt as in myocardial infarction, or latent, as occurs in chronic ischemic heart failure, triggers release of vascular